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Nhamoyebonde S, Chambers M, Ndlovu L, Karim F, Mazibuko M, Mhlane Z, Madziwa L, Moosa Y, Moodley S, Hoque M, Leslie A. Detailed phenotyping reveals diverse and highly skewed neutrophil subsets in both the blood and airways during active tuberculosis infection. Front Immunol 2024; 15:1422836. [PMID: 38947330 PMCID: PMC11212598 DOI: 10.3389/fimmu.2024.1422836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 05/21/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Neutrophils play a complex and important role in the immunopathology of TB. Data suggest they are protective during early infection but become a main driver of immunopathology if infection progresses to active disease. Neutrophils are now recognized to exist in functionally diverse states, but little work has been done on how neutrophil states or subsets are skewed in TB disease. Methods To address this, we carried out comprehensive phenotyping by flow cytometry of neutrophils in the blood and airways of individuals with active pulmonary TB with and without HIV co-infection recruited in Durban, South Africa. Results Active TB was associated with a profound skewing of neutrophils in the blood toward phenotypes associated with activation and apoptosis, reduced phagocytosis, reverse transmigration, and immune regulation. This skewing was also apparently in airway neutrophils, particularly the regulatory subsets expressing PDL-1 and LOX-1. HIV co-infection did not impact neutrophil subsets in the blood but was associated with a phenotypic change in the airways and a reduction in key neutrophil functional proteins cathelicidin and arginase 1. Discussion Active TB is associated with profound skewing of blood and airway neutrophils and suggests multiple mechanisms by which neutrophils may exacerbate the immunopathology of TB. These data indicate potential avenues for reducing neutrophil-mediated lung pathology at the point of diagnosis.
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Affiliation(s)
| | - Mark Chambers
- Africa Health Research Institute, Durban, South Africa
| | - Lerato Ndlovu
- Africa Health Research Institute, Durban, South Africa
| | - Farina Karim
- Africa Health Research Institute, Durban, South Africa
| | | | - Zoey Mhlane
- Africa Health Research Institute, Durban, South Africa
| | | | - Yunus Moosa
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
| | | | - Monjurul Hoque
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Alasdair Leslie
- Africa Health Research Institute, Durban, South Africa
- Department of Infectious Diseases, Nelson R. Mandela School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Infection and Immunity, University College London, London, United Kingdom
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Alkarni M, Lipman M, Lowe DM. The roles of neutrophils in non-tuberculous mycobacterial pulmonary disease. Ann Clin Microbiol Antimicrob 2023; 22:14. [PMID: 36800956 PMCID: PMC9938600 DOI: 10.1186/s12941-023-00562-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/30/2023] [Indexed: 02/19/2023] Open
Abstract
Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is an increasingly recognised global health issue. Studies have suggested that neutrophils may play an important role in controlling NTM infection and contribute to protective immune responses within the early phase of infection. However, these cells are also adversely associated with disease progression and exacerbation and can contribute to pathology, for example in the development of bronchiectasis. In this review, we discuss the key findings and latest evidence regarding the diverse functions of neutrophils in NTM infection. First, we focus on studies that implicate neutrophils in the early response to NTM infection and the evidence reporting neutrophils' capability to kill NTM. Next, we present an overview of the positive and negative effects that characterise the bidirectional relationship between neutrophils and adaptive immunity. We consider the pathological role of neutrophils in driving the clinical phenotype of NTM-PD including bronchiectasis. Finally, we highlight the current promising treatments in development targeting neutrophils in airways diseases. Clearly, more insights on the roles of neutrophils in NTM-PD are needed in order to inform both preventative strategies and host-directed therapy for these important infections.
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Affiliation(s)
- Meyad Alkarni
- grid.83440.3b0000000121901201Institute of Immunity and Transplantation, University College London, Pears Building, Rowland Hill Street, London, NW3 2PP UK
| | - Marc Lipman
- grid.83440.3b0000000121901201UCL Respiratory, University College London, London, UK
| | - David M. Lowe
- grid.83440.3b0000000121901201Institute of Immunity and Transplantation, University College London, Pears Building, Rowland Hill Street, London, NW3 2PP UK
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3
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Rais M, Abdelaal H, Reese VA, Ferede D, Larsen SE, Pecor T, Erasmus JH, Archer J, Khandhar AP, Cooper SK, Podell BK, Reed SG, Coler RN, Baldwin SL. Immunogenicity and protection against Mycobacterium avium with a heterologous RNA prime and protein boost vaccine regimen. Tuberculosis (Edinb) 2023; 138:102302. [PMID: 36586154 PMCID: PMC10361416 DOI: 10.1016/j.tube.2022.102302] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/16/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Prophylactic efficacy of two different delivery platforms for vaccination against Mycobacterium avium (M. avium) were tested in this study; a subunit and an RNA-based vaccine. The vaccine antigen, ID91, includes four mycobacterial antigens: Rv3619, Rv2389, Rv3478, and Rv1886. We have shown that ID91+GLA-SE is effective against a clinical NTM isolate, M. avium 2-151 smt. Here, we extend these results and show that a heterologous prime/boost strategy with a repRNA-ID91 (replicon RNA) followed by protein ID91+GLA-SE boost is superior to the subunit protein vaccine given as a homologous prime/boost regimen. The repRNA-ID91/ID91+GLA-SE heterologous regimen elicited a higher polyfunctional CD4+ TH1 immune response when compared to the homologous protein prime/boost regimen. More significantly, among all the vaccine regimens tested only repRNA-ID91/ID91+GLA-SE induced IFN-γ and TNF-secreting CD8+ T cells. Furthermore, the repRNA-ID91/ID91+GLA-SE vaccine strategy elicited high systemic proinflammatory cytokine responses and induced strong ID91 and an Ag85B-specific humoral antibody response a pre- and post-challenge with M. avium 2-151 smt. Finally, while all prophylactic prime/boost vaccine regimens elicited a degree of protection in beige mice, the heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen provided greater pulmonary protection than the homologous protein prime/boost regimen. These data indicate that a prophylactic heterologous repRNA-ID91/ID91+GLA-SE vaccine regimen augments immunogenicity and confers protection against M. avium.
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Affiliation(s)
- Maham Rais
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Hazem Abdelaal
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Valerie A Reese
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Debora Ferede
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Sasha E Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Tiffany Pecor
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | | | | | | | - Sarah K Cooper
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | - Brendan K Podell
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA
| | | | - Rhea N Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Global Health, University of Washington, Seattle, WA, 98195, USA
| | - Susan L Baldwin
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98145, USA.
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Zarban AA, Chaudhry H, de Sousa Valente J, Argunhan F, Ghanim H, Brain SD. Elucidating the Ability of CGRP to Modulate Microvascular Events in Mouse Skin. Int J Mol Sci 2022; 23:12246. [PMID: 36293102 PMCID: PMC9602655 DOI: 10.3390/ijms232012246] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/28/2022] [Accepted: 10/06/2022] [Indexed: 11/29/2022] Open
Abstract
Oedema formation and polymorphonuclear leukocyte (neutrophil) accumulation are involved in both acute and chronic inflammation. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that is released from stimulated sensory nerves. CGRP is a potent vasodilator neuropeptide, especially when administered to the cutaneous microvasculature, with a long duration of action. Here, we have investigated the ability of vasodilator amounts of CGRP to modulate oedema formation and neutrophil accumulation induced in the cutaneous microvasculature of the mouse. To learn more about the mechanism of action of endogenous CGRP, we have investigated the response to the inflammatory stimulants tumour necrosis factor alpha (TNFα) and carrageenan in three different murine models: a model where sensory nerves were depleted by resiniferatoxin (RTX); a pharmacological method to investigate the effect of a selective CGRP receptor antagonist; and a genetic approach using wildtype (WT) and αCGRP knockout (KO) mice. Our results show that exogenous CGRP potentiates oedema formation induced by substance P (SP) and TNFα. This is further supported by our findings from sensory nerve-depleted mice (in the absence of all neuropeptides), which indicated that sensory nerves are involved in mediating the oedema formation and neutrophil accumulation induced by TNFα, and also carrageenan in cutaneous microvasculature. Furthermore, endogenous CGRP was shown to contribute to this inflammatory response as carrageenan-induced oedema formation is attenuated in WT mice treated with the CGRP receptor antagonist, and in αCGRPKO mice. It is therefore concluded that CGRP can contribute to inflammation by promoting oedema formation in skin, but this response is dependent on the pro-inflammatory stimulus and circumstance.
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Affiliation(s)
- Ali A. Zarban
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Hiba Chaudhry
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
| | - João de Sousa Valente
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
| | - Fulye Argunhan
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
| | - Hala Ghanim
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
| | - Susan D. Brain
- Section of Vascular Biology and Inflammation, School of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, Franklin-Wilkins Building, Waterloo Campus, King’s College London, London SE1 9NH, UK
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Immunometabolism of Immune Cells in Mucosal Environment Drives Effector Responses against Mycobacterium tuberculosis. Int J Mol Sci 2022; 23:ijms23158531. [PMID: 35955665 PMCID: PMC9369211 DOI: 10.3390/ijms23158531] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/10/2022] Open
Abstract
Tuberculosis remains a major threat to global public health, with more than 1.5 million deaths recorded in 2020. Improved interventions against tuberculosis are urgently needed, but there are still gaps in our knowledge of the host-pathogen interaction that need to be filled, especially at the site of infection. With a long history of infection in humans, Mycobacterium tuberculosis (Mtb) has evolved to be able to exploit the microenvironment of the infection site to survive and grow. The immune cells are not only reliant on immune signalling to mount an effective response to Mtb invasion but can also be orchestrated by their metabolic state. Cellular metabolism was often overlooked in the past but growing evidence of its importance in the functions of immune cells suggests that it can no longer be ignored. This review aims to gain a better understanding of mucosal immunometabolism of resident effector cells, such as alveolar macrophages and mucosal-associated invariant T cells (MAIT cells), in response to Mtb infection and how Mtb manipulates them for its survival and growth, which could address our knowledge gaps while opening up new questions, and potentially be applied for future vaccination and therapeutic strategies.
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Nitter TB, Hilt B, Svendsen KVH, Buhagen M, Jørgensen RB. Association between exposure to different stone aggregates from asphalt and blood coagulability: A human exposure chamber study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 778:146309. [PMID: 33714824 DOI: 10.1016/j.scitotenv.2021.146309] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 06/12/2023]
Abstract
A large fraction of particulate matter (PM), especially PM10, concentrations are due to non-exhaust emissions, such as road abrasion and wear on tires and brake pads. Concentrating on road abrasion, we aimed to investigate blood coagulability in healthy adults after exposure to two types of stone materials commonly used in asphalt on Norwegian roads. This study followed a randomized, double-blind, cross-over study design. Using an exposure chamber, 24 healthy young volunteers were exposed to aggregates of two different types of rocks and placebo dust: quartz diorite, rhomb porphyry, and lactose (placebo dust). Each exposure session lasted for 4 hours (h), and blood samples were collected before exposure (baseline), 4 h post-exposure, and 24 h post-exposure to analyse potential changes in the von Willebrand factor (vWF) as well as of fibrinogen, d-dimer, leukocytes, and thrombocytes. The dust concentration in the exposure chamber was measured with real-time instruments and gravimetric samples of total dust, respirable dust, PM10, PM2.5, and ultrafine particles (UFP). The results were analysed using a linear mixed-effect model. Leukocyte blood counts increased post-exposure for all exposure materials; however, none of the increases were statistically significant. The concentration of fibrinogen increased after exposure to quartz diorite, while it decreased after exposures to rhomb porphyry and lactose. Type of material was a statistically significant explanatory variable for the concentration of fibrinogen, with the most significant increase occurring 24 h post-exposure to quartz diorite. After exposure to the three materials, vWF decreased. For the thrombocytes, an increase in blood count was observed 24 h post-exposure to quartz diorite and rhomb porphyry, with a modest (p = 0.09) positive association for quartz diorite. Although the results are limited, we conclude that the different effects observed post-exposure to quartz diorite support considering potential health effects when choosing materials in the production of asphalt.
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Affiliation(s)
- Therese Bergh Nitter
- Department of Industrial Economics and Technology Management, Norwegian University of Science and Technology (NTNU), Norway.
| | - Bjørn Hilt
- Department of Occupational Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Public Health and Nursing, NTNU, Norway
| | - Kristin V Hirsch Svendsen
- Department of Industrial Economics and Technology Management, Norwegian University of Science and Technology (NTNU), Norway
| | - Morten Buhagen
- Department of Occupational Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Public Health and Nursing, NTNU, Norway
| | - Rikke Bramming Jørgensen
- Department of Industrial Economics and Technology Management, Norwegian University of Science and Technology (NTNU), Norway
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7
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Shin MK, Shin SJ. Genetic Involvement of Mycobacterium avium Complex in the Regulation and Manipulation of Innate Immune Functions of Host Cells. Int J Mol Sci 2021; 22:ijms22063011. [PMID: 33809463 PMCID: PMC8000623 DOI: 10.3390/ijms22063011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Mycobacterium avium complex (MAC), a collection of mycobacterial species representing nontuberculous mycobacteria, are characterized as ubiquitous and opportunistic pathogens. The incidence and prevalence of infectious diseases caused by MAC have been emerging globally due to complications in the treatment of MAC-pulmonary disease (PD) in humans and the lack of understating individual differences in genetic traits and pathogenesis of MAC species or subspecies. Despite genetically close one to another, mycobacteria species belonging to the MAC cause diseases to different host range along with a distinct spectrum of disease. In addition, unlike Mycobacterium tuberculosis, the underlying mechanisms for the pathogenesis of MAC infection from environmental sources of infection to their survival strategies within host cells have not been fully elucidated. In this review, we highlight unique genetic and genotypic differences in MAC species and the virulence factors conferring the ability to MAC for the tactics evading innate immune attacks of host cells based on the recent advances in genetic analysis by exemplifying M. avium subsp. hominissuis, a major representative pathogen causing MAC-PD in humans. Further understanding of the genetic link between host and MAC may contribute to enhance host anti-MAC immunity, but also provide novel therapeutic approaches targeting the pangenesis-associated genes of MAC.
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Affiliation(s)
- Min-Kyoung Shin
- Department of Microbiology and Convergence Medical Sciences, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Korea;
| | - Sung Jae Shin
- Department of Microbiology and Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: ; Tel.: +82-2-2228-1813
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Lu Y, Hu Z, Wang F, Yao H, Zhu H, Wang Z, Song Z, Chen R, Liu D. Worsening CSF parameters after the start of anti-tuberculosis treatment predicts intracerebral tuberculoma development. Int J Infect Dis 2020; 101:395-402. [DOI: 10.1016/j.ijid.2020.09.1457] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 02/02/2023] Open
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Abstract
Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. One of the principal barriers to vaccine development against M. tuberculosis is the complexity of the immune response to infection, with uncertainty as to what constitutes an immunological correlate of protection. In this paper, we seek to give an overview of the immunology of M. tuberculosis infection, and by doing so, investigate possible targets of vaccine development. This encompasses the innate, adaptive, mucosal and humoral immune systems. Though MVA85A did not improve protection compared with BCG alone in a large-scale clinical trial, the correlates of protection this has revealed, in addition to promising results from candidate such as VPM1002, M72/ASO1E and H56:IC31 point to a brighter future in the field of TB vaccine development.
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Affiliation(s)
- Benedict Brazier
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK
| | - Helen McShane
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK
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10
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Kang GY, Rhyu HJ, Choi HH, Shin SJ, Hyun YM. 3D Imaging of the Transparent Mycobacterium tuberculosis-Infected Lung Verifies the Localization of Innate Immune Cells With Granuloma. Front Cell Infect Microbiol 2020; 10:226. [PMID: 32500041 PMCID: PMC7243706 DOI: 10.3389/fcimb.2020.00226] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022] Open
Abstract
Using a novel tissue-clearing method, we aimed to visualize the three-dimensional (3D) distribution of immune cells within Mycobacterium tuberculosis (Mtb)-infected mice lungs. Ethyl cinnamate-based tissue clearing of Mtb-infected mice lungs was performed to obtain transparent lung samples, which were then imaged using a light sheet fluorescence microscope. Using the 3D images, we performed quantitative analysis of the immune cell population within multiple granulomas. In addition, to compare the data from the tissue clearing method, we performed histopathological and immunofluorescence analyses, and flow cytometry. We then created 3D images of the Mtb-infected lung that successfully demonstrated the distribution of blood vessels, immune cells, and granulomas. Since the immune cells within a granuloma could be separately selected and counted, the immune cell population within a specific lesion could be quantified. In addition, macroscopic analysis, e.g., the size or shape of a granuloma, as well as microscopic analysis could be performed as intact lung samples were used. The use of the tissue clearing method in infected lungs could be a novel modality for understanding the role of the immune system in the pathogenesis of tuberculosis.
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Affiliation(s)
- Gyeong-Yi Kang
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea.,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyeong-Jun Rhyu
- Department of Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Hong-Hee Choi
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Sung Jae Shin
- BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.,Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.,Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, South Korea
| | - Young-Min Hyun
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea.,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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Hilda JN, Das S, Tripathy SP, Hanna LE. Role of neutrophils in tuberculosis: A bird's eye view. Innate Immun 2020; 26:240-247. [PMID: 31735099 PMCID: PMC7251797 DOI: 10.1177/1753425919881176] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 09/17/2019] [Indexed: 01/06/2023] Open
Abstract
Neutrophils are innate immune cells implicated in the process of killing Mycobacterium tuberculosis early during infection. Once the mycobacteria enter the human system, neutrophils sense and engulf them. By secreting bactericidal enzymes and α-defensins like human neutrophil peptides loaded in their granule armory, neutrophils kill the pathogen. Peripheral blood neutrophils secrete a wide range of cytokines like IL-8, IL-1-β and IFN-γ in response to mycobacterial infection. Thus they signal and activate distant immune cells thereby informing them of prevailing infection. The activated monocytes, dendritic cells and T cells further continue the immune response. As a final call, neutrophils release neutrophil extracellular traps in circulation which can trap mycobacteria in patients with active pulmonary tuberculosis. Extensive neutrophilic response is associated with inflammation, pulmonary destruction, and pathology. For example, inappropriate phagocytosis of mycobacteria-infected neutrophils can damage host cells due to necrosis of neutrophils, leading to chronic inflammation and tissue damage. This dual nature of neutrophils makes them double-edged swords during tuberculosis, and hence data available on neutrophil functions against mycobacterium are controversial and non-uniform. This article reviews the role of neutrophils in tuberculosis infection and highlights research gaps that need to be addressed. We focus on our understanding of new research ideologies targeting neutrophils (a) in the early stages of infection for boosting specific immune functions or (b) in the later stages of infection to prevent inflammatory conditions mediated by activated neutrophils. This would plausibly lead to the development of better tuberculosis vaccines and therapeutics in the future.
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Affiliation(s)
- J Nancy Hilda
- Department of HIV/AIDS, National Institute for Research in
Tuberculosis, Chetpet, Chennai, India
| | - Sulochana Das
- Department of Immunology, National Institute for Research in
Tuberculosis, Chetpet, Chennai, India
| | - Srikanth P Tripathy
- Department of HIV/AIDS, National Institute for Research in
Tuberculosis, Chetpet, Chennai, India
| | - Luke Elizabeth Hanna
- Department of HIV/AIDS, National Institute for Research in
Tuberculosis, Chetpet, Chennai, India
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Kumar R, Singh P, Kolloli A, Shi L, Bushkin Y, Tyagi S, Subbian S. Immunometabolism of Phagocytes During Mycobacterium tuberculosis Infection. Front Mol Biosci 2019; 6:105. [PMID: 31681793 PMCID: PMC6803600 DOI: 10.3389/fmolb.2019.00105] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022] Open
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains as a leading killer among infectious diseases worldwide. The nature of the host immune response dictates whether the initial Mtb infection is cleared or progresses toward active disease, and is ultimately determined by intricate host-pathogen interactions that are yet to be fully understood. The early immune response to infection is mediated by innate immune cells, including macrophages and neutrophils that can phagocytose Mtb and mount an antimicrobial response. However, Mtb can exploit these innate immune cells for its survival and dissemination. Recently, it has become clear that the immune response and metabolic remodeling are interconnected, which is highlighted by the rapid evolution of the interdisciplinary field of immunometabolism. It has been proposed that the net outcome to Mtb infection—clearance or chronic disease—is likely a result of combined immunologic and metabolic activities of the immune cells. Indeed, host cells activated by Mtb infection have strikingly different metabolic requirements than naïve/non-infected cells. Macrophages activated by Mtb-derived molecules or upon phagocytosis acquire a phenotype similar to M1 with elevated production of pro-inflammatory molecules and rely on glycolysis and pentose phosphate pathway to meet their bioenergetic and metabolic requirements. In these macrophages, oxidative phosphorylation and fatty acid oxidation are dampened. However, the non-infected/naive, M2-type macrophages are anti-inflammatory and derive their energy from oxidative phosphorylation and fatty acid oxidation. Similar metabolic adaptations also occur in other phagocytes, including dendritic cells, neutrophils upon Mtb infection. This metabolic reprogramming of innate immune cells during Mtb infection can differentially regulate their effector functions, such as the production of cytokines and chemokines, and antimicrobial response, all of which can ultimately determine the outcome of Mtb-host interactions within the granulomas. In this review, we describe key immune cells bolstering host innate response and discuss the metabolic reprogramming in these phagocytes during Mtb infection. We focused on the major phagocytes, including macrophages, dendritic cells and neutrophils and the key regulators involved in metabolic reprogramming, such as hypoxia-inducible factor-1, mammalian target of rapamycin, the cellular myelocytomatosis, peroxisome proliferator-activator receptors, sirtuins, arginases, inducible nitric acid synthase and sphingolipids.
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Affiliation(s)
- Ranjeet Kumar
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Pooja Singh
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Afsal Kolloli
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Lanbo Shi
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Yuri Bushkin
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Sanjay Tyagi
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
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Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation of Mycobacterium avium. Infect Immun 2019; 87:IAI.00323-18. [PMID: 30642899 PMCID: PMC6434124 DOI: 10.1128/iai.00323-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 01/04/2019] [Indexed: 12/20/2022] Open
Abstract
Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. MAC strains show a wide genetic variability, and there is growing evidence suggesting that genetic differences may contribute to a varied immune response that may impact the infection outcome. Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. MAC strains show a wide genetic variability, and there is growing evidence suggesting that genetic differences may contribute to a varied immune response that may impact the infection outcome. The current study aimed to characterize the genomic changes within M.avium isolates collected from single patients over time and test the host immune responses to these clinical isolates. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on 40 MAC isolates isolated from 15 patients at the Department of Medical Microbiology at St. Olavs Hospital in Trondheim, Norway. Isolates from patients (patients 4, 9, and 13) for whom more than two isolates were available were selected for further analysis. These isolates exhibited extensive sequence variation in the form of single-nucleotide polymorphisms (SNPs), suggesting that M. avium accumulates mutations at higher rates during persistent infections than other mycobacteria. Infection of murine macrophages and mice with sequential isolates from patients showed a tendency toward increased persistence and the downregulation of inflammatory cytokines by host-adapted M. avium strains. The study revealed the rapid genetic evolution of M. avium in chronically infected patients, accompanied by changes in the virulence properties of the sequential mycobacterial isolates.
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Chahar M, Rawat KD, Reddy PVJ, Gupta UD, Natrajan M, Chauhan DS, Katoch K, Prasad GBKS, Katoch VM. Potential of adjunctive Mycobacterium w (MIP) immunotherapy in reducing the duration of standard chemotherapy against tuberculosis. Indian J Tuberc 2018; 65:335-344. [PMID: 30522622 DOI: 10.1016/j.ijtb.2018.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 08/17/2018] [Accepted: 08/29/2018] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The need to shorten the treatment duration in tuberculosis has always been felt. Immunotherapy in combination with chemotherapy has been considered a promising approach for this purpose into tuberculosis. We studied the adjuvant immunotherapeutic activity of Mycobacterium indicus pranii (MIP or Mw) in combination with conventional chemotherapy using guinea pig of pulmonary tuberculosis infected with Mycobacterium tuberculosis H37Rv via aerosol. METHODS Experimental animals treated with standard chemotherapy and immunotherapy (MIP) separately and in combination of both. Guinea pig lungs evaluated following infection and subsequent therapy at predefine time point. Various cytokine mRNA expressions levels were quantified by quantitative reverse transcriptase PCR at the 4th, 8th and 12th week post-infection of M. tuberculosis. RESULTS We determined the time required for bacterial clearance from guinea pig lungs. Standard chemotherapy (RvCh) compared to the animals where chemotherapy plus Mw immunotherpay (RvChMwT) was given. It took 12 weeks to achieve bacterial clearance in the RvCh group while this was achieved in 8 weeks in RvChMwT group. Pro-inflammatory cytokines (IFN-γ, IL-2, IL-12p35 and TNF-α) level were higher in RvCh, RvChMwT and RvMwT group, while the IL-10 and TGF-β were suppressed. CONCLUSION Cytokine expression level showed that Mw in conjunction with chemotherapy enhances the effect of pro-inflammatory cytokines (such as, IFN-γ, IL-2, IL-12 and TNF-α) and reduces the production and effect of anti-inflammatory cytokines (like IL-10 and TGF-β) thereby restoring the pro-inflammatory / anti-inflammatory cytokines balance. Thus, the present study indicates that subject to rigorous testing by other parameters, Mw (MIP) as adjunct immunotherapy has potential for reducing treatment duration.
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Affiliation(s)
- Mamta Chahar
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | - Krishan Dutta Rawat
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India; Department of Bio & Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, 125001, India
| | - P V J Reddy
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | - Umesh Dutt Gupta
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | - Mohan Natrajan
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | - Devendra Singh Chauhan
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | - Kiran Katoch
- National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), Tajganj, Agra, 282004, UP, India
| | | | - Vishwa Mohan Katoch
- Former Secretary, Department of Health Research, Govt of India and Director-General, Indian Council of Medical Research, Ansari Nagar, New Delhi, 110029, India.
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Qu X, Tang Y, Hua S. Immunological Approaches Towards Cancer and Inflammation: A Cross Talk. Front Immunol 2018; 9:563. [PMID: 29662489 PMCID: PMC5890100 DOI: 10.3389/fimmu.2018.00563] [Citation(s) in RCA: 208] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/06/2018] [Indexed: 12/12/2022] Open
Abstract
The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful. The acute inflammatory response tends to resolved once the offending agent is subside but this acute response becomes chronic in nature when the body is unable to successfully neutralized the noxious stimuli. This chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and oncogenic mediators such as nitric oxide (NO), cytokines [IL-1β, IL-2, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)], growth factor, and chemokines. These mediators make the inflammatory microenvironment more vulnerable toward tumorigenesis. The pro-inflammatory mediators released during the chronic inflammation tends to induce several molecular signaling cascades such as nuclear factor kappa B, MAPKinase, nuclear factor erythroid 2-related factor 2, phosphoinositide-3-kinase, Janus kinases/STAT, Wnt/B-catenin, and cyclic AMP response element binding protein. The immune system and its components have a pleiotropic effect on inflammation and cancer progression. Immune components such as T cells, natural killer cells, macrophages, and neutrophils either inhibit or enhance tumor initiation depending on the type of tumor and immune cells involved. Tumor-associated macrophages and tumor-associated neutrophils are pro-tumorigenic cells highly prevalent in inflammation-mediated tumors. Similarly, presence of T regulatory (Treg) cells in an inflammatory and tumor setting suppresses the immune system, thus paving the way for oncogenesis. However, Treg cells also inhibit autoimmune inflammation. By contrast, cytotoxic T cells and T helper cells confer antitumor immunity and are associated with better prognosis in patients with cancer. Cytotoxic T cells inflict a direct cytotoxic effect on cells expressing oncogenic markers. Currently, several anti-inflammatory and antitumor therapies are under trials in which these immune cells are exploited. Adoptive cell transfer composed of tumor-infiltrating lymphocytes has been tried for the treatment of tumors after their ex vivo expansion. Mediators released by cells in a tumorigenic and inflammatory microenvironment cross talk with nearby cells, either promoting or inhibiting inflammation and cancer. Recently, several cytokine-based therapies are either being developed or are under trial to treat such types of manifestations. Monoclonal antibodies directed against TNF-α, VEGF, and IL-6 has shown promising results to ameliorate inflammation and cancer, while direct administration of IL-2 has been shown to cause tumor regression.
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Affiliation(s)
- Xinglong Qu
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Ying Tang
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Shucheng Hua
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
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Tumor Necrosis Factor-Mediated Survival of CD169 + Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection. J Virol 2018; 92:JVI.01637-17. [PMID: 29142134 PMCID: PMC5774891 DOI: 10.1128/jvi.01637-17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/01/2017] [Indexed: 12/14/2022] Open
Abstract
Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169+ cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169+ cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b+ Ly6C+ Ly6G+ cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169+ cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169+ cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169+ cells and innate and adaptive immune activation during VSV infection.IMPORTANCE Over the last decade, strategically placed CD169+ metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169+ macrophages have been shown to activate innate and adaptive immunity via "enforced virus replication," a controlled amplification of virus particles. However, the factors regulating the CD169+ macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169+ macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.
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17
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de Almeida DC, Evangelista LSM, Câmara NOS. Role of aryl hydrocarbon receptor in mesenchymal stromal cell activation: A minireview. World J Stem Cells 2017; 9:152-158. [PMID: 29026461 PMCID: PMC5620424 DOI: 10.4252/wjsc.v9.i9.152] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 06/28/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation. MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response. The aryl-hydrocarbon receptor (AhR) is a sensitive molecule for external signals and it is expressed in MSCs and, upon positive activation, may potentially regulate the MSC-associated immunomodulatory function. Consequently, signalling pathways linked to AhR activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression. In this minireview, we have noted some important findings concerning MSC regulation via AhR, highlighting that its activation is associated with improvement in migration and immunoregulation, as well as an increase in pro-regenerative potential. Thus, AhR-mediated MSC activation can contribute to new perspectives on MSC-based therapies, particularly those directed at immune-associated disorders.
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Affiliation(s)
- Danilo Candido de Almeida
- Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, SP 04039-003, Brazil
| | | | - Niels Olsen Saraiva Câmara
- Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, SP 04039-003, Brazil
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, SP 05508-000, Brazil
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Abstract
Tuberculosis remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis, is acquired by the respiratory route. It is exquisitely adapted to humans and is a prototypic intracellular pathogen of macrophages, with alveolar macrophages being the primary conduit of infection and disease. However, M. tuberculosis bacilli interact with and are affected by several soluble and cellular components of the innate immune system which dictate the outcome of primary infection, most commonly a latently infected healthy human host, in whom the bacteria are held in check by the host immune response within the confines of tissue granuloma, the host histopathologic hallmark. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the early host immune response fails to control bacterial growth, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols. The molecular details of the M. tuberculosis-host innate immune system interaction continue to be elucidated, particularly those occurring within the lung. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. In this article, we describe a contemporary view of the molecular events underlying the interaction between M. tuberculosis and a variety of cellular and soluble components and processes of the innate immune system.
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19
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Abstract
Infection with M. tuberculosis remains one of the most common infections in the world. The outcome of the infection depends on host ability to mount effective protection and balance inflammatory responses. Neutrophils are innate immune cells implicated in both processes. Accordingly, during M. tuberculosis infection, they play a dual role. Particularly, they contribute to the generation of effector T cells, participate in the formation of granuloma, and are directly involved in tissue necrosis, destruction, and infection dissemination. Neutrophils have a high bactericidal potential. However, data on their ability to eliminate M. tuberculosis are controversial, and the results of neutrophil depletion experiments are not uniform. Thus, the overall roles of neutrophils during M. tuberculosis infection and factors that determine these roles are not fully understood. This review analyzes data on neutrophil defensive and pathological functions during tuberculosis and considers hypotheses explaining the dualism of neutrophils during M. tuberculosis infection and tuberculosis disease.
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20
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Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity. J Transl Med 2017; 15:36. [PMID: 28202039 PMCID: PMC5312441 DOI: 10.1186/s12967-017-1141-8] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/03/2017] [Indexed: 12/16/2022] Open
Abstract
Macrophages and neutrophils are key components involved in the regulation of numerous chronic inflammatory diseases, infectious disorders, and especially certain autoimmune disease. However, little is known regarding the contribution of these cells to the pathogenesis of autoimmune disorders. Recent studies have aimed to clarify certain important factors affecting the immunogenicity of these cells, including the type and dose of antigen, the microenvironment of the cell-antigen encounter, and the number, subset, and phenotype of these cells, which can prevent or induce autoimmune responses. This review highlights the role of macrophage subsets and neutrophils in injured tissues, supporting their cooperation during the pathogenesis of certain autoimmune diseases.
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21
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Lake MA, Ambrose LR, Lipman MCI, Lowe DM. '"Why me, why now?" Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection. BMC Med 2016; 14:54. [PMID: 27007918 PMCID: PMC4806462 DOI: 10.1186/s12916-016-0606-6] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 03/18/2016] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The prevalence of nontuberculous mycobacterial (NTM) disease is rising. An understanding of known risk factors for disease sheds light on the immunological and physical barriers to infection, and how and why they may be overcome. This review focuses on human NTM infection, supported by experimental and in vitro data of relevance to the practising clinician who seeks to understand why their patient has NTM infection and how to further investigate. DISCUSSION First, the underlying immune response to NTM disease is examined. Important insights regarding NTM disease susceptibility come from nature's own knockouts, the primary immune deficiency disorders. We summarise the current knowledge surrounding interferon-gamma (IFNγ)-interleukin-12 (IL-12) axis abnormalities, followed by a review of phagocytic defects, T cell lymphopenia and rarer genetic conditions known to predispose to NTM disease. We discuss how these define key immune pathways involved in the host response to NTM. Iatrogenic immunosuppression is also important, and we evaluate the impact of novel biological therapies, as well as bone marrow transplant and chemotherapy for solid organ malignancy, on the epidemiology and presentation of NTM disease, and discuss the host defence dynamics thus revealed. NTM infection and disease in the context of other chronic illnesses including HIV and malnutrition is reviewed. The role of physical barriers to infection is explored. We describe how their compromise through different mechanisms including cystic fibrosis, bronchiectasis and smoking-related lung disease can result in pulmonary NTM colonisation or infection. We also summarise further associations with host factors including body habitus and age. We use the presented data to develop an over-arching model that describes human host defences against NTM infection, where they may fail, and how this framework can be applied to investigation in routine clinical practice.
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Affiliation(s)
- M Alexandra Lake
- Royal Free London NHS Foundation Trust, London, UK.,Division of Infection and Immunity, University College London, London, UK
| | - Lyn R Ambrose
- Institute of Immunity and Transplantation, University College London, Royal Free Campus, Pond Street, London, NW3 2QG, UK
| | - Marc C I Lipman
- Royal Free London NHS Foundation Trust, London, UK.,UCL Respiratory, Division of Medicine, Faculty of Medical Sciences, University College London, Royal Free Campus, London, UK
| | - David M Lowe
- Royal Free London NHS Foundation Trust, London, UK. .,Institute of Immunity and Transplantation, University College London, Royal Free Campus, Pond Street, London, NW3 2QG, UK.
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22
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Rao X, Zhong J, Sun Q. The heterogenic properties of monocytes/macrophages and neutrophils in inflammatory response in diabetes. Life Sci 2014; 116:59-66. [PMID: 25264371 PMCID: PMC4253730 DOI: 10.1016/j.lfs.2014.09.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 08/26/2014] [Accepted: 09/15/2014] [Indexed: 01/03/2023]
Abstract
Inflammation is a complicated biological process in response to harmful stimuli, which involves the cooperation of immune system and vascular system. Upon pathogen invasion or tissue injury, resident innate immune cells such as macrophages and dendritic cells are activated and release inflammatory mediators, which result in the vasodilation and recruitment of leukocytes, mainly monocytes and neutrophils. As two of the most important inflammation-mediating immune cells, macrophages and neutrophils have long been regarded to have a pro-inflammatory effect. However, increasing evidences suggest the role of macrophage and neutrophil in inflammation is more complicated and diversified than we thought. Differently activated macrophages and neutrophils lead to diverse even opposite activities. Precise understanding of the role of different subpopulations is critical to achieve the effective treatment for inflammatory diseases. In this review, we discuss the two potentially distinct activation routes of macrophages and neutrophils in obesity and diabetes.
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Affiliation(s)
- Xiaoquan Rao
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH, United States
| | - Jixin Zhong
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States
| | - Qinghua Sun
- Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH, United States.
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23
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Verrall AJ, Netea MG, Alisjahbana B, Hill PC, van Crevel R. Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. Immunology 2014; 141:506-13. [PMID: 24754048 DOI: 10.1111/imm.12223] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for EC comes from case contact studies that consistently show that a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, natural killer T cells, mucosa-associated invariant T cells and cd T cells may assist. How EC may be impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection.
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McNamara M, Tzeng SC, Maier C, Wu M, Bermudez LE. Surface-exposed proteins of pathogenic mycobacteria and the role of cu-zn superoxide dismutase in macrophages and neutrophil survival. Proteome Sci 2013; 11:45. [PMID: 24283571 PMCID: PMC4176128 DOI: 10.1186/1477-5956-11-45] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 11/17/2013] [Indexed: 12/18/2022] Open
Abstract
Pathogenic mycobacteria are important agents causing human disease. Mycobacterium avium subsp. hominissuis (M. avium) is a species of recalcitrant environmental pathogen. The bacterium forms robust biofilms that allow it to colonize and persist in austere environments, such as residential and commercial water systems. M. avium is also an opportunistic pathogen that is a significant source of mortality for immune-compromised individuals. Proteins exposed at the bacterial surface play a central role in mediating the relationship between the bacterium and its environment. The processes underlying both biofilm formation and pathogenesis are directly dependent on this essential subset of the bacterial proteome. Therefore, the characterization of the surface-exposed proteome is an important step towards an improved understanding of the mycobacterial biology and pathogenesis. Here we examined the complement of surface exposed proteins from Mycobacterium avium 104, a clinical isolate and reference strain of Mycobacterium avium subsp. hominissuis. To profile the surface-exposed proteins of viable M. avium 104, bacteria were covalently labeled with a membrane impermeable biotinylation reagent and labeled proteins were affinity purified via the biotin-streptavidin interaction. The results provide a helpful snapshot of the surface-exposed proteome of this frequently utilized reference strain of M. avium. A Cu-Zn SOD knockout mutant, MAV_2043, a surface identified protein, was evaluated regarding its role in the survival in both macrophages and neutrophils.
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Affiliation(s)
- Michael McNamara
- Department of Biomedical Sciences, Molecular and Cellular Biology Program, Corvallis, USA.,Oregon State University, Corvallis, Oregon 97331-4801, USA
| | - Shin-Cheng Tzeng
- Department of Chemistry, Corvallis, USA.,Oregon State University, Corvallis, Oregon 97331-4801, USA
| | - Claudia Maier
- Department of Chemistry, Corvallis, USA.,Oregon State University, Corvallis, Oregon 97331-4801, USA
| | - Martin Wu
- Department of Biomedical Sciences, Molecular and Cellular Biology Program, Corvallis, USA.,Oregon State University, Corvallis, Oregon 97331-4801, USA
| | - Luiz E Bermudez
- Department of Biomedical Sciences, Molecular and Cellular Biology Program, Corvallis, USA.,Department of Microbiology, Corvallis, USA.,Oregon State University, Corvallis, Oregon 97331-4801, USA
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Haug M, Awuh JA, Steigedal M, Frengen Kojen J, Marstad A, Nordrum IS, Halaas Ø, Flo TH. Dynamics of immune effector mechanisms during infection with Mycobacterium avium in C57BL/6 mice. Immunology 2013; 140:232-43. [PMID: 23746054 DOI: 10.1111/imm.12131] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 05/10/2013] [Accepted: 06/03/2013] [Indexed: 12/22/2022] Open
Abstract
Opportunistic infections with non-tuberculous mycobacteria such as Mycobacterium avium are receiving renewed attention because of increased incidence and difficulties in treatment. As for other mycobacterial infections, a still poorly understood collaboration of different immune effector mechanisms is required to confer protective immunity. Here we have characterized the interplay of innate and adaptive immune effector mechanisms contributing to containment in a mouse infection model using virulent M. avium strain 104 in C57BL/6 mice. M. avium caused chronic infection in mice, as shown by sustained organ bacterial load. In the liver, bacteria were contained in granuloma-like structures that could be defined morphologically by expression of the antibacterial innate effector protein Lipocalin 2 in the adjoining hepatocytes and infiltrating neutrophils, possibly contributing to containment. Circulatory anti-mycobacterial antibodies steadily increased throughout infection and were primarily of the IgM isotype. Highest levels of interferon-γ were found in infected liver, spleen and serum of mice approximately 2 weeks post infection and coincided with a halt in organ bacterial growth. In contrast, expression of tumour necrosis factor was surprisingly low in spleen compared with liver. We did not detect interleukin-17 in infected organs or M. avium-specific T helper 17 cells, suggesting a minor role for T helper 17 cells in this model. A transient and relative decrease in regulatory T cell numbers was seen in spleens. This detailed characterization of M. avium infection in C57BL/6 mice may provide a basis for future studies aimed at gaining better insight into mechanisms leading to containment of infections with non-tuberculous mycobacteria.
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Affiliation(s)
- Markus Haug
- Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, NTNU, Trondheim; St Olav's Hospital, Trondheim
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Park J, Lee H, Kim YK, Kim KH, Lee W, Lee KY, Park YJ, Kahng J, Kwon HJ, Kim Y, Oh EJ, Lim J, Kim M, Han K. Automated screening for tuberculosis by multiparametric analysis of data obtained during routine complete blood count. Int J Lab Hematol 2013; 36:156-64. [PMID: 24034225 DOI: 10.1111/ijlh.12148] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 07/30/2013] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The main goal of this study was to develop a multiparametric cell population data (CPD) model that combines information from several morphologic parameters generated by DxH800, in addition to the traditional parameters regularly reported in the CBC-diff, and to test the performance of this model in screening the general population for primary tuberculosis (TB). METHODS A total of 3741 study cases were divided into two groups, test and validation set at cut-off value of 6000 WBCs/μL. We developed multiparametric model for primary TB screening (TB hemeprint), selected CPD, and calculated parameters which could discriminate primary TB from other non-TB diseases and normal control in test set. We applied it to the validation set, which was a set of completely different samples, to test its reproducibility if applied to a routine laboratory test. RESULTS After screening primary TB using TB hemeprint, sensitivity, specificity, PPV, and NPV were 85.4%, 89.6%, 31.1%, and 99.1%, respectively, in primary TB with lower than 6000 WBCs/μL of test set (test set-L). In primary TB with higher than 6000 WBCs/μL of test set (test set-H), those values were 83.1%, 85.6%, 29.7%, and 98.6%, respectively. There were only 0.4% (2/461) and 0.6% (2/326) of normal control samples included in test set-L and -H, respectively. Diagnostic efficiencies except sensitivity in each validation set were very comparable with those in each test set. CONCLUSION Tuberculosis hemeprint may allow us to screen primary TB with acceptable sensitivity and specificity using combination of TB-specific CPD and calculated parameters.
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Affiliation(s)
- J Park
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Xu X, Jiang SY, Wang TY, Bai Y, Zhong M, Wang A, Lippmann M, Chen LC, Rajagopalan S, Sun Q. Inflammatory response to fine particulate air pollution exposure: neutrophil versus monocyte. PLoS One 2013; 8:e71414. [PMID: 23951156 PMCID: PMC3738512 DOI: 10.1371/journal.pone.0071414] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 06/28/2013] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVES Studies have shown that chronic exposure to ambient fine particulate matter (less than 2.5 µm in aerodynamic diameter, PM₂.₅) pollution induces insulin resistance through alterations in inflammatory pathways. It is critical to study how the immune system responds to this stimulant, which has been linked to cardiovascular and autoimmune diseases, but few studies have been focused on such involvement of both neutrophils and monocytes in a timely manner. We hypothesized that the neutrophil was involved in the inflammatory response to air pollution. METHODS AND RESULTS C57BL/6 mice were exposed to PM₂.₅ or filtered air (6 hours/day, 5 days/week) for 5, 14, and 21 days, respectively, in Columbus, OH. At the end of each of the exposure periods, we investigated the inflammatory response through flow cytometry, histology, intravital microscopy, and real-time PCR. PM₂.₅-exposed mice demonstrated a significant inflammatory response after 5 days of exposure. In the lung tissue and bronchoalveolar lavage fluid, monocytes/macrophages showed a transient response, while neutrophils showed a cumulative response. In addition, exposure to PM₂.₅ resulted in elevation of the monocyte chemoattractant protein 1 (MCP-1) cytokine, a monocyte/macrophage attractant in blood, at an early stage of exposure. CONCLUSIONS These findings suggest that PM₂.₅ exposure induces the inflammatory responses from both macrophages and neutrophils involvement.
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Affiliation(s)
- Xiaohua Xu
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
| | - Silis Y. Jiang
- Division of Environmental Health Sciences, The Ohio State University, Columbus, Ohio, United States of America
| | - Tse-Yao Wang
- Division of Environmental Health Sciences, The Ohio State University, Columbus, Ohio, United States of America
| | - Yuntao Bai
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
| | - Mianhua Zhong
- Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
| | - Aixia Wang
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
| | - Morton Lippmann
- Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
| | - Lung-Chi Chen
- Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
| | - Sanjay Rajagopalan
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
- Division of Cardiovascular Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Qinghua Sun
- Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
- Division of Environmental Health Sciences, The Ohio State University, Columbus, Ohio, United States of America
- Division of Cardiovascular Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Jayachandran R, Scherr N, Pieters J. Elimination of intracellularly residing Mycobacterium tuberculosis through targeting of host and bacterial signaling mechanisms. Expert Rev Anti Infect Ther 2013; 10:1007-22. [PMID: 23106276 DOI: 10.1586/eri.12.95] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
With more than 2 billion latently infected people, TB continues to represent a serious threat to human health. According to the WHO, 1.1 million people died from TB in 2010, which is equal to approximately 3000 deaths per day. The causative agent of the disease, Mycobacterium tuberculosis, is a highly successful pathogen having evolved remarkable strategies to persist within the host. Although normally, upon phagocytosis by macrophages, bacteria are readily eliminated by lysosomes, pathogenic mycobacteria actively prevent destruction within macrophages. The strategies that pathogenic mycobacteria apply range from releasing virulence factors to manipulating host molecules resulting in the modulation of host signal transduction pathways in order to sustain their viability within the infected host. Here, we analyze the current status of how a better understanding of both the bacterial and host factors involved in virulence can be used to develop drugs that may be helpful to curb the TB epidemic.
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Affiliation(s)
- Rajesh Jayachandran
- Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland
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Saitoh T, Yano I, Kumazawa Y, Takimoto H. Pulmonary TCR γδ T cells induce the early inflammation of granuloma formation by a glycolipid trehalose 6,6'-dimycolate (TDM) isolated from Mycobacterium tuberculosis. Immunopharmacol Immunotoxicol 2013; 34:815-23. [PMID: 22963130 DOI: 10.3109/08923973.2012.658922] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We previously showed that formation of pulmonary granulomas in mice in response to a mycobacterial glycolipid, trehalose 6,6'-dimycolate (TDM) is due to the action of TNF-α and not of IFN-γ. However, the mechanisms of formation and maintenance of pulmonary granulomas are not yet clear. The purpose of the present study is to evaluate the mechanisms of granuloma formation by TDM at the early phase. Histological analysis showed that inflammatory cells infiltrated the murine pulmonary interstitium on day 2 after an intravenous injection with TDM as a w/o/w emulsion. Clear granuloma formation was observed on day 7 after the injection. The mRNA expression of IL-17, IFN-γ and macrophage inflammatory protein 2 was found in lung mononuclear cells at the day after TDM injection. The major IL-17-producing cells were T-cell receptor (TCR) γδ T cells expressing Vγ6. In mice depleted of γδ T cells by treatment with anti-TCR γδ monoclonal antibody, the number of TDM-induced granuloma was decreased, but the size of granuloma was not affected. Our results suggest that the mycobacterial glycolipid TDM causes activation of IL-17-producing TCR γδ T cells and stimulates chemotaxis of inflammatory cells including neutrophils in to lung.
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Affiliation(s)
- Takayoshi Saitoh
- Department of Bioscience, Graduate School of Science, Kitasato University, Kitasato, Minami-ku, Sagamihara, Kanagawa, Japan
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Natural transmission of Plasmodium berghei exacerbates chronic tuberculosis in an experimental co-infection model. PLoS One 2012; 7:e48110. [PMID: 23110184 PMCID: PMC3482195 DOI: 10.1371/journal.pone.0048110] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 09/19/2012] [Indexed: 01/23/2023] Open
Abstract
Human populations are rarely exposed to one pathogen alone. Particularly in high incidence regions such as sub-Saharan Africa, concurrent infections with more than one pathogen represent a widely underappreciated public health problem. Two of the world’s most notorious killers, malaria and tuberculosis, are co-endemic in impoverished populations in the tropics. However, interactions between both infections in a co-infected individual have not been studied in detail. Both pathogens have a major impact on the lung as the prime target organ for aerogenic Mycobacterium tuberculosis and the site for one of the main complications in severe malaria, malaria-associated acute respiratory distress syndrome (MA-ARDS). In order to study the ramifications caused by both infections within the same host we established an experimental mouse model of co-infection between Mycobacterium tuberculosis and Plasmodium berghei NK65, a recently described model for MA-ARDS. Our study provides evidence that malaria-induced immune responses impair host resistance to Mycobacterium tuberculosis. Using the natural routes of infection, we observed that co-infection exacerbated chronic tuberculosis while rendering mice less refractory to Plasmodium. Co-infected animals presented with enhanced inflammatory immune responses as reflected by exacerbated leukocyte infiltrates, tissue pathology and hypercytokinemia accompanied by altered T-cell responses. Our results - demonstrating striking changes in the immune regulation by co-infection with Plasmodium and Mycobacterium - are highly relevant for the medical management of both infections in humans.
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31
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Gupta A, Ahmad FJ, Ahmad F, Gupta UD, Natarajan M, Katoch V, Bhaskar S. Efficacy of Mycobacterium indicus pranii immunotherapy as an adjunct to chemotherapy for tuberculosis and underlying immune responses in the lung. PLoS One 2012; 7:e39215. [PMID: 22844392 PMCID: PMC3406023 DOI: 10.1371/journal.pone.0039215] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 05/21/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis. METHODS We sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol. RESULTS MIP-therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology. CONCLUSION MIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung.
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Affiliation(s)
- Ankan Gupta
- Product Development Cell, National Institute of Immunology, New Delhi, Delhi, India
| | | | - Faiz Ahmad
- Product Development Cell, National Institute of Immunology, New Delhi, Delhi, India
| | - Umesh D. Gupta
- Experimental Animal Facility and Department of Pathology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India
| | - Mohan Natarajan
- Experimental Animal Facility and Department of Pathology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India
| | - Vishwamohan Katoch
- Experimental Animal Facility and Department of Pathology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India
| | - Sangeeta Bhaskar
- Product Development Cell, National Institute of Immunology, New Delhi, Delhi, India
- * E-mail:
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Lu Y, Leung TM, Ward SC, Nieto N. Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress. Am J Physiol Gastrointest Liver Physiol 2012; 302:G287-95. [PMID: 22052013 PMCID: PMC3287402 DOI: 10.1152/ajpgi.00375.2011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the L-citrulline/nitric oxide (NO·) salvage pathway to continually supply L-arginine from L-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/- mice (Ass+/+ mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/- mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/- compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration.
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Affiliation(s)
- Yongke Lu
- 1Division of Liver Diseases, Department of Medicine, and
| | | | - Stephen C. Ward
- 2Department of Pathology, Mount Sinai School of Medicine, New York, New York
| | - Natalia Nieto
- 1Division of Liver Diseases, Department of Medicine, and
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Cowan J, Pandey S, Filion LG, Angel JB, Kumar A, Cameron DW. Comparison of interferon-γ-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection. Clin Exp Immunol 2012; 167:317-29. [PMID: 22236009 PMCID: PMC3278699 DOI: 10.1111/j.1365-2249.2011.04520.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2011] [Indexed: 01/17/2023] Open
Abstract
In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-γ-, interleukin (IL)-17- and IL-22-expressing CD4(+) T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4(+) T cells expressing IL-17, IL-22 and IFN-γ were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-γ and tumour necrosis factor (TNF)-α were increased following antigen stimulation in latent infection. Similarly, IL-1β, IL-4, IL-8, IL-22 and TNF-α were increased in the serum of latently infected individuals, whereas IL-6 and TNF-α were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-γ-expressing CD4(+) T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis.
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Affiliation(s)
- J Cowan
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
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34
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A highly efficient Ziehl-Neelsen stain: identifying de novo intracellular Mycobacterium tuberculosis and improving detection of extracellular M. tuberculosis in cerebrospinal fluid. J Clin Microbiol 2012; 50:1166-70. [PMID: 22238448 DOI: 10.1128/jcm.05756-11] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Tuberculous meningitis leads to a devastating outcome, and early diagnosis and rapid chemotherapy are vital to reduce morbidity and mortality. Since Mycobacterium tuberculosis is a kind of cytozoic pathogen and its numbers are very few in cerebrospinal fluid, detecting M. tuberculosis in cerebrospinal fluid from tuberculous meningitis patients is still a challenge for clinicians. Ziehl-Neelsen stain, the current feasible microbiological method for the diagnosis of tuberculosis, often needs a large amount of cerebrospinal fluid specimen but shows a low detection rate of M. tuberculosis. Here, we developed a modified Ziehl-Neelsen stain, involving cytospin slides with Triton processing, in which only 0.5 ml of cerebrospinal fluid specimens was required. This method not only improved the detection rate of extracellular M. tuberculosis significantly but also identified intracellular M. tuberculosis in the neutrophils, monocytes, and lymphocytes clearly. Thus, our modified method is more effective and sensitive than the conventional Ziehl-Neelsen stain, providing clinicians a convenient yet powerful tool for rapidly diagnosing tuberculous meningitis.
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35
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Neutrophils in tuberculosis: friend or foe? Trends Immunol 2011; 33:14-25. [PMID: 22094048 DOI: 10.1016/j.it.2011.10.003] [Citation(s) in RCA: 242] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 10/06/2011] [Accepted: 10/17/2011] [Indexed: 12/22/2022]
Abstract
Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. Whether neutrophils can kill mycobacteria in vivo probably depends on the tissue microenvironment, stage of infection, individual host, and infecting organism. The interaction of neutrophils with macrophages, as well as the downstream effects on T cell activity, could result in a range of outcomes from early clearance of infection to dissemination of viable bacteria together with an attenuated acquired immune response. In established disease, neutrophils accumulate in situations of high pathogen load or immunological dysfunction, and are likely to contribute to pathology. These activities may have clinical importance in terms of new treatments, targeted interventions and vaccine strategies.
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36
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Bai X, Ovrutsky AR, Kartalija M, Chmura K, Kamali A, Honda JR, Oberley-Deegan RE, Dinarello CA, Crapo JD, Chang LY, Chan ED. IL-32 expression in the airway epithelial cells of patients with Mycobacterium avium complex lung disease. Int Immunol 2011; 23:679-91. [PMID: 22033195 DOI: 10.1093/intimm/dxr075] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Lung disease due to Mycobacterium avium complex (MAC) organisms is increasing. A greater understanding of the host immune response to MAC organisms will provide a foundation to develop novel therapies for these recalcitrant infections. IL-32 is a newly described pro-inflammatory cytokine that enhances host immunity against various microbial pathogens. Cytokines that induce IL-32 such as interferon-gamma, IL-18, IL-12 and tumor necrosis factor-alpha are of considerable importance to mycobacterial immunity. We performed immunohistochemistry and morphometric analysis to quantify IL-32 expression in the lungs of 11 patients with MAC lung disease and 10 controls with normal lung tissues. After normalizing for basement membrane length, there was a profound increase in IL-32 expression in the airway epithelial cells of the MAC-infected lungs compared with controls. Following normalization for alveolar surface area, there was a trend toward increased IL-32 expression in type II alveolar cells and alveolar macrophages in the lungs of MAC patients. Human airway epithelial cells (BEAS-2B) infected with M. avium produced IL-32 by a nuclear factor-kappa B-dependent mechanism. In both BEAS-2B cells and human monocyte-derived macrophages, exogenous IL-32γ significantly reduced the growth of intracellular M. avium. This finding was corroborated by an increase in the number of intracellular M. avium recovered from THP-1 monocytes silenced for endogenous IL-32 expression. The anti-mycobacterial effect of IL-32 may be due, in part, to increased apoptosis of infected cells. These findings indicate that IL-32 facilitates host defense against MAC organisms but may also contribute to the airway inflammation associated with MAC pulmonary disease.
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Affiliation(s)
- Xiyuan Bai
- Department of Medicine, Denver Veterans Affairs Medical Center, Denver, CO 80220, USA.
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Blomgran R, Ernst JD. Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection. THE JOURNAL OF IMMUNOLOGY 2011; 186:7110-9. [PMID: 21555529 DOI: 10.4049/jimmunol.1100001] [Citation(s) in RCA: 177] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously published observations that 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis-infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naive M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role of neutrophils in DC migration, we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results revealed a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that makes DCs more effective initiators of naive CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis.
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Affiliation(s)
- Robert Blomgran
- Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
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38
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Eum SY, Kong JH, Hong MS, Lee YJ, Kim JH, Hwang SH, Cho SN, Via LE, Barry CE. Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB. Chest 2009; 137:122-8. [PMID: 19749004 DOI: 10.1378/chest.09-0903] [Citation(s) in RCA: 376] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The exact role of neutrophils in the pathogenesis of TB is poorly understood. Recent evidence suggests that neutrophils are not simply scavenging phagocytes in Mycobacterium tuberculosis (Mtb) infection. METHODS Three different types of clinical specimens from patients with active pulmonary TB who underwent lung surgery were examined: sputum, BAL fluid, and cavity contents. Differential cell separation and quantification were performed for intracellular and extracellular bacteria, and bacterial length was measured using microscopy. RESULTS Neutrophils were more abundant than macrophages in sputum (86.6% +/- 2.2% vs 8.4% +/- 1.3%) and in BAL fluid (78.8% +/- 5.8% vs 11.8% +/- 4.1%). Inside the cavity, lymphocytes (41.3% +/- 11.2%) were the most abundant cell type, followed by neutrophils (38.8% +/- 9.4%) and macrophages (19.5% +/- 7.5%). More intracellular bacilli were found in neutrophils than macrophages in sputum (67.6% +/- 5.6% vs 25.2% +/- 6.5%), in BAL fluid (65.1% +/- 14.4% vs 28.3% +/- 11.6%), and in cavities (61.8% +/- 13.3% vs 23.9% +/- 9.3%). The lengths of Mtb were shortest in cavities (1.9+/- 0.1 microm), followed by in sputum (2.9 +/- 0.1 microm) and in BAL fluid (3.6 +/- 0.2 microm). CONCLUSIONS Our results show that neutrophils are the predominant cell types infected with Mtb in patients with TB and that these intracellular bacteria appear to replicate rapidly. These results are consistent with a role for neutrophils in providing a permissive site for a final burst of active replication of the bacilli prior to transmission.
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Affiliation(s)
- Seok-Yong Eum
- International Tuberculosis Research Center, Division of Immunopathology and Cellular Immunology, 475-1, Gapo, Masan 631-320, Republic of Korea.
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Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, Suda T, Sudo K, Nakae S, Iwakura Y, Matsuzaki G. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. THE JOURNAL OF IMMUNOLOGY 2007; 178:3786-96. [PMID: 17339477 DOI: 10.4049/jimmunol.178.6.3786] [Citation(s) in RCA: 429] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-17 is a cytokine that induces neutrophil-mediated inflammation, but its role in protective immunity against intracellular bacterial infection remains unclear. In the present study, we demonstrate that IL-17 is an important cytokine not only in the early neutrophil-mediated inflammatory response, but also in T cell-mediated IFN-gamma production and granuloma formation in response to pulmonary infection by Mycobacterium bovis bacille Calmette-Guérin (BCG). IL-17 expression in the BCG-infected lung was detected from the first day after infection and the expression depended on IL-23. Our observations indicated that gammadelta T cells are a primary source of IL-17. Lung-infiltrating T cells of IL-17-deficient mice produced less IFN-gamma in comparison to those from wild-type mice 4 wk after BCG infection. Impaired granuloma formation was also observed in the infected lungs of IL-17-deficient mice, which is consistent with the decreased delayed-type hypersensitivity response of the infected mice against mycobacterial Ag. These data suggest that IL-17 is an important cytokine in the induction of optimal Th1 response and protective immunity against mycobacterial infection.
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MESH Headings
- Animals
- Cytokines/immunology
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Hypersensitivity, Delayed/pathology
- Immunity, Cellular
- Immunity, Innate/genetics
- Inflammation/genetics
- Inflammation/immunology
- Inflammation/pathology
- Interleukin-17/deficiency
- Interleukin-17/immunology
- Mice
- Mycobacterium bovis/immunology
- Neutrophils/immunology
- Neutrophils/pathology
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Th1 Cells/immunology
- Th1 Cells/pathology
- Time Factors
- Tuberculoma/genetics
- Tuberculoma/immunology
- Tuberculoma/pathology
- Tuberculoma/veterinary
- Tuberculosis, Pulmonary/genetics
- Tuberculosis, Pulmonary/immunology
- Tuberculosis, Pulmonary/veterinary
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Affiliation(s)
- Masayuki Umemura
- Molecular Microbiology Group, Center of Molecular Biosciences, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan.
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Sawant KV, McMurray DN. Guinea pig neutrophils infected with Mycobacterium tuberculosis produce cytokines which activate alveolar macrophages in noncontact cultures. Infect Immun 2007; 75:1870-7. [PMID: 17283104 PMCID: PMC1865707 DOI: 10.1128/iai.00858-06] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The early influx of neutrophils to the site of infection may be an important step in host resistance against Mycobacterium tuberculosis. In this study, we investigated the effect of M. tuberculosis infection on the ability of guinea pig neutrophils to produce interleukin-8 (IL-8; CXCL8) and tumor necrosis factor alpha (TNF-alpha) and to activate alveolar macrophages. Neutrophils and alveolar macrophages were isolated from naïve guinea pigs, cultured together or alone, and infected with virulent M. tuberculosis for 3, 12, and 24 h. IL-8 protein production in cocultures, as measured by using an enzyme-linked immunosorbent assay, was found to be additive at 24 h and significantly greater in M. tuberculosis-infected cocultures than in uninfected cocultures and in cultures of the infected neutrophils or macrophages alone. The IL-8 mRNA levels, determined by real-time reverse transcription-PCR, were elevated at 24 h in infected cocultures and infected cells cultured alone. In order to elucidate the contributions of neutrophils and their soluble mediators to the activation of alveolar macrophages, neutrophils and alveolar macrophages were cultured in a contact-independent manner by using a Transwell insert system. Neutrophils were infected with virulent M. tuberculosis in the upper wells, and alveolar macrophages were cultured in the lower wells. The release of hydrogen peroxide from alveolar macrophages exposed to soluble products from infected neutrophils was significantly increased compared to that from unexposed alveolar macrophages. Significant up-regulation of IL-1beta and TNF-alpha mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products. Treatment with anti-guinea pig TNF-alpha polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products. This finding suggests that TNF-alpha produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection.
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Affiliation(s)
- Kirti V Sawant
- Department of Microbial and Molecular Pathogenesis, The Texas A&M University System Health Science Center, 407 Reynolds Medical Building, College Station, TX 77843-1114, USA.
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41
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Appelberg R. Neutrophils and intracellular pathogens: beyond phagocytosis and killing. Trends Microbiol 2007; 15:87-92. [PMID: 17157505 DOI: 10.1016/j.tim.2006.11.009] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2006] [Revised: 10/25/2006] [Accepted: 11/28/2006] [Indexed: 01/21/2023]
Abstract
Neutrophils are not simply scavenging phagocytes that clear extracellular spaces of rapidly proliferating microbes; they are also active in the control of infections by intracellular pathogens. Several mechanisms for nonphagocytic roles of neutrophils in protective immunity have been put forth over the years but further evidence has recently been accumulating at an increasing pace. In this review, I present the evidence that suggests neutrophils are involved in pathogen shuttling into the lymphoid tissues, in antigen presentation, and in early T cell recruitment and initiation of granuloma organization. Also, a clearer view on the antimicrobial molecules that can be acquired by macrophages to enhance their antimicrobial activity is now emerging. Finally, neutrophils can adversely affect immunity against certain parasites by causing immune deviation.
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Affiliation(s)
- Rui Appelberg
- Laboratory of Microbiology and Immunology of Infection, Institute for Molecular and Cell Biology (IBMC) and Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Porto, 4150-180 Porto, Portugal.
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Appelberg R. Pathogenesis of Mycobacterium avium infection: typical responses to an atypical mycobacterium? Immunol Res 2007; 35:179-90. [PMID: 17172645 DOI: 10.1385/ir:35:3:179] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/1999] [Revised: 11/30/1999] [Accepted: 11/30/1999] [Indexed: 01/02/2023]
Abstract
Studying infections with Mycobacterium avium in mouse models has allowed the dissection of the antimycobacterial pathways of the mammalian host. Whereas the paradigm of cell-mediated immunity to intracellular pathogens has been confirmed, namely with regard to the pivotal roles of CD4+ T cells, macrophages, and the IL12-IFNgamma cytokine axis, atypical features have been uncovered such as the resistance to NO, the involvement of minor players in the induction of type 1 protective immunity (such as TLR2, CD40, and CD30), and the development of immunopathology during the infection with highly virulent strains such as the development of caseous necrosis of granulomas or the progressive emergence of severe lymphopenia.
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Affiliation(s)
- Rui Appelberg
- Laboratory of Microbiology and Immunology of Infection, IBMC-Institute for Molecular and Cell Biology and ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Portugal.
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Feng CG, Kaviratne M, Rothfuchs AG, Cheever A, Hieny S, Young HA, Wynn TA, Sher A. NK cell-derived IFN-gamma differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis. THE JOURNAL OF IMMUNOLOGY 2007; 177:7086-93. [PMID: 17082625 DOI: 10.4049/jimmunol.177.10.7086] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although it is known that IFN-gamma-secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN-gamma produced by NK cells to host resistance to the pathogen is less well understood. By using T cell-deficient RAG(-/-) mice, we showed that M. tuberculosis stimulates NK cell-dependent IFN-gamma production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor gamma-chain(-/-)RAG(-/-) animals deficient in NK cells, p40(-/-)RAG(-/-), or anti-IFN-gamma mAb-treated RAG(-/-) mice displayed significantly increased susceptibility to M. tuberculosis infection compared with untreated NK-sufficient RAG(-/-) controls. Studies comparing IL-12 p40- and p35-deficient RAG(-/-) mice indicated that IL-12 plays a more critical role in the induction of IFN-gamma-mediated antimycobacterial effector functions than IL-23 or other p40-containing IL-12 family members. The increased susceptibility of IL-12-deficient or anti-IFN-gamma mAb-treated RAG(-/-) mice was associated not only with elevated bacterial loads, but also with the development of granulocyte-enriched foci in lungs. This tissue response correlated with increased expression of the granulocyte chemotactic chemokines KC and MIP-2 in NK as well as other leukocyte populations. Interestingly, depletion of granulocytes further increased bacterial burdens and exacerbated pulmonary pathology in these animals, revealing a compensatory function for neutrophils in the absence of IFN-gamma. The above observations indicate that NK cell-derived IFN-gamma differentially regulates T-independent resistance and granulocyte function in M. tuberculosis infection and suggest that this response could serve as an important barrier in AIDS patients or other individuals with compromised CD4+ T cell function.
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Affiliation(s)
- Carl G Feng
- Immunobiology Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-8003, USA.
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Maletto BA, Ropolo AS, Alignani DO, Liscovsky MV, Ranocchia RP, Moron VG, Pistoresi-Palencia MC. Presence of neutrophil-bearing antigen in lymphoid organs of immune mice. Blood 2006; 108:3094-102. [PMID: 16835380 DOI: 10.1182/blood-2006-04-016659] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Neutrophils play a crucial early role during the innate response, but little is known about their possible contribution when an adaptive immune response is installed. A robust neutrophilia and a T helper 1 (Th1) immune response are present after immunization with Complete Freund Adjuvant (CFA). We show that when FITC-labeled OVA was injected into the footpad of OVA/CFA immunized mice, the main OVA-FITC+ cells recruited in draining popliteal lymph nodes (LNs) were neutrophils, with most of them arriving at the LN by means of lymphatic vessels. The development of this OVA-FITC+ neutrophil influx requires an immune response against OVA. The OVA-FITC+ neutrophils present in LNs displayed mainly intracellular TNF-α, and their depletion resulted in an increase in the specific IL-5 levels. These data provide new evidence about the role played by neutrophils in vivo in adaptive immunity.
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Affiliation(s)
- Belkys A Maletto
- Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Tavener SA, Kubes P. Cellular and molecular mechanisms underlying LPS-associated myocyte impairment. Am J Physiol Heart Circ Physiol 2006; 290:H800-6. [PMID: 16172157 DOI: 10.1152/ajpheart.00701.2005] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Recently we reported that Toll-like receptor 4 (TLR4)-positive immune cells of unknown identity were responsible for the LPS-induced depression of cardiac myocyte shortening. The aim of this study is to identify the TLR4-positive cell type that is responsible for the LPS-induced cardiac dysfunction. Neither neutrophil depletion alone nor mast cell deficiency had any impact on the impairment of myocyte shortening during LPS treatment. In contrast, LPS-treated, macrophage-deficient mice demonstrated a partial reduction in shortening compared with saline-treated, macrophage-deficient mice. Because the removal of macrophages could only partially restore myocyte shortening, we also investigated the effects of removing both neutrophils and macrophages on myocyte shortening. Interestingly, endotoxemic, neutrophil-depleted, and macrophage-deficient mice had completely restored myocyte shortening. Because both macrophages and neutrophils can produce nitric oxide (NO) and TNF-α, we examined LPS-treated inducible NO synthase knockout (iNOSKO) mice and TNF receptor (TNFR)-deficient mice. Eliminating both TNFR1 and TNFR2 was required to restore myocyte shortening during LPS treatment, whereas iNOS deficiency had no effect. These data suggest that macrophages and to a lesser degree neutrophils cause cardiac impairment, presumably via TNF-α.
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Affiliation(s)
- Samantha A Tavener
- Dept. of Physiology and Biophysics, Univ. of Calgary Medical Centre, AB, Canada
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Ehlers S, Lehmann J, Mossmann H, Alber G, Hölscher C. Interleukin-12p40 mediates transient protection against Mycobacterium avium infection in the absence of interleukin-12. Immunobiology 2005; 210:217-27. [PMID: 16164029 DOI: 10.1016/j.imbio.2005.05.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Produced by macrophages and dendritic cells, interleukin (IL)-12 is composed of a p35 and a p40 subunit and promotes protection against intracellular pathogens through the development of interferon-gamma (IFNgamma) -producing T cells. The p40 subunit is also shared by the dimeric cytokines IL-12p40 homodimer and IL-23. In man, genetic defects in IL-12p40-mediated mechanisms are responsible for the familial occurrence of nontuberculous mycobacterial infections, the most common of which is infection with Mycobacterium avium. To experimentally differentiate the contribution of IL-12p40-containing cytokines in the outcome of M. avium infection, we studied wild-type, p35- and p35/p40 doubly deficient mice in an intravenous infection model which reflects many parameters of the disseminated infection in humans. Our study shows that in contrast to p35/p40 doubly deficient mice, p35-deficient mice mount a transient antibacterially protective response against M. avium although such animals were unable to produce detectable levels of IFNgamma or generate efficient granulomas. In conclusion, our results identify an antibacterial effector mechanism preserved in p35-deficient mice that is absent in mice devoid of p35 and p40. This phenotype probably reflects an IL-12p40-dependent effect on macrophage activation at the level of innate immunity.
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Affiliation(s)
- Stefan Ehlers
- Division of Molecular Infection Biology, Research Center Borstel, Germany
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Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV, Orlova MO, Apt AS. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun 2005; 73:1744-53. [PMID: 15731075 PMCID: PMC1064912 DOI: 10.1128/iai.73.3.1744-1753.2005] [Citation(s) in RCA: 221] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Revised: 08/17/2004] [Accepted: 09/27/2004] [Indexed: 12/21/2022] Open
Abstract
The role of neutrophils in tuberculosis (TB) resistance and pathology is poorly understood. Neutrophil reactions are meant to target the offending pathogen but may lead to destruction of the host lung tissue, making the defending cells an enemy. Here, we show that mice of the I/St strain which are genetically susceptible to TB show an unusually high and prolonged neutrophil accumulation in their lungs after intratracheal infection. Compared to neutrophils from more resistant A/Sn mice, I/St neutrophils display an increased mobility and tissue influx, prolonged lifespan, low expression of the CD95 (Fas) apoptotic receptor, relative resistance to apoptosis, and an increased phagocytic capacity for mycobacteria. Segregation genetic analysis in (I/St x A/Sn)F2 hybrids indicates that the alleles of I/St origin at the chromosome 3 and 17 quantitative trait loci which are involved in the control of TB severity also determine a high level of neutrophil influx. These features, along with the poor ability of neutrophils to restrict mycobacterial growth compared to that of lung macrophages, indicate that the prevalence of neutrophils in TB inflammation contributes to the development of pathology, rather than protection of the host, and that neutrophils may play the role of a "Trojan horse" for mycobacteria.
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Affiliation(s)
- Evgenyi B Eruslanov
- Laboratory for Immunogenetics, Central Institute for Tuberculosis, Yauza Alley 2, Moscow 107564, Russia
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Herring AC, Falkowski NR, Chen GH, McDonald RA, Toews GB, Huffnagle GB. Transient neutralization of tumor necrosis factor alpha can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells. Infect Immun 2005; 73:39-49. [PMID: 15618139 PMCID: PMC538928 DOI: 10.1128/iai.73.1.39-49.2005] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-alpha) deficiency remain to be defined. The objective of our studies was to determine the potential contribution of neutropenia and immature dendritic cells to the immune deviation. Administration of an anti-TNF-alpha monoclonal antibody at day 0 neutralized TNF-alpha only during the first week of a pulmonary Cryptococcus neoformans infection. Transient neutralization of TNF-alpha resulted in transient depression of interleukin-12 (IL-12), monocyte chemotactic protein 1 (MCP-1), and gamma interferon (IFN-gamma) production but permanently impaired long-term clearance of the infection from the lungs even after the levels of these cytokines increased and a vigorous inflammatory response developed. Early neutrophil recruitment was defective in the absence of TNF-alpha. However, as demonstrated by neutrophil depletion studies, this did not account for the decrease in IL-12 and IFN-gamma levels and did not play a role in establishing chronic pulmonary cryptococcal infection. Transient TNF-alpha neutralization also produced a deficiency in CD11c(+) MHC II(+) cells and IL-12 in the lymph nodes, potentially implicating a defect in mature dendritic cell trafficking. Transfer of cryptococcal antigen-pulsed immature dendritic cells into naive mice prior to intratracheal challenge resulted in the development of a nonprotective immune response to C. neoformans that was similar to that observed in anti-TNF-alpha-treated mice (increased IL-4, IL-5, and IL-10 levels, pulmonary eosinophilia, and decreased clearance). Thus, stimulation of an antifungal response by immature dendritic cells can result in an immune deviation similar to that produced by transient TNF-alpha deficiency, identifying a new mechanism by which a chronic fungal infection can occur in an immunocompetent host.
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Affiliation(s)
- Amy C Herring
- Pulmonary and Critical Care Medicine, 6301 MSRB III, The University of Michigan, Ann Arbor, MI 48109-0642, USA
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Lyons MJ, Yoshimura T, McMurray DN. Interleukin (IL)-8 (CXCL8) induces cytokine expression and superoxide formation by guinea pig neutrophils infected with Mycobacterium tuberculosis. Tuberculosis (Edinb) 2004; 84:283-92. [PMID: 15207803 DOI: 10.1016/j.tube.2003.09.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
SETTING Interleukin (IL)-8, a neutrophil attracting chemokine, is known to be made by a variety of leukocyte populations following stimulation by Mycobacterium tuberculosis. OBJECTIVE The effect of recombinant guinea pig IL-8 on the ability of neutrophils to generate a cytokine response after infection with M. tuberculosis H37Ra was examined. DESIGN Recombinant gpIL-8 was produced by subcloning the gene into Escherichia coli and purification over a nickel column. The identity of the rgpIL-8 was confirmed by sequencing. Neutrophils were harvested from the blood of non-vaccinated or M. bovis BCG-vaccinated guinea pigs and tested for their ability to migrate toward media alone, 10 microg/ml PPD, f-Met-Leu-Phe (f-MLP), or rgpIL-8 in 96-well chemotactic chambers. Neutrophils were also pre-stimulated with rgpIL-8 then restimulated with LPS (10 microg/ml) or infected in vitro with M. tuberculosis H37Ra (MOI 1:1). RESULTS Recombinant gpIL-8 and f-MLP induced significant chemotaxis in neutrophils from both non-vaccinated and BCG-vaccinated guinea pigs, with the best chemotaxis occurring at a concentration of 10(-7)M. Real-time PCR analysis revealed that pre-treatment of neutrophils induced elevated levels of IL-8 and TNF-alpha mRNA and protein as well as superoxide, but not mRNA for MCP-1, IFN-gamma, or TGF-beta when compared to neutrophils pre-stimulated with media alone. CONCLUSIONS The presence of IL-8 early in the host response to M. tuberculosis infection may be an important contributor to a successful immune response. How essential a role IL-8 plays remains unknown and merits further study.
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Affiliation(s)
- Mark J Lyons
- Department of Medical Microbiology and Immunology, Texas A&M University, System Health Science Center, Reynolds Medical Building Room 463, University Drive, College Station, TX 77843-1114, USA
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Chaffin MK, Cohen ND, Martens RJ, Edwards RF, Nevill M, Smith R. Hematologic and immunophenotypic factors associated with development of Rhodococcus equi pneumonia of foals at equine breeding farms with endemic infection. Vet Immunol Immunopathol 2004; 100:33-48. [PMID: 15182994 DOI: 10.1016/j.vetimm.2004.02.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2003] [Revised: 01/05/2004] [Accepted: 02/25/2004] [Indexed: 11/20/2022]
Abstract
Rhodococcus equi causes severe pyogranulomatous pneumonia in foals and in immunocompromised people. In mice, both CD4+ and CD8+ T lymphocytes contribute to host defense against R. equi, but CD4+ T lymphocytes are required for pulmonary clearance of the bacteria. In this prospective study of 208 foals at two equine breeding farms with endemic R. equi infections, we collected peripheral blood samples at 2 and 4 weeks of age and at the time of diagnosis of R. equi pneumonia. Samples were analyzed for concentrations of total and differential leukocytes, EqCD4+ and EqCD8+ T lymphocytes, and B lymphocytes. Thirty (14.4%) foals developed R. equi pneumonia. At the 2nd week of life, affected foals had significantly lower concentrations of white blood cells (WBC) and segmented neutrophils, significantly lower proportions of EqCD4+ T lymphocytes, and significantly higher proportions of EqCD8+ T lymphocytes. The EqCD4:EqCD8 ratio was significantly lower for affected foals. At the 4th week of life, affected foals had significantly lower concentrations of segmented neutrophils and EqCD4+ T lymphocytes than did unaffected foals. The ratio of EqCD4:EqCD8 was significantly lower for affected foals. Two- and 4-week-old foals with ratios of EqCD4:EqCD8<3 were significantly more likely to develop R. equi pneumonia. There was a significant farm effect which diluted our statistical power to detect differences; however; after adjusting for the farm effect, 2-week-old foals with ratios of EqCD4:EqCD8<3 remained significantly more likely to develop R. equi pneumonia. There were no significant differences in immunophenotypic variables between affected foals (at the time of diagnosis) and age-matched control foals. These data suggest that there are hematologic and immunophenotypic differences between affected and unaffected foals during the first 2-4 weeks of life, prior to onset of clinical signs of R. equi pneumonia. These differences may represent important immunologic mechanisms associated with increased susceptibility of individual foals to infection with R. equi. Because there was considerable overlap between values for affected and unaffected foals, we cannot yet recommend immunophenotyping of foals at endemically-infected farms as a clinically useful screening tool to identify foals at increased risk of developing R. equi pneumonia.
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Affiliation(s)
- M Keith Chaffin
- Department of Large Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4475, USA.
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