|
1
|
Cerdeira CD, Brigagão MRPL. Targeting Macrophage Polarization in Infectious Diseases: M1/M2 Functional Profiles, Immune Signaling and Microbial Virulence Factors. Immunol Invest 2024; 53:1030-1091. [PMID: 38913937 DOI: 10.1080/08820139.2024.2367682] [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] [Indexed: 06/26/2024]
Abstract
INTRODUCTION An event of increasing interest during host-pathogen interactions is the polarization of patrolling/naive monocytes (MOs) into macrophage subsets (MФs). Therapeutic strategies aimed at modulating this event are under investigation. METHODS This review focuses on the mechanisms of induction/development and profile of MФs polarized toward classically proinflammatory (M1) or alternatively anti-inflammatory (M2) phenotypes in response to bacteria, fungi, parasites, and viruses. RESULTS AND DISCUSSION It highlights nuclear, cytoplasmic, and cell surface receptors (pattern recognition receptors/PPRs), microenvironmental mediators, and immune signaling. MФs polarize into phenotypes: M1 MФs, activated by IFN-γ, pathogen-associated molecular patterns (PAMPs, e.g. lipopolysaccharide) and membrane-bound PPRs ligands (TLRs/CLRs ligands); or M2 MФs, induced by interleukins (ILs-4, -10 and -13), antigen-antibody complexes, and helminth PAMPs. Polarization toward M1 and M2 profiles evolve in a pathogen-specific manner, with or without canonicity, and can vary widely. Ultimately, this can result in varying degrees of host protection or more severe disease outcome. On the one hand, the host is driving effective MФs polarization (M1 or M2); but on the other hand, microorganisms may skew the polarization through virulence factors to increase pathogenicity. Cellular/genomic reprogramming also ensures plasticity of M1/M2 phenotypes. Because modulation of polarization can occur at multiple points, new insights and emerging perspectives may have clinical implications during the inflammation-to-resolution transition; translated into practical applications as for therapeutic/vaccine design target to boost microbicidal response (M1, e.g. triggering oxidative burst) with specifics PAMPs/IFN-γ or promote tissue repair (M2, increasing arginase activity) via immunotherapy.
Collapse
|
|
2
|
Goughenour KD, Nair AS, Xu J, Olszewski MA, Wozniak KL. Dendritic Cells: Multifunctional Roles in Host Defenses to Cryptococcus Infections. J Fungi (Basel) 2023; 9:1050. [PMID: 37998856 PMCID: PMC10672120 DOI: 10.3390/jof9111050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/25/2023] Open
Abstract
Fungal infections are an increasingly growing public health concern, and Cryptococcus is one of the most problematic fungal organisms causing substantial mortality and morbidity worldwide. Clinically, this high incidence of cryptococcosis is most commonly seen in immunocompromised patients, especially those who lack an adaptive T cell response, such as HIV/AIDS patients. However, patients with other underlying immunodeficiencies are also at an increased risk for cryptococcosis. The adaptive immune response, in particular the Th1/Th17 T-cell-mediated responses, to pulmonary Cryptococcus infections are required for host protection. Dendritic cells (DCs), encompassing multiple subsets identified to date, are recognized as the major professional antigen-presenting cell (APC) subset essential for the initiation and execution of T-cell immunity. Apart from their prominent role in orchestration of the adaptive arm of the immune defenses, DCs are fully armed cells from the innate immune system capable of the recognition, uptake, and killing of the fungal cells. Thus, DCs serve as a critical point for the endpoint outcomes of either fungal control or unrestrained fungal infection. Multiple studies have shown that DCs are required for anti-cryptococcal defense in the lungs. In addition, the role of DCs in Cryptococcus gattii infections is just starting to be elucidated. C. gattii has recently risen to prominence with multiple outbreaks in the US and Canada, demonstrating increased virulence in non-immunocompromised individuals. C. gattii infection fails to generate an inflammatory immune response or a protective Th1/Th17 T cell response, at least in part, through a lack of proper DC function. Here we summarize the multiple roles of DCs, including subsets of DCs in both mouse and human models, the roles of DCs during cryptococcal infection, and mechanisms by cryptococcal cells to attempt to undermine these host defenses.
Collapse
Affiliation(s)
- Kristie D. Goughenour
- Research Service, Department of Veterans Affairs Health System, Ann Arbor VA Healthcare System, Ann Arbor, MI 48105, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| | - Ayesha S. Nair
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74078, USA
| | - Jintao Xu
- Research Service, Department of Veterans Affairs Health System, Ann Arbor VA Healthcare System, Ann Arbor, MI 48105, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| | - Michal A. Olszewski
- Research Service, Department of Veterans Affairs Health System, Ann Arbor VA Healthcare System, Ann Arbor, MI 48105, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| | - Karen L. Wozniak
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74078, USA
| |
Collapse
|
|
3
|
Conn BN, Wozniak KL. Innate Pulmonary Phagocytes and Their Interactions with Pathogenic Cryptococcus Species. J Fungi (Basel) 2023; 9:617. [PMID: 37367553 PMCID: PMC10299524 DOI: 10.3390/jof9060617] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that causes over 180,000 annual deaths in HIV/AIDS patients. Innate phagocytes in the lungs, such as dendritic cells (DCs) and macrophages, are the first cells to interact with the pathogen. Neutrophils, another innate phagocyte, are recruited to the lungs during cryptococcal infection. These innate cells are involved in early detection of C. neoformans, as well as the removal and clearance of cryptococcal infections. However, C. neoformans has developed ways to interfere with these processes, allowing for the evasion of the host's innate immune system. Additionally, the innate immune cells have the ability to aid in cryptococcal pathogenesis. This review discusses recent literature on the interactions of innate pulmonary phagocytes with C. neoformans.
Collapse
Affiliation(s)
| | - Karen L. Wozniak
- Department of Microbiology and Molecular Genetics, Oklahoma State University, 307 Life Science East, Stillwater, OK 74078, USA;
| |
Collapse
|
|
4
|
Pulmonary Fibrosis and Hypereosinophilia in TLR9-/- Mice Infected by Cryptococcus gattii. Pathogens 2022; 11:pathogens11090987. [PMID: 36145419 PMCID: PMC9505093 DOI: 10.3390/pathogens11090987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 11/20/2022] Open
Abstract
Cryptococcus gattii is a worldwide-distributed basidiomycetous yeast that can infect immunocompetent hosts. However, little is known about the mechanisms involved in the disease. The innate immune response is essential to the control of infections by microorganisms. Toll-like receptor 9 (TLR9) is an innate immune receptor, classically described as a non-methylated DNA recognizer and associated with bacteria, protozoa and opportunistic mycosis infection models. Previously, our group showed that TLR9-/- mice were more susceptible to C. gattii after 21 days of infection. However, some questions about the innate immunity involving TLR9 response against C. gattii remain unknown. In order to investigate the systemic cryptococcal infection, we evaluated C57BL/6 mice and C57BL/6 TLR9-/- after intratracheal infection with 104C. gattii yeasts for 21 days. Our data evidenced that TLR9-/- was more susceptible to C. gattii. TLR9-/- mice had hypereosinophilia in pulmonary mixed cellular infiltrate, severe bronchiolitis and vasculitis and type 2 alveolar cell hyperplasia. In addition, TLR9-/- mice developed severe pulmonary fibrosis and areas with strongly birefringent fibers. Together, our results corroborate the hypothesis that TLR9 is important to support the Th1/Th17 response against C. gattii infection in the murine experimental model.
Collapse
|
|
5
|
Berguson HP, Caulfield LW, Price MS. Influence of Pathogen Carbon Metabolism on Interactions With Host Immunity. Front Cell Infect Microbiol 2022; 12:861405. [PMID: 35372116 PMCID: PMC8968422 DOI: 10.3389/fcimb.2022.861405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/24/2022] [Indexed: 11/22/2022] Open
Abstract
Cryptococcus neoformans is a ubiquitous opportunistic fungal pathogen typically causing disease in immunocompromised individuals and is globally responsible for about 15% of AIDS-related deaths annually. C. neoformans first causes pulmonary infection in the host and then disseminates to the brain, causing meningoencephalitis. The yeast must obtain and metabolize carbon within the host in order to survive in the central nervous system and cause disease. Communication between pathogen and host involves recognition of multiple carbon-containing compounds on the yeast surface: polysaccharide capsule, fungal cell wall, and glycosylated proteins comprising the major immune modulators. The structure and function of polysaccharide capsule has been studied for the past 70 years, emphasizing its role in virulence. While protected by the capsule, fungal cell wall has likewise been a focus of study for several decades for its role in cell integrity and host recognition. Associated with both of these major structures are glycosylated proteins, which exhibit known immunomodulatory effects. While many studies have investigated the role of carbon metabolism on virulence and survival within the host, the precise mechanism(s) affecting host-pathogen communication remain ill-defined. This review summarizes the current knowledge on mutants in carbon metabolism and their effect on the host immune response that leads to changes in pathogen recognition and virulence. Understanding these critical interactions will provide fresh perspectives on potential treatments and the natural history of cryptococcal disease.
Collapse
Affiliation(s)
- Hannah P. Berguson
- Department of Anatomical Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States
| | - Lauren W. Caulfield
- Department of Biology and Chemistry, Liberty University, Lynchburg, VA, United States
| | - Michael S. Price
- Department of Molecular and Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States
- Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- *Correspondence: Michael S. Price,
| |
Collapse
|
|
6
|
Goughenour KD, Zhao J, Xu J, Zhao ZP, Ganguly A, Freeman CM, Olszewski MA. Murine Inducible Nitric Oxide Synthase Expression Is Essential for Antifungal Defenses in Kidneys during Disseminated Cryptococcus deneoformans Infection. THE JOURNAL OF IMMUNOLOGY 2021; 207:2096-2106. [PMID: 34479942 DOI: 10.4049/jimmunol.2100386] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/04/2021] [Indexed: 12/11/2022]
Abstract
Disseminated cryptococcosis has a nearly 70% mortality, mostly attributed to CNS infection, with lesser-known effects on other organs. Immune protection against Cryptococcus relies on Th1 immunity with M1 polarization, rendering macrophages fungicidal. The importance of M1-upregulated inducible NO synthase (iNOS) has been documented in pulmonary anticryptococcal defenses, whereas its role in disseminated cryptococcosis remains controversial. Here we examined the effect of iNOS deletion in disseminated (i.v.) C. deneoformans 52D infection, comparing wild-type (C57BL/6J) and iNOS-/- mice. iNOS-/- mice had significantly reduced survival and nearly 100-fold increase of the kidney fungal burden, without increases in the lungs, spleen, or brain. Histology revealed extensive lesions and almost complete destruction of the kidney cortical area with a loss of kidney function. The lack of fungal control was not due to a failure to recruit immune cells because iNOS-/- mice had increased kidney leukocytes. iNOS-/- mice also showed no defect in T cell polarization. We conclude that iNOS is critically required for local anticryptococcal defenses in the kidneys, whereas it appears to be dispensable in other organs during disseminated infection. This study exemplifies a unique phenotype of local immune defenses in the kidneys and the organ-specific importance of a single fungicidal pathway.
Collapse
Affiliation(s)
- Kristie D Goughenour
- Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| | - Jessica Zhao
- Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| | - Jintao Xu
- Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| | - Ziyin P Zhao
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| | - Anutosh Ganguly
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and.,Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Christine M Freeman
- Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| | - Michal A Olszewski
- Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI; .,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; and
| |
Collapse
|
|
7
|
Xu J, Ganguly A, Zhao J, Ivey M, Lopez R, Osterholzer JJ, Cho CS, Olszewski MA. CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis. mBio 2021; 12:e0107621. [PMID: 34311579 PMCID: PMC8406332 DOI: 10.1128/mbio.01076-21] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/25/2021] [Indexed: 12/21/2022] Open
Abstract
Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45hiCD11b+Ly6C+ inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4+ T cells and CD8+ T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4+ T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.
Collapse
Affiliation(s)
- Jintao Xu
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Anutosh Ganguly
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Jessica Zhao
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Michel Ivey
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
| | - Rafael Lopez
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
| | - John J. Osterholzer
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Clifford S. Cho
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Michal A. Olszewski
- Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| |
Collapse
|
|
8
|
da Silva-Junior EB, Firmino-Cruz L, Guimarães-de-Oliveira JC, De-Medeiros JVR, de Oliveira Nascimento D, Freire-de-Lima M, de Brito-Gitirana L, Morrot A, Previato JO, Mendonça-Previato L, Decote-Ricardo D, de Matos Guedes HL, Freire-de-Lima CG. The role of Toll-like receptor 9 in a murine model of Cryptococcus gattii infection. Sci Rep 2021; 11:1407. [PMID: 33446850 PMCID: PMC7809259 DOI: 10.1038/s41598-021-80959-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/31/2020] [Indexed: 02/07/2023] Open
Abstract
Toll-like receptor 9 (TLR9) is crucial to the host immune response against fungi, such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, but its importance in Cryptococcus gattii infection is unknown. Our study aimed to understand the role of TLR9 during the course of experimental C. gattii infection in vivo, considering that the cryptococcal DNA interaction with the receptor could contribute to host immunity even in an extremely susceptible model. We inoculated C57BL/6 (WT) and TLR9 knock-out (TLR9−/−) mice intratracheally with 104C. gattii yeast cells. TLR9−/− mice had a higher mortality rate compared to WT mice and more yeast cells that had abnormal size, known as titan cells, in the lungs. TLR9−/− mice also had a greater number of CFUs in the spleen and brain than WT mice, in addition to having lower levels of IFN-γ and IL-17 in the lung. With these markers of aggressive cryptococcosis, we can state that TLR9−/− mice are more susceptible to C. gattii, probably due to a mechanism associated with the decrease of a Th1 and Th17-type immune response that promotes the formation of titan cells in the lungs. Therefore, our results indicate the participation of TLR9 in murine resistance to C. gattii infection.
Collapse
Affiliation(s)
- Elias Barbosa da Silva-Junior
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Luan Firmino-Cruz
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil.,Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, 21045-900, Brazil
| | | | - Juliana Valente Rodrigues De-Medeiros
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil.,Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, 21045-900, Brazil
| | | | - Matheus Freire-de-Lima
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Lycia de Brito-Gitirana
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Alexandre Morrot
- Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, 21045-900, Brazil.,Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Jose Osvaldo Previato
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Lucia Mendonça-Previato
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil
| | - Debora Decote-Ricardo
- Instituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Seropédica, 23890-000, Brazil.
| | - Herbert Leonel de Matos Guedes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil. .,Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, 21045-900, Brazil.
| | - Celio Geraldo Freire-de-Lima
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-900, Brazil.
| |
Collapse
|
|
9
|
Dobashi-Okuyama K, Kawakami K, Miyasaka T, Sato K, Ishii K, Kawakami K, Masuda C, Suzuki S, Kasamatsu J, Yamamoto H, Tanno D, Kanno E, Tanno H, Kawano T, Takayanagi M, Takahashi T, Ohno I. Novel Toll-Like Receptor 9 Agonist Derived from Cryptococcus neoformans Attenuates Allergic Inflammation Leading to Asthma Onset in Mice. Int Arch Allergy Immunol 2020; 181:651-664. [PMID: 32585675 DOI: 10.1159/000508535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 04/22/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION The enhanced type 2 helper (Th2) immune response is responsible for the pathogenesis of allergic asthma. To suppress the enhanced Th2 immune response, activation of the Th1 immune response has been an alternative strategy for anti-asthma therapy. In this context, effective Th1-inducing adjuvants that inhibit the development of allergic asthma but do not flare the side effects of the primary agent are required in clinical treatment and preventive medicine. OBJECTIVE In this study, we aimed to determine the regulation of the Th2 type immune response in asthma by a novel immunostimulatory oligodeoxynucleotide (ODN) derived from Cryptococcus neoformans, termed ODN112, which contains a cytosine-guanine (CG) sequence but not canonical CpG motifs. METHODS Using an ovalbumin-induced asthma mouse model, we assessed the effect of ODN112 on prototypical asthma-related features in the lung and on the Th1/Th2 profile in the lymph nodes and lung of mice treated with ODN112 during sensitization. RESULTS AND CONCLUSION ODN112 treatment attenuated asthma features in mice. In the bronchial lymph nodes of the lungs and in the spleen, ODN112 increased interferon-γ production and attenuated Th2 recall responses. In dendritic cells (DCs) after allergen sensitization, ODN112 enhanced cluster of differentiation (CD) 40 and CD80 expression but did not alter CD86 expression. Interleukin-12p40 production from DCs was also increased in a Th2-polarizing condition. Our results suggest that ODN112 is a potential Th1-inducing adjuvant during Th2 cell differentiation in the sensitization phase.
Collapse
Affiliation(s)
- Kaori Dobashi-Okuyama
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomomitsu Miyasaka
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan,
| | - Ko Sato
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kaori Kawakami
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Chiaki Masuda
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Syugo Suzuki
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Kasamatsu
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Yamamoto
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Daiki Tanno
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tasuku Kawano
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Motoaki Takayanagi
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Tomoko Takahashi
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Isao Ohno
- Center for Medical Education, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| |
Collapse
|
|
10
|
Nelson BN, Hawkins AN, Wozniak KL. Pulmonary Macrophage and Dendritic Cell Responses to Cryptococcus neoformans. Front Cell Infect Microbiol 2020; 10:37. [PMID: 32117810 PMCID: PMC7026008 DOI: 10.3389/fcimb.2020.00037] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/20/2020] [Indexed: 12/12/2022] Open
Abstract
The fungal pathogen Cryptococcus neoformans can cause life-threatening infections in immune compromised individuals. This pathogen is typically acquired via inhalation, and enters the respiratory tract. Innate immune cells such as macrophages and dendritic cells (DCs) are the first host cells that encounter C. neoformans, and the interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease. Cryptococcus possesses several virulence factors and evasion strategies to prevent its killing and destruction by pulmonary phagocytes, but these phagocytic cells can also contribute to anti-cryptococcal responses. This review will focus on the interactions between Cryptococcus and primary macrophages and dendritic cells (DCs), dealing specifically with the cryptococcal/pulmonary cell interface.
Collapse
Affiliation(s)
- Benjamin N Nelson
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States
| | - Ashlee N Hawkins
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States
| | - Karen L Wozniak
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States
| |
Collapse
|
|
11
|
Rudman J, Evans RJ, Johnston SA. Are macrophages the heroes or villains during cryptococcosis? Fungal Genet Biol 2019; 132:103261. [DOI: 10.1016/j.fgb.2019.103261] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/06/2019] [Accepted: 08/06/2019] [Indexed: 10/26/2022]
|
|
12
|
Hazra I, Sk Md OF, Datta A, Mondal S, Moitra S, Singh MK, Chaudhuri S, Das PK, Basu AK, Dhar I, Basu N, Chaudhuri S. T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain. Scand J Immunol 2018; 89:e12733. [PMID: 30450625 DOI: 10.1111/sji.12733] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 10/10/2018] [Accepted: 11/12/2018] [Indexed: 12/16/2022]
Abstract
Cryptococcus neoformans, the encapsulated yeast acquired through inhalation, remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long-term usage of drugs leads to organ damage. As T11-target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C neoformans infection was prepared by intraperitoneal injection and the brains of rats examined 7 days post-infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on Cryptococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C neoformans infected rats, upregulates toll-like receptors 2, -4 and -9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T-lymphocytes along with increased MHC I and MHC II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease.
Collapse
Affiliation(s)
- Iman Hazra
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Omar Faruk Sk Md
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Ankur Datta
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Somnath Mondal
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Saibal Moitra
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Manoj Kumar Singh
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Suhnrita Chaudhuri
- Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Prasanta Kumar Das
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Anjan Kumar Basu
- Department of Biochemistry and Medical Biotechnology, School of Tropical Medicine, Kolkata, India
| | - Indranil Dhar
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| | - Nandita Basu
- Department of Pathology, School of Tropical Medicine, Kolkata, India
| | - Swapna Chaudhuri
- Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, India
| |
Collapse
|
|
13
|
Brunet K, Alanio A, Lortholary O, Rammaert B. Reactivation of dormant/latent fungal infection. J Infect 2018; 77:463-468. [DOI: 10.1016/j.jinf.2018.06.016] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/23/2018] [Accepted: 06/25/2018] [Indexed: 12/18/2022]
|
|
14
|
Esher SK, Ost KS, Kohlbrenner MA, Pianalto KM, Telzrow CL, Campuzano A, Nichols CB, Munro C, Wormley FL, Alspaugh JA. Defects in intracellular trafficking of fungal cell wall synthases lead to aberrant host immune recognition. PLoS Pathog 2018; 14:e1007126. [PMID: 29864141 PMCID: PMC6002136 DOI: 10.1371/journal.ppat.1007126] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 06/14/2018] [Accepted: 05/29/2018] [Indexed: 11/19/2022] Open
Abstract
The human fungal pathogen, Cryptococcus neoformans, dramatically alters its cell wall, both in size and composition, upon entering the host. This cell wall remodeling is essential for host immune avoidance by this pathogen. In a genetic screen for mutants with changes in their cell wall, we identified a novel protein, Mar1, that controls cell wall organization and immune evasion. Through phenotypic studies of a loss-of-function strain, we have demonstrated that the mar1Δ mutant has an aberrant cell surface and a defect in polysaccharide capsule attachment, resulting in attenuated virulence. Furthermore, the mar1Δ mutant displays increased staining for exposed cell wall chitin and chitosan when the cells are grown in host-like tissue culture conditions. However, HPLC analysis of whole cell walls and RT-PCR analysis of cell wall synthase genes demonstrated that this increased chitin exposure is likely due to decreased levels of glucans and mannans in the outer cell wall layers. We observed that the Mar1 protein differentially localizes to cellular membranes in a condition dependent manner, and we have further shown that the mar1Δ mutant displays defects in intracellular trafficking, resulting in a mislocalization of the β-glucan synthase catalytic subunit, Fks1. These cell surface changes influence the host-pathogen interaction, resulting in increased macrophage activation to microbial challenge in vitro. We established that several host innate immune signaling proteins are required for the observed macrophage activation, including the Card9 and MyD88 adaptor proteins, as well as the Dectin-1 and TLR2 pattern recognition receptors. These studies explore novel mechanisms by which a microbial pathogen regulates its cell surface in response to the host, as well as how dysregulation of this adaptive response leads to defective immune avoidance.
Collapse
Affiliation(s)
- Shannon K. Esher
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Kyla S. Ost
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Maria A. Kohlbrenner
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Kaila M. Pianalto
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Calla L. Telzrow
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Althea Campuzano
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, United States of America
| | - Connie B. Nichols
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| | - Carol Munro
- MRC Centre for Medical Mycology, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom
| | - Floyd L. Wormley
- Department of Biology, University of Texas at San Antonio, San Antonio, Texas, United States of America
| | - J. Andrew Alspaugh
- Departments of Molecular Genetics and Microbiology/Medicine, Duke University School of Medicine, Durham, NC, United States of America
| |
Collapse
|
|
15
|
Wozniak KL. Interactions of Cryptococcus with Dendritic Cells. J Fungi (Basel) 2018; 4:jof4010036. [PMID: 29543719 PMCID: PMC5872339 DOI: 10.3390/jof4010036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 03/12/2018] [Accepted: 03/14/2018] [Indexed: 12/15/2022] Open
Abstract
The fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening infections in immune compromised and immune competent hosts. These pathogens enter the host via inhalation, and respiratory tract innate immune cells such as dendritic cells (DCs) are one of the first host cells they encounter. The interactions between Cryptococcus and innate immune cells play a critical role in the progression of disease in the host. This review will focus specifically on the interactions between Cryptococcus and dendritic cells (DCs), including recognition/processing by DCs, effects of immune mediators on DC recruitment and activity, and the potential for DC vaccination against cryptococcosis.
Collapse
Affiliation(s)
- Karen L Wozniak
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74078, USA.
| |
Collapse
|
|
16
|
Dutra FF, Albuquerque PC, Rodrigues ML, Fonseca FL. Warfare and defense: The host response to Cryptococcus infection. FUNGAL BIOL REV 2018. [DOI: 10.1016/j.fbr.2017.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
17
|
Sato K, Kawakami K. Recognition of Cryptococcus neoformans by Pattern Recognition Receptors and its Role in Host Defense to This Infection. Med Mycol J 2018; 58:J83-J90. [PMID: 28855484 DOI: 10.3314/mmj.17.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cryptococcus neoformans is a yeast-type opportunistic fungal pathogen with a capsule structure consisting of polysaccharides, such as glucuronoxylomannan and galactoxylomannan, and infects the lungs via an air-borne route. Most healthy individuals undergo asymptomatic infection with granulomatous lesions in the lungs caused by C. neoformans. However, immunocompromised hosts with severely impaired cellular immunity, such as those with acquired immune deficiency syndrome (AIDS), often suffer from disseminated infection into the central nervous system, leading to life-threatening meningoencephalitis. The recognition of pathogen-associated molecular patterns (PAMPs) by macrophages and dendritic cells plays an important role as the first line of host defense in the elimination of pathogens. Recently, numerous pattern recognition receptors (PRRs) that recognize these PAMPs have been identified. Also, the involvement of these PRRs, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), in cryptococcal infection has been analyzed. In particular, TLR9, NLR family pyrin domain-containing 3 (NLRP3), Dectin-2, mannose receptor (MR), and DC-SIGN have been found to recognize the DNA, cell wall components, intracellular polysaccharides, and mannoproteins, respectively. Future studies are expected to promote elucidation of the mechanisms of host immune response to C. neoformans, which will lead to the development of new vaccines and therapies for cryptococcal infection.
Collapse
Affiliation(s)
- Ko Sato
- Department of Medical Microbiology, Mycology and Immunology,Tohoku University Graduate School of Medicine.,Virus Research Center, Clinical Research Division, Sendai Medical Center
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology,Tohoku University Graduate School of Medicine
| |
Collapse
|
|
18
|
Shourian M, Ralph B, Angers I, Sheppard DC, Qureshi ST. Contribution of IL-1RI Signaling to Protection against Cryptococcus neoformans 52D in a Mouse Model of Infection. Front Immunol 2018; 8:1987. [PMID: 29403476 PMCID: PMC5780350 DOI: 10.3389/fimmu.2017.01987] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/21/2017] [Indexed: 12/15/2022] Open
Abstract
Interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) are pro-inflammatory cytokines that are induced after Cryptococcus neoformans infection and activate the interleukin-1 receptor type I (IL-1RI). To establish the role of IL-1RI signaling in protection against cryptococcal infection, we analyzed wild-type (WT) and IL-1RI-deficient (IL-1RI−/−) mice on the BALB/c background. IL-1RI−/− mice had significantly reduced survival compared to WT mice after intratracheal challenge with C. neoformans 52D. Microbiological analysis showed a significant increase in the lung and brain fungal burden of IL-1RI−/− compared to WT mice beginning at weeks 1 and 4 postinfection, respectively. Histopathology showed that IL-1RI−/− mice exhibit greater airway epithelial mucus secretion and prominent eosinophilic crystals that were absent in WT mice. Susceptibility of IL-1RI−/− mice was associated with significant induction of a Th2-biased immune response characterized by pulmonary eosinophilia, M2 macrophage polarization, and recruitment of CD4+ IL-13+ T cells. Expression of pro-inflammatory [IL-1α, IL-1β, TNFα, and monocyte chemoattractant protein 1 (MCP-1)], Th1-associated (IFNγ), and Th17-associated (IL-17A) cytokines was significantly reduced in IL-1RI−/− lungs compared to WT. WT mice also had higher expression of KC/CXCL1 and sustained neutrophil recruitment to the lung; however, antibody-mediated depletion of these cells showed that they were dispensable for lung fungal clearance. In conclusion, our data indicate that IL-1RI signaling is required to activate a complex series of innate and adaptive immune responses that collectively enhance host defense and survival after C. neoformans 52D infection in BALB/c mice.
Collapse
Affiliation(s)
- Mitra Shourian
- Division of Experimental Medicine, McGill University, Montreal, QC, Canada.,Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada
| | - Ben Ralph
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, The Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Isabelle Angers
- Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.,Program in Translational Research in Respiratory Diseases, Department of Critical Care, The Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada
| | - Donald C Sheppard
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, The Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.,Department of Medicine, McGill University, Montreal, QC, Canada
| | - Salman T Qureshi
- Division of Experimental Medicine, McGill University, Montreal, QC, Canada.,Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.,Program in Translational Research in Respiratory Diseases, Department of Critical Care, The Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada.,Department of Medicine, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
19
|
Abstract
PURPOSE OF REVIEW Sarcoidosis is a disease caused by a complex combination of genetic susceptibility, immune networks and infectious and/or environmental agents. The onset and phenotypic variability of sarcoidosis remain poorly elucidated, not only due to the lack of clearly identified causes, but also because it is widely considered that no reliable model of this disease is available. In this review, we discuss the various models of granulomatous diseases in order to challenge this assertion. RECENT FINDINGS A large number of models of granulomatous diseases are available, both cellular models used to study the natural history of granulomas and experimental animal models mostly developed in rodents. SUMMARY Although none of the available models fully reproduces sarcoidosis, most of them generate various data supporting key concepts. Selected models with a high level of confidence among those already published may provide various pieces of the sarcoidosis jigsaw puzzle, whereas clinical data can provide other elements. A 'systems biology' approach for modelling may be a way of piecing together the various pieces of the puzzle. Finally, experimental models and a systemic approach should be considered to be tools for preclinical evaluation of the efficacy of drugs prior to testing in clinical trials.
Collapse
|
|
20
|
Taghavi M, Khosravi A, Mortaz E, Nikaein D, Athari SS. Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections. Eur J Pharmacol 2017; 808:8-13. [DOI: 10.1016/j.ejphar.2016.11.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 10/22/2016] [Accepted: 11/08/2016] [Indexed: 12/26/2022]
|
|
21
|
Abstract
Cryptococcus species are encapsulated fungi found in the environment that predominantly cause disease in immunocompromised hosts after inhalation into the lungs. Even with contemporary antifungal regimens, patients with cryptococcosis continue to have high morbidity and mortality rates. The development of more effective therapies may depend on our understanding of the cellular and molecular mechanisms by which the host promotes sterilizing immunity against the fungus. This review will highlight our current knowledge of how Cryptococcus, primarily the species C. neoformans, is sensed by the mammalian host and how subsequent signaling pathways direct the anti-cryptococcal response by effector cells of the innate immune system.
Collapse
Affiliation(s)
- Lena J Heung
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| |
Collapse
|
|
22
|
Xu J, Flaczyk A, Neal LM, Fa Z, Eastman AJ, Malachowski AN, Cheng D, Moore BB, Curtis JL, Osterholzer JJ, Olszewski MA. Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection. THE JOURNAL OF IMMUNOLOGY 2017; 198:3548-3557. [PMID: 28298522 DOI: 10.4049/jimmunol.1700057] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 02/21/2017] [Indexed: 12/19/2022]
Abstract
The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO-/- mice was accompanied by impaired recruitment of Ly6Chigh monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO-/- mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
Collapse
Affiliation(s)
- Jintao Xu
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Adam Flaczyk
- Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Lori M Neal
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Zhenzong Fa
- Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Alison J Eastman
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Antoni N Malachowski
- Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Daphne Cheng
- Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Bethany B Moore
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Jeffrey L Curtis
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - John J Osterholzer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| | - Michal A Olszewski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; .,Pulmonary Section, Medical Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and
| |
Collapse
|
|
23
|
Malachowski AN, Yosri M, Park G, Bahn YS, He Y, Olszewski MA. Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence. Front Microbiol 2016; 7:1652. [PMID: 27833589 PMCID: PMC5081415 DOI: 10.3389/fmicb.2016.01652] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 10/04/2016] [Indexed: 11/13/2022] Open
Abstract
Cryptococcus neoformans is pathogenic yeast, responsible for highly lethal infections in compromised patients around the globe. C. neoformans typically initiates infections in mammalian lung tissue and subsequently disseminates to the central nervous system where it causes significant pathologies. Virulence genes of C. neoformans are being characterized at an increasing rate, however, we are far from a comprehensive understanding of their roles and genetic interactions. Some of these reported virulence genes are scattered throughout different databases, while others are not yet included. This study gathered and analyzed 150 reported virulence associated factors (VAFs) of C. neoformans. Using the web resource STRING database, our study identified different interactions between the total VAFs and those involved specifically in lung and brain infections and identified a new strain specific virulence gene, SHO1, involved in the mitogen-activated protein kinase signaling pathway. As predicted by our analysis, SHO1 expression enhanced C. neoformans virulence in a mouse model of pulmonary infection, contributing to enhanced non-protective immune Th2 bias and progressively enhancing fungal growth in the infected lungs. Sequence analysis indicated 77.4% (116) of total studied VAFs are soluble proteins, and 22.7% (34) are transmembrane proteins. Motifs involved in regulation and signaling such as protein kinases and transcription factors are highly enriched in Cryptococcus VAFs. Altogether, this study represents a pioneering effort in analysis of the virulence composite network of C. neoformans using a systems biology approach.
Collapse
Affiliation(s)
- Antoni N Malachowski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA
| | - Mohamed Yosri
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA; The Regional Center for Mycology and Biotechnology, Al-Azhar UniversityCairo, Egypt
| | - Goun Park
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University Seoul, South Korea
| | - Yong-Sun Bahn
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University Seoul, South Korea
| | - Yongqun He
- Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann ArborMI, USA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann ArborMI, USA; Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann ArborMI, USA
| | - Michal A Olszewski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA
| |
Collapse
|
|
24
|
Eastman AJ, Osterholzer JJ, Olszewski MA. Role of dendritic cell-pathogen interactions in the immune response to pulmonary cryptococcal infection. Future Microbiol 2016; 10:1837-57. [PMID: 26597428 DOI: 10.2217/fmb.15.92] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review discusses the unique contributions of dendritic cells (DCs) to T-cell priming and the generation of effective host defenses against Cryptococcus neoformans (C.neo) infection. We highlight DC subsets involved in the early and later stages of anticryptococcal immune responses, interactions between C.neo pathogen-associated molecular patterns and pattern recognition receptors expressed by DC, and the influence of DC on adaptive immunity. We emphasize recent studies in mouse models of cryptococcosis that illustrate the importance of DC-derived cytokines and costimulatory molecules and the potential role of DC epigenetic modifications that support maintenance of these signals throughout the immune response to C.neo. Lastly, we stipulate where these advances can be developed into new, immune-based therapeutics for treatment of this global pathogen.
Collapse
Affiliation(s)
- Alison J Eastman
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.,VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
| | - John J Osterholzer
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.,VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA.,Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| | - Michal A Olszewski
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.,VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA.,Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
25
|
Van Prooyen N, Henderson CA, Hocking Murray D, Sil A. CD103+ Conventional Dendritic Cells Are Critical for TLR7/9-Dependent Host Defense against Histoplasma capsulatum, an Endemic Fungal Pathogen of Humans. PLoS Pathog 2016; 12:e1005749. [PMID: 27459510 PMCID: PMC4961300 DOI: 10.1371/journal.ppat.1005749] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 06/17/2016] [Indexed: 11/23/2022] Open
Abstract
Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNγ from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNγ, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi. Innate immune cells such as macrophages and dendritic cells (DCs) are critical elements of the initial response to pathogens. Whereas both of these cell types utilize robust anti-microbial strategies to kill internalized microbes, intracellular pathogens have developed mechanisms to manipulate the host response and survive within host cells. In the case of the intracellular fungal pathogen Histoplasma capsulatum, the fungus proliferates within macrophages, resulting in host-cell lysis. In contrast, DCs are able to restrict Histoplasma growth. Here we discovered that the ability of DCs to produce Type I interferons (IFN-I) is critical to their capacity to restrict fungal proliferation and survive infection. IFN-I are cytokines that are elicited during a variety of viral, bacterial, and fungal infections. We performed in vivo and in vitro experiments to show that pattern recognition receptors TLR7 and TLR9 are critical for the IFN-I response and host survival in the mouse model of infection. Additionally we defined a specific DC subset (CD103+ conventional DCs) in the mouse lung that is responsible for the IFN-I response, revealing a previously unknown role for these cells. These data provide insight on the pivotal role of a specific host-response pathway at both a cellular and organismal level during infection with endemic fungi.
Collapse
Affiliation(s)
- Nancy Van Prooyen
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
| | - C. Allen Henderson
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
| | - Davina Hocking Murray
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
| | - Anita Sil
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
- Howard Hughes Medical Institute, San Francisco, California, United States of America
- * E-mail:
| |
Collapse
|
|
26
|
DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans. Infect Immun 2016; 84:1879-86. [PMID: 27068093 DOI: 10.1128/iai.00222-16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 04/05/2016] [Indexed: 01/17/2023] Open
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response to C. neoformans Infectious outcomes in DAP12(-/-) mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12(-/-) mice. In contrast to WT NK cells, DAP12(-/-) NK cells are able to repress C. neoformans growth in vitro Additionally, DAP12(-/-) macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing of C. neoformans These findings suggest that DAP12 acts as a brake on the pulmonary immune response to C. neoformans by promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.
Collapse
|
|
27
|
Intracellular Action of a Secreted Peptide Required for Fungal Virulence. Cell Host Microbe 2016; 19:849-64. [PMID: 27212659 DOI: 10.1016/j.chom.2016.05.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/24/2015] [Accepted: 04/28/2016] [Indexed: 01/02/2023]
Abstract
Quorum sensing (QS) is a bacterial communication mechanism in which secreted signaling molecules impact population function and gene expression. QS-like phenomena have been reported in eukaryotes with largely unknown contributing molecules, functions, and mechanisms. We identify Qsp1, a secreted peptide, as a central signaling molecule that regulates virulence in the fungal pathogen Cryptococcus neoformans. QSP1 is a direct target of three transcription factors required for virulence, and qsp1Δ mutants exhibit attenuated infection, slowed tissue accumulation, and greater control by primary macrophages. Qsp1 mediates autoregulatory signaling that modulates secreted protease activity and promotes cell wall function at high cell densities. Peptide production requires release from a secreted precursor, proQsp1, by a cell-associated protease, Pqp1. Qsp1 sensing requires an oligopeptide transporter, Opt1, and remarkably, cytoplasmic expression of mature Qsp1 complements multiple phenotypes of qsp1Δ. Thus, C. neoformans produces an autoregulatory peptide that matures extracellularly but functions intracellularly to regulate virulence.
Collapse
|
|
28
|
Leopold Wager CM, Hole CR, Wozniak KL, Wormley FL. Cryptococcus and Phagocytes: Complex Interactions that Influence Disease Outcome. Front Microbiol 2016; 7:105. [PMID: 26903984 PMCID: PMC4746234 DOI: 10.3389/fmicb.2016.00105] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 01/19/2016] [Indexed: 12/18/2022] Open
Abstract
Cryptococcus neoformans and C. gattii are fungal pathogens that cause life-threatening disease. These fungi commonly enter their host via inhalation into the lungs where they encounter resident phagocytes, including macrophages and dendritic cells, whose response has a pronounced impact on the outcome of disease. Cryptococcus has complex interactions with the resident and infiltrating innate immune cells that, ideally, result in destruction of the yeast. These phagocytic cells have pattern recognition receptors that allow recognition of specific cryptococcal cell wall and capsule components. However, Cryptococcus possesses several virulence factors including a polysaccharide capsule, melanin production and secretion of various enzymes that aid in evasion of the immune system or enhance its ability to thrive within the phagocyte. This review focuses on the intricate interactions between the cryptococci and innate phagocytic cells including discussion of manipulation and evasion strategies used by Cryptococcus, anti-cryptococcal responses by the phagocytes and approaches for targeting phagocytes for the development of novel immunotherapeutics.
Collapse
Affiliation(s)
- Chrissy M Leopold Wager
- Department of Biology, The University of Texas at San AntonioSan Antonio, TX, USA; The South Texas Center for Emerging Infectious Diseases, The University of Texas at San AntonioSan Antonio, TX, USA
| | - Camaron R Hole
- Department of Biology, The University of Texas at San AntonioSan Antonio, TX, USA; The South Texas Center for Emerging Infectious Diseases, The University of Texas at San AntonioSan Antonio, TX, USA
| | - Karen L Wozniak
- Department of Biology, The University of Texas at San AntonioSan Antonio, TX, USA; The South Texas Center for Emerging Infectious Diseases, The University of Texas at San AntonioSan Antonio, TX, USA
| | - Floyd L Wormley
- Department of Biology, The University of Texas at San AntonioSan Antonio, TX, USA; The South Texas Center for Emerging Infectious Diseases, The University of Texas at San AntonioSan Antonio, TX, USA
| |
Collapse
|
|
29
|
Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections. Mucosal Immunol 2014; 7:1023-35. [PMID: 25073676 DOI: 10.1038/mi.2014.65] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 06/21/2014] [Indexed: 02/04/2023]
Abstract
Macrophages are innate immune cells that possess unique abilities to polarize toward different phenotypes. Classically activated macrophages are known to have major roles in host defense against various microbial pathogens, including fungi, while alternatively activated macrophages are instrumental in immune-regulation and wound healing. Macrophages in the lungs are often the first responders to pulmonary fungal pathogens, and the macrophage polarization state has the potential to be a deciding factor in disease progression or resolution. This review discusses the distinct macrophage polarization states and their roles during pulmonary fungal infection. We focus primarily on Cryptococcus neoformans and Pneumocystis model systems as disease resolution of these two opportunistic fungal pathogens is linked to classically or alternatively activated macrophages, respectively. Further research considering macrophage polarization states that result in anti-fungal activity has the potential to provide a novel approach for the treatment of fungal infections.
Collapse
|
|
30
|
Sanclemente G, Moreno A, Navasa M, Lozano F, Cervera C. Genetic variants of innate immune receptors and infections after liver transplantation. World J Gastroenterol 2014; 20:11116-11130. [PMID: 25170199 PMCID: PMC4145753 DOI: 10.3748/wjg.v20.i32.11116] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 05/14/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, and thus immunosuppressive therapy is necessary after transplantation. In this setting, the presence of genetic variants of innate immunity receptors may increase the risk of post-transplant infection, in comparison with patients carrying wild-type alleles. Numerous studies have investigated the role of genetic variants of innate immune receptors and the risk of complication after liver transplantation, but their results are discordant. Toll-like receptors and mannose-binding lectin are arguably the most important studied molecules; however, many other receptors could increase the risk of infection after transplantation. In this article, we review the published studies analyzing the impact of genetic variants in the innate immune system on the development of infectious complications after liver transplantation.
Collapse
|
|
31
|
Defect of CARD9 leads to impaired accumulation of gamma interferon-producing memory phenotype T cells in lungs and increased susceptibility to pulmonary infection with Cryptococcus neoformans. Infect Immun 2014; 82:1606-15. [PMID: 24470469 DOI: 10.1128/iai.01089-13] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule signal that is critical for NF-κB activation and is triggered through C-type lectin receptors (CLRs), which are pattern recognition receptors that recognize carbohydrate structures. Previous studies have reported that Cryptococcus neoformans, a fungal pathogen that causes meningoencephalitis in AIDS patients, is recognized through some CLRs, such as mannose receptors or DC-SIGN. However, the role of CARD9 in the host defense against cryptococcal infection remains to be elucidated. In the present study, we analyzed the role of CARD9 in the host defense against pulmonary infection with C. neoformans. CARD9 gene-disrupted (knockout [KO]) mice were highly susceptible to this infection, as shown by the reduced fungal clearance in the infected lungs of CARD9 KO mice, compared to that in wild-type (WT) mice. Gamma interferon (IFN-γ) production was strongly reduced in CARD9 KO mice during the innate-immunity phase of infection. Reduced IFN-γ synthesis was due to impaired accumulation of NK and memory phenotype T cells, which are major sources of IFN-γ innate-immunity-phase production; a reduction in the accumulation of these cells was correlated with reduced CCL4, CCL5, CXCL9, and CXCL10 synthesis. However, differentiation of Th17 cells, but not of Th1 cells, was impaired at the adaptive-immunity phase in CARD9 KO mice compared to WT mice, although there was no significant difference in the infection susceptibility between interleukin 17A (IL-17A) KO and WT mice. These results suggest that CARD9 KO mice are susceptible to C. neoformans infection probably due to the reduced accumulation of IFN-γ-expressing NK and memory phenotype T cells at the early stage of infection.
Collapse
|
|
32
|
Macrophage M1/M2 polarization dynamically adapts to changes in cytokine microenvironments in Cryptococcus neoformans infection. mBio 2013; 4:e00264-13. [PMID: 23781069 PMCID: PMC3684832 DOI: 10.1128/mbio.00264-13] [Citation(s) in RCA: 345] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using in vitro macrophages. Coculture of macrophages with Cryptococcus neoformans resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The C. neoformans-induced M1-like polarization state was plastic, as macrophages stimulated first with C. neoformans and then with gamma interferon (IFN-γ) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-γ and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-α) protein production. Switching IFN-γ- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit C. neoformans reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis.
Collapse
|
|
33
|
Qiu Y, Dayrit JK, Davis MJ, Carolan JF, Osterholzer JJ, Curtis JL, Olszewski MA. Scavenger receptor A modulates the immune response to pulmonary Cryptococcus neoformans infection. THE JOURNAL OF IMMUNOLOGY 2013; 191:238-48. [PMID: 23733871 DOI: 10.4049/jimmunol.1203435] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA(+/+) mice and SRA(-/-) mice were infected intratracheally with C. neoformans. Results show that infection of SRA(-/-) mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA(+/+) mice. Improved fungal clearance in SRA(-/-) mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4(+) T cells and CD11b(+) dendritic cells. Additional parameters were consistent with enhanced anticryptococcal immunity in the infected SRA(-/-) mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.
Collapse
Affiliation(s)
- Yafeng Qiu
- Veterans Administration Ann Arbor Health System, Ann Arbor, MI 48105, USA
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Qiu J, Olszewski MA, Williamson PR. Cryptococcus neoformans growth and protection from innate immunity are dependent on expression of a virulence-associated DEAD-box protein, Vad1. Infect Immun 2013; 81:777-88. [PMID: 23264050 PMCID: PMC3584887 DOI: 10.1128/iai.00821-12] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 12/19/2012] [Indexed: 12/31/2022] Open
Abstract
The fungus Cryptococcus neoformans has emerged as a major cause of meningoencephalitis worldwide. Host response to the fungus involves both innate and adaptive immunity, but fungal genes that modulate these processes are poorly understood. Previous studies demonstrated attenuated virulence of a mutant of a virulence-associated DEAD-box protein (VAD1) in mice, despite normal growth at host temperatures, suggesting modulation of the immune response. In the present study, the Δvad1 mutant demonstrated progressive clearance from lung and was unable to induce pathological lesions or to cause extrapulmonary disease, despite retaining its ability to grow in mouse serum and a J774.16 macrophage cell line. Pulmonary clearance occurred with a minimal cellular infiltrate, marked by reduced CD4 cells, CD11b(+) Ly6C(high) monocytes, and F4/80(+) macrophages, but the mutant strain retained recruitment of CD8 cells, compared to infections with wild-type fungi. Adaptive cytokine responses were reduced, including Th1, Th2, and Th17 cytokines; however, early gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) responses were retained while nonprotective interleukin 4 (IL-4) and IL-5 were diminished. Furthermore, the Δvad1 mutant was controlled in lungs despite CD4/CD8 cell depletion. These data, along with improved phagocytosis by macrophages and increases in early/innate IL-1α, IFN-γ, and chemokines elicited in the lungs within 3 days of infection with the Δvad1 mutant, indicate that VAD1 expression reduces innate recognition of C. neoformans, rendering the yeast resistant to elimination by the innate mechanisms of host defense. Thus, our studies define a novel role of the cryptococcal Vad1 protein as a central regulator of cryptococcal virulence and illustrate that Vad1 promotes microbe resistance to innate host defenses.
Collapse
Affiliation(s)
- Jin Qiu
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Michal A. Olszewski
- VA Medical Center, Ann Arbor
- University of Michigan, Ann Arbor, Ann Arbor, Michigan, USA
| | - Peter R. Williamson
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
- Section of Infectious Diseases, Immunology and International Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| |
Collapse
|
|
35
|
Abstract
Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of host-fungus interactions encompasses efficient fungal sensing, tolerance at mucosal surfaces, as well as antifungal defenses. Decrease in host immune fitness or increase in fungal burden may favor pathologies, ranging from superficial mucocutaneous diseases to invasive life-threatening fungal infections. Toll-like receptors (TLRs) are essential players in this balance, due to their ability to control both inflammatory and anti-inflammatory processes upon recognition of fungal-specific pathogen-associated molecular patterns (PAMPs). Certain members of the TLR family participate to the initial recognition of fungal PAMPs on the cell surface, as well as inside phagosomes of innate immune cells. Active signaling cascades in phagocytes ultimately enable fungus clearance and the release of cytokines that shape and instruct other innate immune cells and the adaptive immune system. Some TLRs cooperate with other pattern recognition receptors (PRRs) (e.g., C-type lectins and Galectins), thus allowing for a tailored immune response. The spatio-temporal and physiological contributions of individual TLRs in fungal infections remains ill-defined, although in humans, TLR gene polymorphisms have been linked to increased susceptibility to fungal infections. This review focuses entirely on the role of TLRs that control the host susceptibility to environmental fungi (e.g., Aspergillus, Cryptoccocus, and Coccidoides), as well as to the most frequent human fungal pathogens represented by the commensal Candida species. The emerging roles of TLRs in modulating host tolerance to fungi, and the strategies that evolved in some of these fungi to evade or use TLR recognition to their advantage will also be discussed, as well as their potential suitability as targets in vaccine therapies.
Collapse
Affiliation(s)
- Christelle Bourgeois
- Medical University of Vienna, Max F. Perutz Laboratories Vienna, Austria. christelle.bourgeois@ meduniwien.ac.at
| | | |
Collapse
|
|
36
|
Ramirez-Ortiz ZG, Means TK. The role of dendritic cells in the innate recognition of pathogenic fungi (A. fumigatus, C. neoformans and C. albicans). Virulence 2012; 3:635-46. [PMID: 23076328 PMCID: PMC3545945 DOI: 10.4161/viru.22295] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Dendritic cells (DCs) are the bridge between the innate and adaptive immune system. DCs are responsible for sensing and patrolling the environment, initiating a host response and instructing the proper adaptive immune response against pathogens. Recent advances in medical treatments have led to increased use of immunosuppressive drugs, leading to the emergence of fungal species that cause life-threatening infections in humans. Three of these opportunistic fungal pathogens: Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans pose the biggest concern for the immune-compromised host. Here we will review the interactions between DCs and these fungal pathogens, the receptors expressed on DCs that mediate these responses and the signaling mechanisms that shape the adaptive host response.
Collapse
Affiliation(s)
- Zaida G Ramirez-Ortiz
- Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | | |
Collapse
|
|
37
|
He X, Lyons DM, Toffaletti DL, Wang F, Qiu Y, Davis MJ, Meister DL, Dayrit JK, Lee A, Osterholzer JJ, Perfect JR, Olszewski MA. Virulence factors identified by Cryptococcus neoformans mutant screen differentially modulate lung immune responses and brain dissemination. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1356-66. [PMID: 22846723 DOI: 10.1016/j.ajpath.2012.06.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 05/29/2012] [Accepted: 06/26/2012] [Indexed: 01/07/2023]
Abstract
Deletions of cryptococcal PIK1, RUB1, and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by comparing wild-type Cryptococcus neoformans strain H99 with deletant and complement strains in a BALB/c mouse model of pulmonary infection. Survival of infected mice; pulmonary cryptococcal growth and pathology; immunological parameters; dissemination kinetics; and CNS pathology were examined. Deletion of each PIK1, RUB1, and ENA1 differentially reduced pulmonary growth and dissemination rates of C. neoformans and extended mice survival. Furthermore, pik1Δ induced similar pathologies to H99, however, with significantly delayed onset; rub1Δ was more efficiently contained within pulmonary macrophages and was further delayed in causing CNS dissemination/pathology; whereas ena1Δ was progressively eliminated from the lungs and did not induce pathological lesions or disseminate into the CNS. The diminished virulence of mutant strains was associated with differential modulation of pulmonary immune responses, including changes in leukocyte subsets, cytokine responses, and macrophage activation status. Compared to H99 infection, mutants induced more hallmarks of a protective Th1 immune response, rather than Th2, and more classical, rather than alternative, macrophage activation. The magnitude of immunological effects precisely corresponded to the level of virulence displayed by each strain. Thus, cryptococcal PIK1, RUB1, and ENA1 differentially contribute to cryptococcal virulence, in correlation with their differential capacity to modulate immune responses.
Collapse
Affiliation(s)
- Xiumiao He
- VA Ann Arbor Health System, Research Service, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Wozniak KL, Hardison S, Olszewski M, Wormley FL. Induction of protective immunity against cryptococcosis. Mycopathologia 2012; 173:387-94. [PMID: 22143898 DOI: 10.1007/s11046-011-9505-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 10/22/2011] [Indexed: 02/08/2023]
Abstract
Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an encapsulated fungal pathogen that can cause life-threatening infections of the central nervous system in immune compromised individuals resulting in high morbidity and mortality. Consequently, several studies have endeavored to understand those mechanisms that mediate resistance and susceptibility to Cryptococcus infection. In this review, we will examine the contributions of various components of the innate and adaptive immune response toward protection against cryptococcosis. We will focus our discussion on studies presented at the 8th International Conference on Cryptococcus and Cryptococcosis (ICCC). Remarkable progress has been made toward our understanding of host immunity and susceptibility to cryptococcal infection and the potential for vaccine development.
Collapse
Affiliation(s)
- Karen L Wozniak
- Department of Biology, The University of Texas, San Antonio, TX 78249-0062, USA
| | | | | | | |
Collapse
|
|
39
|
Qiu Y, Zeltzer S, Zhang Y, Wang F, Chen GH, Dayrit J, Murdock BJ, Bhan U, Toews GB, Osterholzer JJ, Standiford TJ, Olszewski MA. Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection. THE JOURNAL OF IMMUNOLOGY 2012; 188:3940-8. [PMID: 22422883 DOI: 10.4049/jimmunol.1103053] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-γ and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9(-/-) mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b(+) DCs at week 1, 2) restored early IFN-γ production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9(+/+) and TLR9(-/-) mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7-treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9(+/+) mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-γ and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia.
Collapse
Affiliation(s)
- Yafeng Qiu
- Department of Research Service, Veterans Administration Ann Arbor Health System, Ann Arbor, MI 48105, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Espinosa V, Rivera A. Cytokines and the regulation of fungus-specific CD4 T cell differentiation. Cytokine 2011; 58:100-6. [PMID: 22133343 DOI: 10.1016/j.cyto.2011.11.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/02/2011] [Accepted: 11/03/2011] [Indexed: 12/11/2022]
Abstract
CD4 T cells play important and non-redundant roles in protection against infection with diverse fungi. Distinct CD4 T cell subsets can mediate protection against fungal disease where Th1 and Th17 CD4 T cell subsets have been found to promote fungal clearance and protective immunity against diverse fungal pathogens. The differentiation of naïve CD4 T cells into Th1 or Th17 cells is crucially controlled by their interaction with dendritic cells and instructed by cytokines. IL-12 and IFN-γ promote Th1 differentiation while TGF-β, IL-6, IL-1, IL-21 and IL-23 promote Th17 differentiation and maintenance. The production of these cytokines by DCs is in turn regulated by innate receptors triggered in response to fungal infection. In this review we will discuss the contributions of cytokines found to influence fungus-specific CD4 T cell differentiation and their role in defense against fungal disease. We will also highlight the contributions of innate receptors involved in recognition of fungi and how they shape cytokine secretion and CD4 T cell differentiation.
Collapse
Affiliation(s)
- Vanessa Espinosa
- Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 So Orange Avenue, MSB-F601, Newark, NJ 07101, USA.
| | | |
Collapse
|
|
41
|
Toll-like receptor 9-dependent activation of bone marrow-derived dendritic cells by URA5 DNA from Cryptococcus neoformans. Infect Immun 2011; 80:778-86. [PMID: 22104112 DOI: 10.1128/iai.05570-11] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense against C. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using the URA5 gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bp URA5 gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5' 129-bp DNA fragment of URA5 and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that the C. neoformans URA5 gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif.
Collapse
|
|
42
|
Wang JP, Lee CK, Akalin A, Finberg RW, Levitz SM. Contributions of the MyD88-dependent receptors IL-18R, IL-1R, and TLR9 to host defenses following pulmonary challenge with Cryptococcus neoformans. PLoS One 2011; 6:e26232. [PMID: 22039448 PMCID: PMC3198470 DOI: 10.1371/journal.pone.0026232] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 09/22/2011] [Indexed: 01/19/2023] Open
Abstract
Signaling via the adapter protein, MyD88, is important in the host defense against Cryptococcus neoformans infection. While certain Toll-like receptors (TLRs) can enhance the clearance of Cryptococcus, the contributions of MyD88-dependent, TLR-independent pathways have not been fully investigated. We examined the roles of IL-1R and IL-18R in vivo by challenging C57BL/6 mice with a lethal strain of Cryptococcus. We found that the absence of IL-18R, but not IL-1R, causes a shift in the survival curve following pulmonary delivery of a virulent strain of C. neoformans (H99). Specifically, IL-18R-deficient mice have significantly shorter median survival times compared to wild-type mice following infection. Cytokine analysis of lung homogenates revealed that deficiency of IL-IR, IL-18R, or MyD88 is associated with diminished lung levels of IL-1β. In order to compare these findings with those related to TLR-deficiency, we studied the effects of TLR9-deficiency and found that deficiency of TLR9 also affects the survival curve of mice following challenge with C. neoformans. Yet the lungs from infected TLR9-deficient mice have robust levels of IL-1β. In summary, we found that multiple signaling components can contribute the MyD88-dependent host responses to cryptococcal infection in vivo and each drives distinct pulmonary responses.
Collapse
Affiliation(s)
- Jennifer P Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
| | | | | | | | | |
Collapse
|
|
43
|
Bhan U, Newstead MJ, Zeng X, Ballinger MN, Standiford LR, Standiford TJ. Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:2779-87. [PMID: 21982832 DOI: 10.1016/j.ajpath.2011.08.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 08/17/2011] [Accepted: 08/26/2011] [Indexed: 12/18/2022]
Abstract
Hypersensitivity pneumonitis (HP), an inflammatory lung disease, develops after repeated exposure to inhaled particulate antigen and is characterized by a vigorous T helper type 1-mediated immune response, resulting in the release of IL-12 and interferon (IFN)-γ. These T helper type 1 cytokines may participate in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus implicated in a number of respiratory illnesses, including HP. Here, we have developed a murine model of SC-induced HP that reproduces pathology observed in human HP and hypothesized that toll receptor-like 9 (TLR9)-mediated dendritic cell responses are required for the generation of granulomatous inflammation induced by inhaled SC. Mice sensitized and challenged with 10(6) SC spores develop granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of neutrophils and CD4(+) and CD8(+) T cells. SC sensitization and challenge resulted in robust pulmonary expression of tumor necrosis factor-α, IL-12, and IFN-γ. SC-mediated granulomatous inflammation required IFN-γ and was TLR9 dependent, because TLR9(-/-) mice displayed reduced peribronchial inflammation, decreased accumulation and/or activation of polymorphonuclear (PMN) and CD4(+) and CD8(+) T cells, and reduced lung expression of type 1 cytokines and chemokines. T-cell production of IFN-γ was IL-12 dependent. Our studies suggest that TLR9 is critical for dendritic cell-mediated development of a type 1 granulomatous inflammation in the lung in response to SC.
Collapse
Affiliation(s)
- Urvashi Bhan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
| | | | | | | | | | | |
Collapse
|
|
44
|
Kovach MA, Standiford TJ. Toll like receptors in diseases of the lung. Int Immunopharmacol 2011; 11:1399-406. [PMID: 21624505 PMCID: PMC3575025 DOI: 10.1016/j.intimp.2011.05.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 05/11/2011] [Accepted: 05/12/2011] [Indexed: 12/16/2022]
Abstract
The lung is in continuous contact with a diverse array of infectious agents, foreign antigens, and host-derived danger signals. To sample this expansive internal and external milieu, both resident myeloid and stromal/structure cells of the lung express a full complement of toll like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). TLRs play a vital role in immune host defense against bacterial, mycobacterial, fungal, and viral pathogens of the lung. Additionally, TLRs contribute to disease pathogenesis in non-infectious pulmonary disorders, including airway disease, acute lung injury, and interstitial lung disease. In this review, TLR biology in the context of experimental infectious and non-infectious lung disease is discussed, and correlates to human lung disease, including therapeutic implications of these findings, are defined.
Collapse
Affiliation(s)
- Melissa A Kovach
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, United States
| | | |
Collapse
|
|
45
|
Piehler D, Stenzel W, Grahnert A, Held J, Richter L, Köhler G, Richter T, Eschke M, Alber G, Müller U. Eosinophils contribute to IL-4 production and shape the T-helper cytokine profile and inflammatory response in pulmonary cryptococcosis. THE AMERICAN JOURNAL OF PATHOLOGY 2011. [PMID: 21699881 DOI: 10.1016/j.ajpath2011.04025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ΔdblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ΔdblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis.
Collapse
Affiliation(s)
- Daniel Piehler
- Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Piehler D, Stenzel W, Grahnert A, Held J, Richter L, Köhler G, Richter T, Eschke M, Alber G, Müller U. Eosinophils contribute to IL-4 production and shape the T-helper cytokine profile and inflammatory response in pulmonary cryptococcosis. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:733-44. [PMID: 21699881 DOI: 10.1016/j.ajpath.2011.04.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 03/14/2011] [Accepted: 04/05/2011] [Indexed: 12/15/2022]
Abstract
Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ΔdblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ΔdblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis.
Collapse
Affiliation(s)
- Daniel Piehler
- Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans. Infect Immun 2011; 79:1915-26. [PMID: 21383052 DOI: 10.1128/iai.01270-10] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The immune response to Cryptococcus neoformans following pulmonary infection of C57BL/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status in C. neoformans-infected WT, interleukin-4-deficient (IL-4(-/-)), and gamma interferon-deficient (IFN-γ(-/-)) C57BL/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-γ regulate the polarization state of Macs in this model. A higher IL-4/IFN-γ ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-γ/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-γ during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-γ and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology in C. neoformans-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac/aaMac phenotype, which in turn may support chronic "steady-state" fungal infection and the resultant ABPM pathology.
Collapse
|