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Rago F, Ahmed MY, Marinelli MA, Miller LM, Duray AM, Dresden BP, Constantinesco NJ, Sims PKF, Richwalls LJ, Kupul S, Kolls JK, Gopal R, Alcorn JF. CD209d/e are required for macrophage-mediated phagocytosis and activation during methicillin-resistant Staphylococcus aureus pulmonary host defense. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:703-713. [PMID: 40101753 PMCID: PMC12041778 DOI: 10.1093/jimmun/vkae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 12/20/2024] [Indexed: 03/20/2025]
Abstract
Staphylococcus aureus is a commensal and opportunist pathogen of the upper respiratory tract. The recognition of pathogen-associated molecular patterns through pattern-recognition receptors is crucial for eliminating microorganisms such as S. aureus. DC-SIGN (CD209) is a pattern-recognition receptor that binds to a broad range of pathogens, promoting phagocytosis. Here we aimed to study the role of mouse homologues of DC-SIGN, CD209d/e, in a methicillin-resistant S. aureus (MRSA) pulmonary infection model. CD209d/e-/- and wild-type C57BL/6 mice were infected with MRSA and inflammatory parameters were evaluated. CD209d/e-/- mice had delayed bacterial burden and mortality together with increased frequency of neutrophils and decreased dendritic cells in the lung compared with control mice. iNOS+ macrophages, and regulatory T cell frequency were decreased in the lungs of CD209d/e-/- mice. CD209d/e-/- mice had increased levels of inflammatory cytokines in the lungs, but levels of IL-12p40 were decreased. MRSA reduced expression of interferon-γ and pattern-recognition receptors in CD209d/e-/- mice. MRSA uptake by phagocytes was decreased in the lungs of CD209d/e-/- versus control mice. CD209d/e-/- bone marrow derived macrophages showed impaired MRSA uptake and killing. These data suggest that CD209d/e are essential receptors to control inflammation by activating macrophages leading to MRSA uptake and killing.
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Affiliation(s)
- Flavia Rago
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Mohamed Y Ahmed
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Michael A Marinelli
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Leigh M Miller
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
- Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Alexis M Duray
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
- Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Brooke P Dresden
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
- Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Nicholas J Constantinesco
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Peyton K F Sims
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Lacee J Richwalls
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Saran Kupul
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - Jay K Kolls
- Center for Translational Research in Infection & Inflammation, Tulane University School of Medicine, New Orleans, LA, United States
| | - Radha Gopal
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
| | - John F Alcorn
- Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
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2
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Cavaillon JM, Chaudry IH. Facing stress and inflammation: From the cell to the planet. World J Exp Med 2024; 14:96422. [PMID: 39713080 PMCID: PMC11551703 DOI: 10.5493/wjem.v14.i4.96422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/27/2024] [Accepted: 09/19/2024] [Indexed: 10/31/2024] Open
Abstract
As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.
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Affiliation(s)
| | - Irshad H Chaudry
- Department of Surgery, University of Alabama Birmingham, Birmingham, AL 35294, United States
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3
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Ru X, Chen S, Chen D, Shao Q, Shao W, Ye Q. Simulating the clinical manifestations and disease progression of human sepsis: A monobacterial injection approach for animal modeling. Virulence 2024; 15:2395835. [PMID: 39219264 PMCID: PMC11370922 DOI: 10.1080/21505594.2024.2395835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 08/08/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, with great clinical heterogeneity, high morbidity, and high mortality. At the same time, there are many kinds of infection sources, the pathophysiology is very complex, and the pathogenesis has not been fully elucidated. An ideal animal model of sepsis can accurately simulate clinical sepsis and promote the development of sepsis-related pathogenesis, treatment methods, and prognosis. The existing sepsis model still uses the previous Sepsis 2.0 modelling standard, which has some problems, such as many kinds of infection sources, poor repeatability, inability to take into account single-factor studies, and large differences from clinical sepsis patients. To solve these problems, this study established a new animal model of sepsis. The model uses intravenous tail injection of a single bacterial strain, simplifying the complexity of multibacterial infection, and effectively solving the above problems.
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Affiliation(s)
- Xuanwen Ru
- Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Simiao Chen
- Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Danlei Chen
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qingyi Shao
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenxia Shao
- Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qing Ye
- Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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4
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Cavaillon JM, Chousterman BG, Skirecki T. Compartmentalization of the inflammatory response during bacterial sepsis and severe COVID-19. JOURNAL OF INTENSIVE MEDICINE 2024; 4:326-340. [PMID: 39035623 PMCID: PMC11258514 DOI: 10.1016/j.jointm.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 01/04/2024] [Accepted: 01/06/2024] [Indexed: 07/23/2024]
Abstract
Acute infections cause local and systemic disorders which can lead in the most severe forms to multi-organ failure and eventually to death. The host response to infection encompasses a large spectrum of reactions with a concomitant activation of the so-called inflammatory response aimed at fighting the infectious agent and removing damaged tissues or cells, and the anti-inflammatory response aimed at controlling inflammation and initiating the healing process. Fine-tuning at the local and systemic levels is key to preventing local and remote injury due to immune system activation. Thus, during bacterial sepsis and Coronavirus disease 2019 (COVID-19), concomitant systemic and compartmentalized pro-inflammatory and compensatory anti-inflammatory responses are occurring. Immune cells (e.g., macrophages, neutrophils, natural killer cells, and T-lymphocytes), as well as endothelial cells, differ from one compartment to another and contribute to specific organ responses to sterile and microbial insult. Furthermore, tissue-specific microbiota influences the local and systemic response. A better understanding of the tissue-specific immune status, the organ immunity crosstalk, and the role of specific mediators during sepsis and COVID-19 can foster the development of more accurate biomarkers for better diagnosis and prognosis and help to define appropriate host-targeted treatments and vaccines in the context of precision medicine.
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Affiliation(s)
| | - Benjamin G. Chousterman
- Department of Anesthesia and Critical Care, Lariboisière University Hospital, DMU Parabol, APHP Nord, Paris, France
- Inserm U942, University of Paris, Paris, France
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
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5
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Zhou G, Zhang L, Shao S. The application of MARCO for immune regulation and treatment. Mol Biol Rep 2024; 51:246. [PMID: 38300385 DOI: 10.1007/s11033-023-09201-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/30/2023] [Indexed: 02/02/2024]
Abstract
Macrophage receptor with collagen structure (MARCO) is a member of scavenger receptor class A (SR-A) and shares structural and functional similarities with SR-A1. In recent years, many studies have shown that MARCO can trigger an immune response and has therapeutic potential as a target for immunotherapy. Studies have shown that alterations in MARCO expression following pathogen infection cause changes in the functions of innate and adaptive immune cells, including macrophages, dendritic cells, B cells, and T cells, affecting the body's immune response to invading pathogens; thus, MARCO plays a crucial role in triggering the immune response, bridging innate and adaptive immunity, and eliminating pathogens. This paper is a comprehensive summary of the recent research on MARCO. This review focuses on the multiple functions of MARCO, including adhesion, migration, phagocytosis, and cytokine secretion with special emphasis on the complex interactions between MARCO and various types of cells involved in the immune response, as well as possible immune-related mechanisms. In summary, in this review, we discuss the structure and function of MARCO and its role in the immune response and highlight the therapeutic potential of MARCO as a target for immunotherapy. We hope that this review provides a theoretical basis for future research on MARCO.
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Affiliation(s)
- Guiyuan Zhou
- Department of Histology and Embryology, Hebei Medical University, No. 361, Zhongshan East Road, Chang'an District, Shijiazhuang, 050017, China
| | - Lei Zhang
- Shijiazhuang Vocational College of City Economy, No. 12, Wenming Road, Economic and Technological Development Zone, Shijiazhuang, 050017, China.
| | - Suxia Shao
- Department of Histology and Embryology, Hebei Medical University, No. 361, Zhongshan East Road, Chang'an District, Shijiazhuang, 050017, China.
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6
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Warheit-Niemi HI, Edwards SJ, SenGupta S, Parent CA, Zhou X, O'Dwyer DN, Moore BB. Fibrotic lung disease inhibits innate immune responses to Staphylococcal pneumonia via impaired neutrophil and macrophage function. JCI Insight 2022; 7:152690. [PMID: 34990413 PMCID: PMC8876506 DOI: 10.1172/jci.insight.152690] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 01/05/2022] [Indexed: 11/30/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized patients with IPF. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like humans with IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared with uninfected fibrotic mice. We determine that fibrosis conferred a defect in MRSA clearance compared with nonfibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibited neutrophil intracellular killing of MRSA through impaired neutrophil elastase release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments of antimicrobial responses upon pulmonary fibrosis development, and our findings suggest a possible mechanism for why patients with IPF are at greater risk of morbidity and mortality related to infection.
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Affiliation(s)
- Helen I Warheit-Niemi
- Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, United States of America
| | - Summer J Edwards
- Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, United States of America
| | - Shuvasree SenGupta
- Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
| | - Carole A Parent
- Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
| | - Xiaofeng Zhou
- Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, United States of America
| | - David N O'Dwyer
- The University of Michigan Medical School, Ann Arbor, United States of America
| | - Bethany B Moore
- Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, United States of America
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Uddin MB, Sajib EH, Hoque SF, Hassan MM, Ahmed SSU. Macrophages in respiratory system. RECENT ADVANCEMENTS IN MICROBIAL DIVERSITY 2022:299-333. [DOI: 10.1016/b978-0-12-822368-0.00014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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Pidwill GR, Gibson JF, Cole J, Renshaw SA, Foster SJ. The Role of Macrophages in Staphylococcus aureus Infection. Front Immunol 2021; 11:620339. [PMID: 33542723 PMCID: PMC7850989 DOI: 10.3389/fimmu.2020.620339] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/02/2020] [Indexed: 12/23/2022] Open
Abstract
Staphylococcus aureus is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of serious diseases. This requires an ability to circumvent the innate immune system to establish an infection. Professional phagocytes, primarily macrophages and neutrophils, are key innate immune cells which interact with S. aureus, acting as gatekeepers to contain and resolve infection. Recent studies have highlighted the important roles of macrophages during S. aureus infections, using a wide array of killing mechanisms. In defense, S. aureus has evolved multiple strategies to survive within, manipulate and escape from macrophages, allowing them to not only subvert but also exploit this key element of our immune system. Macrophage-S. aureus interactions are multifaceted and have direct roles in infection outcome. In depth understanding of these host-pathogen interactions may be useful for future therapeutic developments. This review examines macrophage interactions with S. aureus throughout all stages of infection, with special emphasis on mechanisms that determine infection outcome.
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Affiliation(s)
- Grace R. Pidwill
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
| | - Josie F. Gibson
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- The Bateson Centre, University of Sheffield, Sheffield, United Kingdom
| | - Joby Cole
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Stephen A. Renshaw
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
- The Bateson Centre, University of Sheffield, Sheffield, United Kingdom
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Simon J. Foster
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
- Florey Institute, University of Sheffield, Sheffield, United Kingdom
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Mirzaei R, Ranjbar R, Karampoor S, Goodarzi R, Hasanvand H. The Human Immune System toward Staphylococcus aureus. Open Microbiol J 2020; 14:164-170. [DOI: 10.2174/1874285802014010164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 01/10/2023] Open
Abstract
The immune system is responsible for protecting the host from pathogens, and it has evolved to deal with these pathogens. On the other hand, the co-evolution of pathogenic bacteria with hosts has led to the rise of an array of virulence genes that enable pathogen bacteria to evade or modulate the immune system.Staphylococcus aureusis a significant pathogen of humans that encodes several virulence factors that can modulate or evade from the innate and adaptive arm of the immune system. Overall, the immune reaction towardS. aureuscontributes to stimulate innate and adaptive reactions. A profound understanding of the immune response toS. aureusinfections will be critical for the development of vaccines and novel therapies. In this review, we summarized and discussed the novel information about the human immune system againstS. aureus.
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10
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Watkins KE, Unnikrishnan M. Evasion of host defenses by intracellular Staphylococcus aureus. ADVANCES IN APPLIED MICROBIOLOGY 2020; 112:105-141. [PMID: 32762866 DOI: 10.1016/bs.aambs.2020.05.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Staphylococcus aureus is one of the leading causes of hospital and community-acquired infections worldwide. The increasing occurrence of antibiotic resistant strains and the high rates of recurrent staphylococcal infections have placed several treatment challenges on healthcare systems. In recent years, it has become evident that S. aureus is a facultative intracellular pathogen, able to invade and survive in a range of cell types. The ability to survive intracellularly provides this pathogen with yet another way to evade antibiotics and immune responses during infection. Intracellular S. aureus have been strongly linked to several recurrent infections, including severe bone infections and septicemias. S. aureus is armed with an array of virulence factors as well as an intricate network of regulators that enable it to survive, replicate and escape from a number of immune and nonimmune host cells. It is able to successfully manipulate host cell pathways and use it as a niche to multiply, disseminate, as well as persist during an infection. This bacterium is also known to adapt to the intracellular environment by forming small colony variants, which are metabolically inactive. In this review we will discuss the clinical evidence, the molecular pathways involved in S. aureus intracellular persistence, and new treatment strategies for targeting intracellular S. aureus.
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11
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Zingarelli B, Coopersmith CM, Drechsler S, Efron P, Marshall JC, Moldawer L, Wiersinga WJ, Xiao X, Osuchowski MF, Thiemermann C. Part I: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Study Design and Humane Modeling Endpoints. Shock 2019; 51:10-22. [PMID: 30106874 PMCID: PMC6296871 DOI: 10.1097/shk.0000000000001243] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Preclinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on preclinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. Part I of this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all preclinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.
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Affiliation(s)
- Basilia Zingarelli
- Department of Pediatrics, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio
| | | | - Susanne Drechsler
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Philip Efron
- Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, Florida
| | - John C Marshall
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Lyle Moldawer
- Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, Florida
| | - W Joost Wiersinga
- Division of Infectious Diseases, Center for Experimental and Molecular Medicine, The Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Xianzhong Xiao
- Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China
| | - Marcin F Osuchowski
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Christoph Thiemermann
- The William Harvey Research Institute, Barts and London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
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Skerrett SJ, Braff MH, Liggitt HD, Rubens CE. Toll-like receptor 2 has a prominent but nonessential role in innate immunity to Staphylococcus aureus pneumonia. Physiol Rep 2018; 5:5/21/e13491. [PMID: 29142002 PMCID: PMC5688782 DOI: 10.14814/phy2.13491] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/08/2017] [Accepted: 10/11/2017] [Indexed: 11/30/2022] Open
Abstract
Staphylococcus aureus is an important cause of acute bacterial pneumonia. Toll‐like receptor 2 (TLR2) recognizes multiple components of the bacterial cell wall and activates innate immune responses to gram‐positive bacteria. We hypothesized that TLR2 would have an important role in pulmonary host defense against S. aureus. TLR null (TLR2−/−) mice and wild type (WT) C57BL/6 controls were challenged with aerosolized S. aureus at a range of inocula for kinetic studies of cytokine and antimicrobial peptide expression, lung inflammation, bacterial killing by alveolar macrophages, and bacterial clearance. Survival was measured after intranasal infection. Pulmonary induction of most pro‐inflammatory cytokines was significantly blunted in TLR2−/− mice 4 and 24 h after infection in comparison with WT controls. Bronchoalveolar concentrations of cathelicidin‐related antimicrobial peptide also were reduced in TLR2−/− mice. Lung inflammation, measured by enumeration of bronchoalveolar neutrophils and scoring of histological sections, was significantly blunted in TLR2−/− mice. Phagocytosis of S. aureus by alveolar macrophages in vivo after low‐dose infection was unimpaired, but viability of ingested bacteria was significantly greater in TLR2−/− mice. Bacterial clearance from the lungs was slightly impaired in TLR2−/− mice after low‐dose infection only; bacterial elimination from the lungs was slightly accelerated in the TLR2−/− mice after high‐dose infection. Survival after high‐dose intranasal challenge was 50–60% in both groups. TLR2 has a significant role in early innate immune responses to S. aureus in the lungs but is not required for bacterial clearance and survival from S. aureus pneumonia.
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Affiliation(s)
- Shawn J Skerrett
- Department of Medicine, University of Washington, Seattle, Washington
| | - Marissa H Braff
- Seattle Children's Hospital Research Institute, Seattle, Washington
| | - H Denny Liggitt
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Craig E Rubens
- Seattle Children's Hospital Research Institute, Seattle, Washington
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13
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Targeting CD36 as Biomarker for Metastasis Prognostic: How Far from Translation into Clinical Practice? BIOMED RESEARCH INTERNATIONAL 2018; 2018:7801202. [PMID: 30069479 PMCID: PMC6057354 DOI: 10.1155/2018/7801202] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 05/21/2018] [Indexed: 12/15/2022]
Abstract
Metastasis requires cellular changes related to cell-to-cell and cell-to-matrix adhesion, immune surveillance, activation of growth and survival signalling pathways, and epigenetic modifications. In addition to tumour cells, tumour stroma is also modified in relationship to the primary tumour as well as to distant metastatic sites (forming a metastatic niche). A common denominator of most stromal partners in tumour progression is CD36, a scavenger receptor for fatty acid uptake that modulates cell-to-extracellular matrix attachment, stromal cell fate (for adipocytes, endothelial cells), TGFβ activation, and immune signalling. CD36 has been repeatedly proposed as a prognostic marker in various cancers, mostly of epithelial origin (breast, prostate, ovary, and colon) and also for hepatic carcinoma and gliomas. Data gathered in preclinical models of various cancers have shown that blocking CD36 might prove beneficial in stopping metastasis spread. However, targeting the receptor in clinical trials with thrombospondin mimetic peptides has proven ineffective, and monoclonal antibodies are not yet available for patient use. This review presents data to support CD36 as a potential prognostic biomarker in cancer, its current stage towards achieving bona fide biomarker status, and knowledge gaps that must be filled before further advancement towards clinical practice.
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Abstract
Like many other pathological infectious processes, sepsis is mainly studied in vivo using mice models. Over the past 30 years, such studies have led to significant achievements in understanding of the sepsis pathophysiology. However, unfortunately, none of them led to any «discoveries» in the treatment of patients. In this review, we question the relevance of the experimental models applied, list some aspects rarely taken into account and discuss ways to resolve the deadlock.The text is a translation of the article: Cavail-lon J. M. New methods of treating sepsis: failure of animal models, Bull. Assoc. Anc. El. Inst. Pastor, 2017, 59,230, 58—60. Translation from French by «Akademperevod», Moscow, Russia.
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15
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Brandt SL, Putnam NE, Cassat JE, Serezani CH. Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 200:3871-3880. [PMID: 29866769 PMCID: PMC6028009 DOI: 10.4049/jimmunol.1701574] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 03/12/2018] [Indexed: 01/18/2023]
Abstract
Staphylococcus aureus causes a wide range of diseases that together embody a significant public health burden. Aided by metabolic flexibility and a large virulence repertoire, S. aureus has the remarkable ability to hematogenously disseminate and infect various tissues, including skin, lung, heart, and bone, among others. The hallmark lesions of invasive staphylococcal infections, abscesses, simultaneously denote the powerful innate immune responses to tissue invasion as well as the ability of staphylococci to persist within these lesions. In this article, we review the innate immune responses to S. aureus during infection of skin and bone, which serve as paradigms for soft tissue and bone disease, respectively.
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Affiliation(s)
- Stephanie L Brandt
- Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Nicole E Putnam
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - James E Cassat
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
- Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232; and
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232
| | - C Henrique Serezani
- Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
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16
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Rasid O, Cavaillon JM. Compartment diversity in innate immune reprogramming. Microbes Infect 2018; 20:156-165. [PMID: 29287986 DOI: 10.1016/j.micinf.2017.12.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/11/2017] [Indexed: 02/07/2023]
Abstract
Pathogens or endogenous molecules can reprogram innate immunity. This process can take the form of priming or tolerance depending on the activating signal, and favors enhanced resistance to infection and other insults, by modulating inflammation. Similarly to their organ-specific properties, reprogramming of macrophages and NK cells, is also compartmentalized.
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Affiliation(s)
- Orhan Rasid
- Chromatin and Infection, Institut Pasteur, Paris, France
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17
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Abstract
The hydrophobicity of vitamin E poses transport and metabolic challenges to regulate its bioavailability and to prevent its accumulation in lipid-rich tissues such as adipose tissue, brain, and liver. Water-soluble precursors of vitamin E (α-tocopherol, αT), such as its esters with acetate (αTA), succinate (αTS), or phosphate (αTP), have increased solubility in water and stability against reaction with free radicals, but they are rapidly converted during their uptake into the lipid-soluble vitamin E. Therefore, the bioavailability of these precursors as intact molecules is low; nevertheless, at least for αTS and αTP, the recent research has revealed unique regulatory effects on signal transduction and gene expression and the modulation of cellular events ranging from proliferation, survival/apoptosis, lipid uptake and metabolism, phagocytosis, long term potentiation, cell migration, telomere maintenance, and angiogenesis. Moreover, water-soluble derivatives of vitamin E including some based on αTP are increasingly used as components of nanocarriers for enhanced and targeted delivery of drugs and other molecules (vitamins, including αT and αTP itself, vitamin D3, carnosine, caffeine, docosahexaenoic acid (DHA), insulin) and cofactors such as coenzyme Q10. In this review, the chemical characteristics, transport, metabolic pathways, and molecular mechanisms of action of αTP in cells and tissues are summarized and put into perspective with its possible role in the prevention of a number of diseases.
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Affiliation(s)
- Jean-Marc Zingg
- Miller School of Medicine, University of Miami, Miami, FL, United States.
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18
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Zou B, Jiang W, Han H, Li J, Mao W, Tang Z, Yang Q, Qian G, Qian J, Zeng W, Gu J, Chu T, Zhu N, Zhang W, Yan D, He R, Chu Y, Lu M. Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury. PLoS Pathog 2017. [PMID: 28622363 PMCID: PMC5489216 DOI: 10.1371/journal.ppat.1006436] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection.
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Affiliation(s)
- Benkun Zou
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Wei Jiang
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Han Han
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing Li
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Weiying Mao
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Zihui Tang
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Qian Yang
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Guojun Qian
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Jing Qian
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Wenjiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jie Gu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianqing Chu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ning Zhu
- Departments of Infectious Diseases and Pulmonary Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Departments of Infectious Diseases and Pulmonary Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Dapeng Yan
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Rui He
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
| | - Mingfang Lu
- Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China
- * E-mail:
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19
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Zingg JM, Azzi A, Meydani M. α-Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP-1 Monocytes. J Cell Biochem 2017; 118:1855-1867. [PMID: 28059487 DOI: 10.1002/jcb.25871] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 01/05/2017] [Indexed: 12/20/2022]
Abstract
The CD36 scavenger receptor binds several ligands and mediates ligand uptake and ligand-dependent signal transduction and gene expression, events that may involve CD36 internalization. Here we show that CD36 internalization in THP-1 monocytes is triggered by α-tocopherol (αT) and more strongly by α-tocopheryl phosphate (αTP) and EPC-K1, a phosphate diester of αTP and L-ascorbic acid. αTP-triggered CD36 internalization is prevented by the specific covalent inhibitor of selective lipid transport by CD36, sulfo-N-succinimidyl oleate (SSO). Moreover, SSO inhibited the CD36-mediated uptake of 14C-labelled αTP suggesting that αTP binding and internalization of CD36 is involved in cellular αTP uptake, whereas the uptake of αT was less affected. Similar to that, inhibition of selective lipid transport of the SR-BI scavenger receptor resulted mainly in reduction of αTP and not αT uptake. In contrast, uptake of αT was mainly inhibited by Dynasore, an inhibitor of clathrin-mediated endocytosis, suggesting that the differential regulatory effects of αTP and αT on signaling may be influenced by their different routes of uptake. Interestingly, αTP and EPC-K1 also reduced the neutral lipid content of THP-1 cells and the phagocytosis of fluorescent Staphylococcus aureus bioparticles. Moreover, induction of the vascular endothelial growth factor (VEGF) promoter activity by αTP occurred via CD36/PI3Kγ/Akt, as it could be inhibited by specific inhibitors of this pathway (SSO, Wortmannin, AS-605240). These results suggest that αTP activates PI3Kγ/Akt signaling leading to VEGF expression in monocytes after binding to and/or transport by CD36, a receptor known to modulate angiogenesis in response to amyloid beta, oxLDL, and thrombospondin. J. Cell. Biochem. 118: 1855-1867, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Jean-Marc Zingg
- Vascular Biology Laboratory, JM USDA-Human Nutr. Res. Ctr. on Aging, Tufts University, Boston, Massachusetts 02111
| | - Angelo Azzi
- Vascular Biology Laboratory, JM USDA-Human Nutr. Res. Ctr. on Aging, Tufts University, Boston, Massachusetts 02111
| | - Mohsen Meydani
- Vascular Biology Laboratory, JM USDA-Human Nutr. Res. Ctr. on Aging, Tufts University, Boston, Massachusetts 02111
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20
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Peruń A, Biedroń R, Konopiński MK, Białecka A, Marcinkiewicz J, Józefowski S. Phagocytosis of live versus killed or fluorescently labeled bacteria by macrophages differ in both magnitude and receptor specificity. Immunol Cell Biol 2016; 95:424-435. [PMID: 27826145 DOI: 10.1038/icb.2016.112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/03/2016] [Accepted: 11/03/2016] [Indexed: 01/23/2023]
Abstract
Scavenger receptor (SR)-mediated opsonin-independent phagocytosis of bacteria by macrophages has been suggested to represent an important, early mechanism of anti-bacterial host defense. However, although the ability to bind bacteria has been demonstrated to be a shared feature of all types of SRs, in many cases the evidence is limited to the demonstration of increased binding of killed, fluorescently labeled bacteria to non-phagocytic cells transfected with these receptors. We sought to verify the ability of SRs to mediate non-opsonic phagocytosis of live Escherichia coli (Ec) and Staphylococcus aureus (Sa), model species of Gram-negative and -positive bacteria, respectively, and to assess the relative contributions of different SRs expressed on murine macrophages in this process. We found that the class A SR SR-A/CD204 was the major receptor mediating phagocytosis of fluorescently labeled Sa, whereas different SRs had highly redundant roles in the phagocytosis of live Sa. Conversely, different SRs contributed to the phagocytosis of fluorescently labeled Ec. In comparison, phagocytosis of live Ec was of much lower magnitude and was selectively mediated by SR-A. These results question the use of fluorescently labeled bacteria as valid replacements for live bacteria. The low magnitude of opsonin-independent phagocytosis of Ec and unimpaired phagocytosis of Sa in SR-A- or CD36-deficient macrophages indicate that the defect in this process might not be responsible for the reported impaired bacteria clearance in mice deficient in these receptors. We postulate that this impairment might result to a larger extent from inhibition of intracellular bacteria killing caused by pro-inflammatory cytokines, produced in excessive amounts by SR-deficient cells in response to bacterial products.
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Affiliation(s)
- Angelika Peruń
- Department of Immunology, Jagiellonian University Medical College, Cracow, Poland
| | - Rafał Biedroń
- Department of Immunology, Jagiellonian University Medical College, Cracow, Poland
| | - Maciej K Konopiński
- Institute of Nature Conservation, Polish Academy of Sciences, Cracow, Poland
| | - Anna Białecka
- Centre of Microbiological Research and Autovaccines, Cracow, Poland
| | - Janusz Marcinkiewicz
- Department of Immunology, Jagiellonian University Medical College, Cracow, Poland
| | - Szczepan Józefowski
- Department of Immunology, Jagiellonian University Medical College, Cracow, Poland
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21
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Dodd CE, Pyle CJ, Glowinski R, Rajaram MVS, Schlesinger LS. CD36-Mediated Uptake of Surfactant Lipids by Human Macrophages Promotes Intracellular Growth of Mycobacterium tuberculosis. THE JOURNAL OF IMMUNOLOGY 2016; 197:4727-4735. [PMID: 27913648 DOI: 10.4049/jimmunol.1600856] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 10/19/2016] [Indexed: 12/22/2022]
Abstract
Mycobacterium tuberculosis imposes a large global health burden as the airborne agent of tuberculosis. Mycobacterium tuberculosis has been flourishing in human populations for millennia and is therefore highly adapted to the lung environment. Alveolar macrophages, a major host cell niche for M. tuberculosis, are not only phagocytose inhaled microbes and particulate matter but are also crucial in catabolizing lung surfactant, a lipid-protein complex that lines the alveolar spaces. Because macrophage host defense properties can be regulated by surfactant and M. tuberculosis can use host lipids as a carbon source during infection, we sought to determine the receptor(s) involved in surfactant lipid uptake by human macrophages and whether the presence of those lipids within macrophages prior to infection with M. tuberculosis enhances bacterial growth. We show that preformed scavenger receptor CD36 is redistributed to the cell membrane following exposure to surfactant lipids and surfactant protein A. Subsequently, surfactant lipids and/or surfactant protein A enhance CD36 transcript and protein levels. We show that CD36 participates in surfactant lipid uptake by human macrophages, as CD36 knockdown reduces uptake of dipalmitoylphosphatidylcholine, the most prevalent surfactant lipid species. Finally, exposing human macrophages to surfactant lipids prior to infection augments M. tuberculosis growth in a CD36-dependent manner. Thus, we provide evidence that CD36 mediates surfactant lipid uptake by human macrophages and that M. tuberculosis exploits this function for growth.
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Affiliation(s)
- Claire E Dodd
- Department of Microbiology, The Ohio State University, Columbus, OH 43210; and.,The Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
| | - Charlie J Pyle
- The Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
| | - Rebecca Glowinski
- The Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
| | - Murugesan V S Rajaram
- The Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
| | - Larry S Schlesinger
- Department of Microbiology, The Ohio State University, Columbus, OH 43210; and .,The Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
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22
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Georgitsi MD, Vitoros V, Panou C, Tsangaris I, Aimoniotou E, Gatselis NK, Chasou E, Kouliatsis G, Leventogiannis K, Velissaris D, Belesiotou E, Dioritou-Aggaliadou O, Giannitsioti E, Netea MG, Giamarellos-Bourboulis EJ, Giannikopoulos G, Alexiou Z, Voloudakis N, Koutsoukou A. Individualized significance of the -251 A/T single nucleotide polymorphism of interleukin-8 in severe infections. Eur J Clin Microbiol Infect Dis 2016; 35:563-70. [PMID: 26768584 DOI: 10.1007/s10096-015-2571-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 12/28/2015] [Indexed: 12/29/2022]
Abstract
Based on the concept of the individualized nature of sepsis, we investigated the significance of the -251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8.
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Affiliation(s)
- M D Georgitsi
- 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece
| | - V Vitoros
- 1st Department of Internal Medicine, Thriasion Elefsis General Hospital, Elefsis, Greece
| | - C Panou
- Department of Urology, Lamia General Hospital, Lamia, Greece
| | - I Tsangaris
- 2nd Department of Critical Care Medicine, University of Athens, Medical School, Athens, Greece
| | - E Aimoniotou
- Intensive Care Unit, Aghios Dimitrios General Hospital, Thessaloniki, Greece
| | - N K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - E Chasou
- Intensive Care Unit, "G.Gennimatas" General Hospital, Thessaloniki, Greece
| | - G Kouliatsis
- Department of Critical Care Medicine, University of Thrace, Medical School, Alexandroupolis, Greece
| | - K Leventogiannis
- 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece
| | - D Velissaris
- Department of Internal Medicine, University of Patras, Patras, Greece
| | - E Belesiotou
- Department of Clinical Microbiology, Evangelismos General Hospital, Athens, Greece
| | | | - E Giannitsioti
- 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece
| | - M G Netea
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - E J Giamarellos-Bourboulis
- 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.
- 4th Department of Internal Medicine, ATTIKON University General Hospital, 1 Rimini Street, 12462, Athens, Greece.
| | - G Giannikopoulos
- Department of Internal Medicine, Chios General Hospital, Chios, Greece
| | - Z Alexiou
- 2nd Department of Internal Medicine, Thriasion Elefsis General Hospital, Elefsis, Greece
| | - N Voloudakis
- 2nd Department of Surgery, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - A Koutsoukou
- 1st Department of Respiratory Medicine, University of Athens, Medical School, Athens, Greece
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23
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Rasid O, Cavaillon JM. Recent developments in severe sepsis research: from bench to bedside and back. Future Microbiol 2016; 11:293-314. [PMID: 26849633 DOI: 10.2217/fmb.15.133] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Severe sepsis remains a worldwide threat, not only in industrialized countries, due to their aging population, but also in developing countries where there still are numerous cases of neonatal and puerperal sepsis. Tools for early diagnosis, a prerequisite for rapid and appropriate antibiotic therapy, are still required. In this review, we highlight some recent developments in our understanding of the associated systemic inflammatory response that help deciphering pathophysiology (e.g., epigenetic, miRNA, regulatory loops, compartmentalization, apoptosis and synergy) and discuss some of the consequences of sepsis (e.g., immune status, neurological and muscular alterations). We also emphasize the challenge to better define animal models and discuss past failures in clinical investigations in order to define new efficient therapies.
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Affiliation(s)
- Orhan Rasid
- Unit Cytokines & Inflammation, Institut Pasteur, 28 rue Dr. Roux, Paris, France
| | - Jean-Marc Cavaillon
- Unit Cytokines & Inflammation, Institut Pasteur, 28 rue Dr. Roux, Paris, France
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24
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Depke M, Michalik S, Rabe A, Surmann K, Brinkmann L, Jehmlich N, Bernhardt J, Hecker M, Wollscheid B, Sun Z, Moritz RL, Völker U, Schmidt F. A peptide resource for the analysis of Staphylococcus aureus in host-pathogen interaction studies. Proteomics 2015. [PMID: 26224020 DOI: 10.1002/pmic.201500091] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Staphylococcus aureus is an opportunistic human pathogen, which can cause life-threatening disease. Proteome analyses of the bacterium can provide new insights into its pathophysiology and important facets of metabolic adaptation and, thus, aid the recognition of targets for intervention. However, the value of such proteome studies increases with their comprehensiveness. We present an MS-driven, proteome-wide characterization of the strain S. aureus HG001. Combining 144 high precision proteomic data sets, we identified 19 109 peptides from 2088 distinct S. aureus HG001 proteins, which account for 72% of the predicted ORFs. Peptides were further characterized concerning pI, GRAVY, and detectability scores in order to understand the low peptide coverage of 8.7% (19 109 out of 220 245 theoretical peptides). The high quality peptide-centric spectra have been organized into a comprehensive peptide fragmentation library (SpectraST) and used for identification of S. aureus-typic peptides in highly complex host-pathogen interaction experiments, which significantly improved the number of identified S. aureus proteins compared to a MASCOT search. This effort now allows the elucidation of crucial pathophysiological questions in S. aureus-specific host-pathogen interaction studies through comprehensive proteome analysis. The S. aureus-specific spectra resource developed here also represents an important spectral repository for SRM or for data-independent acquisition MS approaches. All MS data have been deposited in the ProteomeXchange with identifier PXD000702 (http://proteomecentral.proteomexchange.org/dataset/PXD000702).
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Affiliation(s)
- Maren Depke
- ZIK-FunGene Junior Research Group "Applied Proteomics", Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Stephan Michalik
- ZIK-FunGene Junior Research Group "Applied Proteomics", Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Alexander Rabe
- ZIK-FunGene Junior Research Group "Applied Proteomics", Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Kristin Surmann
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Lars Brinkmann
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Nico Jehmlich
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Jörg Bernhardt
- Institute for Microbiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
| | - Michael Hecker
- Institute for Microbiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
| | - Bernd Wollscheid
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Zhi Sun
- Institute for Systems Biology (ISB), Seattle, WA, USA
| | | | - Uwe Völker
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Frank Schmidt
- ZIK-FunGene Junior Research Group "Applied Proteomics", Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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25
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Wang W, Liu R, Zhang T, Zhang R, Song X, Wang L, Song L. A novel phagocytic receptor (CgNimC) from Pacific oyster Crassostrea gigas with lipopolysaccharide and gram-negative bacteria binding activity. FISH & SHELLFISH IMMUNOLOGY 2015; 43:103-110. [PMID: 25541078 DOI: 10.1016/j.fsi.2014.12.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 12/01/2014] [Accepted: 12/15/2014] [Indexed: 06/04/2023]
Abstract
Phagocytosis is an evolutionarily conserved process to ingest the invading microbes and apoptotic or necrotic corpses, playing vital roles in defensing invaders and maintenance of normal physiological conditions. In the present study, a new Nimrod family phagocytic receptor with three EGF-like domains was identified in Pacific oyster Crassostrea gigas (designated CgNimC). CgNimC shared homology with other identified multiple EGF-like domain containing proteins. The mRNA transcripts of CgNimC were mainly distributed in mantle and hemocytes. Its relative expression level in hemocytes was significantly (P < 0.01) up-regulated after the injection of bacteria Vibrio anguillarum. Different to the NimC in Drosophila and Anopheles gambiae, the recombinant protein of CgNimC (rCgNimC) could bind directly to two gram-negative bacteria V. anguillarum and Vibrio splendidus, but not to gram-positive bacteria Staphylococci aureus, Micrococcus luteus or fungi Yarrowia lipolytica and Pichia pastoris. The affinity of rCgNimC toward M. luteus and Y. lipolytica was enhanced when the microorganisms were pre-incubated with the cell free hemolymph. rCgNimC exhibited higher affinity to lipopolysaccharide (LPS) and relatively lower affinity to peptidoglycan (PGN), while no affinity to glucan (GLU). After the CgNimC receptor was blocked by anti-rCgNimC antibody in vitro, the phagocytic rate of hemocytes toward two gram-negative bacteria V. anguillarum and V. splendidus was reduced significantly (P < 0.05), but no significant change of phagocytic rate was observed toward M. luteus and Y. lipolytica. All these results implied that CgNimC, with significant binding capability to LPS and gram-negative bacteria, was a novel phagocytic receptor involved in immune response of Pacific oyster. Further, it was speculated that receptors of Nimrod family might function as a phagocytic receptor to recognize PAMPs on the invaders and its recognition could be promoted by opsonization of molecules in hemolymph.
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Affiliation(s)
- Weilin Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Rui Liu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Tao Zhang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ran Zhang
- Ningbo University, Ningbo 315211, China
| | - Xuan Song
- SUN YAT-SEN University, Guangzhou 510275, China
| | - Lingling Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
| | - Linsheng Song
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
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26
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27
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Cole J, Aberdein J, Jubrail J, Dockrell DH. The role of macrophages in the innate immune response to Streptococcus pneumoniae and Staphylococcus aureus: mechanisms and contrasts. Adv Microb Physiol 2014; 65:125-202. [PMID: 25476766 DOI: 10.1016/bs.ampbs.2014.08.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Macrophages are critical mediators of innate immune responses against bacteria. The Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus aureus express a range of virulence factors, which challenge macrophages' immune competence. We review how macrophages respond to this challenge. Macrophages employ a range of strategies to phagocytose and kill each pathogen. When the macrophages capacity to clear bacteria is overwhelmed macrophages play important roles in orchestrating the inflammatory response through pattern recognition receptor-mediated responses. Macrophages also ensure the inflammatory response is tightly constrained, to avoid tissue damage, and play an important role in downregulating the inflammatory response once initial bacterial replication is controlled.
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Affiliation(s)
- Joby Cole
- Department of Infection and Immunity, University of Sheffield Medical School and Sheffield Teaching Hospitals, Sheffield, United Kingdom
| | - Jody Aberdein
- Department of Infection and Immunity, University of Sheffield Medical School and Sheffield Teaching Hospitals, Sheffield, United Kingdom
| | - Jamil Jubrail
- Department of Infection and Immunity, University of Sheffield Medical School and Sheffield Teaching Hospitals, Sheffield, United Kingdom
| | - David H Dockrell
- Department of Infection and Immunity, University of Sheffield Medical School and Sheffield Teaching Hospitals, Sheffield, United Kingdom.
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Werner JL, Steele C. Innate receptors and cellular defense against pulmonary infections. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 193:3842-50. [PMID: 25281754 PMCID: PMC4185409 DOI: 10.4049/jimmunol.1400978] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the United States, lung infections consistently rank in the top 10 leading causes of death, accounting for >50,000 deaths annually. Moreover, >140,000 deaths occur annually as a result of chronic lung diseases, some of which may be complicated by an infectious process. The lung is constantly exposed to the environment and is susceptible to infectious complications caused by bacterial, viral, fungal, and parasitic pathogens. Indeed, we are continually faced with the threat of morbidity and mortality associated with annual influenza virus infections, new respiratory viruses (e.g., SARS-CoV), and lung infections caused by antibiotic-resistant "ESKAPE pathogens" (three of which target the lung). This review highlights innate immune receptors and cell types that function to protect against infectious challenges to the respiratory system yet also may be associated with exacerbations in chronic lung diseases.
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Affiliation(s)
- Jessica L Werner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and
| | - Chad Steele
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
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BDCA1-positive dendritic cells (DCs) represent a unique human myeloid DC subset that induces innate and adaptive immune responses to Staphylococcus aureus Infection. Infect Immun 2014; 82:4466-76. [PMID: 25114114 DOI: 10.1128/iai.01851-14] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Staphylococcus aureus bloodstream infection (bacteremia) is a major cause of morbidity and mortality and places substantial cost burdens on health care systems. The role of peripheral blood dendritic cells (PBDCs) in the immune responses against S. aureus infection has not been well characterized. In this study, we demonstrated that BDCA1(+) myeloid DCs (mDCs) represent a unique PBDC subset that can induce immune responses against S. aureus infection. BDCA1(+) mDCs could engulf S. aureus and strongly upregulated the expression of costimulatory molecules and production of proinflammatory cytokines. Furthermore, BDCA1(+) mDCs expressed high levels of major histocompatibility complex (MHC) class I and II molecules in response to S. aureus and greatly promoted proliferation and gamma interferon (IFN-γ) production in CD4 and CD8 T cells. Moreover, BDCA1(+) mDCs expressed higher levels of Toll-like receptor 2 (TLR-2) and scavenger receptor A (SR-A) than those on CD16(+) and BDCA3(+) mDCs, and these two receptors were both required for the recognition of S. aureus and the subsequent activation of BDCA1(+) mDCs. Finally, BDCA1(+) mDC-mediated immune responses against S. aureus were dependent on MyD88 signaling pathways. These results demonstrate that human BDCA1(+) mDCs represent a unique subset of mDCs that can respond to S. aureus to undergo maturation and activation and to induce Th1 and Tc1 immune responses.
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Abstract
A relative immunosuppression is observed in patients after sepsis, trauma, burns, or any severe insults. It is currently proposed that selected patients will benefit from treatment aimed at boosting their immune systems. However, the host immune response needs to be considered in context with pathogen-type, timing,and mainly tissue specificity. Indeed, the immune status of leukocytes is not universally decreased and their activated status in tissues contributes to organ failure. Accordingly, any new immune-stimulatory therapeutic intervention should take into consideration potentially deleterious effects in some situations.
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Affiliation(s)
- Jean-Marc Cavaillon
- Unit Cytokines & Inflammation, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France
| | - Damon Eisen
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, 300 Grattan Street, Parkville 3050 Victoria, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victorian Infectious Diseases Service, Royal Melbourne Hospital, 300 Grattan Street, Parkville 3050 Victoria, Australia
| | - Djilalli Annane
- Intensive Care Unit, Hôpital Raymond Poincaré, 104, boulevard Raymond-Poincaré, 92380 Garches, France
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