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Principal Investigator: Katrin Mayer-Barber
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $1,293,685
Funding agency: National Institute of Allergy and Infectious Diseases
The development of effective vaccines and host directed therapies (HDT) against M. tuberculosis (Mtb) infection requires a detailed understanding of the cellular basis of protective immunity. Considerable progress has been made in our understanding of protective adaptive immunity, yet relatively little is known about the contribution of innate effector cells. Particularly, the biological relevance of granulocytes like neutrophils and eosinophils is poorly understood. The innate inflammatory response is a prime target for HDT and manipulation of granulocytes could have major inflammatory and immunoregulatory implications for host resistance. Recent advances in vaccine design were highlighted by our group through an invited commentary in Immunity.
Similar to neutrophils, eosinophils are phagocytic cells of the myeloid lineage that are thought to play an important effector role in the innate immune response. Their lineage-specific secondary granules contain cytotoxic cationic granular proteins (ECP, EDN, MBP and EPO) that have been shown to exhibit anti-microbial activity and cause tissue damage. Preformed cytokines contained in these same granules include inflammatory cytokines like TNF-, IL-1, IL-6 and IL-8 and pro-fibrogenic cytokines that can stimulate fibroblast proliferation, fibrotic and wound healing responses. In addition, lipid bodies, which form in response to eosinophil activation, contain a wide variety of leukotrienes, prostaglandins and reactive oxygen species that can contribute to these processes. More recently, eosinophils have been shown to play an important role in immunoregulation and homeostatic functions, including maintenance of long-lived plasma cells in the bone marrow and alternatively activated macrophages in adipose tissue. Eosinophils and their biological functions of have been studied primarily in the context of type 2 immunity, including parasitic helminth and pulmonary fungal infection, allergies and asthma. The role of eosinophils during bacterial infection remains largely unexplored. However, a comprehensive study on the role of eosinophils during Mtb infection is lacking, both in animal models as well human clinical studies. Another barrier to our understanding of eosinophils in host resistance to TB is a paucity of data from the mouse model of Mtb infection. There are likely two major contributing factors to be considered for this: 1) Mtb infection primarily causes a type I immune response, and eosinophils are rare in numbers compared to neutrophils in the lungs of Mtb infected mice (KDMB unpublished data) and 2) the pathology of Mtb infected mouse lungs and human lungs is vastly different. Eosinophils were found to be enriched in areas of tissue remodeling and fibrosis in TB resected lungs from patients (KDMB unpublished data). While fibrotic responses are often seen in TB patients, they are not considered a feature in the mouse model of Mtb infection. Indeed, the physiological role and function of eosinophils in type 1 immune responses to intracellular bacterial infections remains unknown. Here, in exploring the pulmonary granulocytic response to Mtb infection across species, we discovered that eosinophils migrated rapidly to Mtb-infected lungs. Because surface antibodies used to identify human eosinophils did not cross-react with eosinophils from rhesus macaques, we developed a strategy to quantify eosinophil responses in macaques by flow cytometry. We found that intracellular staining with EPX selectively and specifically stains eosinophils in both NHP and human whole blood samples and demonstrated that eosinophils rapidly migrate into Mtb infected rhesus macaque airways. We also identified eosinophils as the first cells sensing and repsondong to Mtb infection in the mouse lung after Mtb infection. Importantly, eosinophil deficient mouse strains demonstrated increased susceptibility to disease, with significantly reduced survival times. We also examined the chemokines responsible for eosinophil migration during tuberculosis and found that CCR3-mediated recognition of eotaxins were dispensible for tissue migration.
We have previously characterized two major innate cytokine pathways, IL-1 and type I interferons, respectively, that play pivotal roles in governing host resistance versus disease in the murine model of Mtb infection by intersecting the eicosanoid lipid network. In particular, we uncovered that IL-1 can in turn counter-regulate type I IFN driven detrimental responses during Mtb infection. In murine and human macrophages IL-1 and IL-1 potently inhibit type I IFN induction at both the mRNA and protein level and similarly IFN mRNA and protein levels are upregulated in the lungs of Mtb infected Il1r1-/- deficient mice. This inhibition is of functional importance because mice doubly deficient in Il1r1,Ifnar1-/- are partially protected while Il1r1-/- singly deficient animals succumb rapidly to Mtb aerosol challenge. Moreover, when IL-1 is present in type I IFN treated cultures, it even suppresses the pro-bacterial effects downstream of IFN that lead to increased bacterial replication. Interestingly, IL-1 induced PGE2 is also able to potently inhibit type I IFNs in a dose dependent manner. These data highlighted and provided proof-of-concept that the cross-talk of IL-1 and type I IFN provides a valuable target for host-directed therapies of Mtb and plays a major role during infection in mice.
Moreover, we measured and analyzed cytokines, chemokines, and lipid mediators of the IL-1, type IFN and eicosanoid axis in a prospective cohort of Chinese individuals infected with M. tuberculosis. We are currently investigating the exact nature of IL-1 and type I IFN induced cell death mechanisms, lipid regulation and host resistance pathways during tuberculosis.
Terms: <(TNF)-α><3-10C><AMCF-I><Active Oxygen><Address><Adipose tissue><Aerosols><Allergy><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Area><Asthma><Autoimmune Diseases><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bacterial Infections><Biological><Biological Function><Biological Process><Blood Eosinophil><Blood Neutrophil><Blood Plasma Cell><Blood Polymorphonuclear Neutrophil><Blood Sample><Blood granulocytic cell><Blood specimen><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bronchial Asthma><CCL11 protein><CXCL8><Cachectin><Cancers><Cations><Cell Body><Cell Communication><Cell Death><Cell Interaction><Cell-to-Cell Interaction><Cells><Chemotactic Cytokines><Chinese><Chinese People><Chronic><Chronic Disease><Chronic Illness><Clinical Research><Clinical Study><Comment><Commentary><Cryptococcus><Cytoplasmic Granules><Data><Development><Dinoprostone><Disease><Disorder><Dose><Editorial Comment><Effector Cell><Eicosanoids><Eosinophil Chemotactic Protein><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Eotaxin><Exhibits><Fatty Tissue><Fibroblasts><Fibrosis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fungus Diseases><GCP1><Goals><Granular Leukocytes><Granulocytic cell><HPGF><Helminths><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Host resistance><Human><Hybridoma Growth Factor><Hypersensitivity><IFN><IFN-beta 2><IFNB2><IL-1><IL-6><IL-8><IL1><IL6 Protein><IL8><IL8 gene><Immune mediated therapy><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Technics><Immunologic Techniques><Immunological><Immunological Technics><Immunological Techniques><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunotherapy><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Innate Immune Response><Intercrines><Interferon Type I><Interferons><Interleukin I><Interleukin-1><Interleukin-6><Investigation><K60><Lead><Leukotrienes><Light><Lipids><Lung><Lung Respiratory System><Lung infections><Lymphocyte-Stimulating Hormone><M avium><M mulatta><M tb><M tuberculosis><M tuberculosis infection><M. avium><M. mulatta><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MGI-2><MTB infection><Macaca><Macaca mulatta><Macaque><Macrophage Cell Factor><Macrophage-Derived TNF><Maintenance><Malignant Neoplasms><Malignant Tumor><Marrow Eosinophil><Marrow Neutrophil><Measures><Mediating><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monocyte-Derived TNF><Mouse Strains><Murine><Mus><Mycobacterium avium><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mycoses><Myelogenous><Myeloid><Myeloid Differentiation-Inducing Protein><Nature><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Orthomyxovirus Type A><Outcome><Oxygen Radicals><PGE2><PGE2 alpha><PGE2alpha><Parasitic Worms><Pathology><Pathway interactions><Patients><Pb element><Phagocytes><Phagocytic Cell><Photoradiation><Physiologic><Physiological><Plasma Cells><Plasmacytes><Plasmacytoma Growth Factor><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Predisposition><Primary Infection><Pro-Oxidants><Process><Prospective cohort><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandins><Prostanoids><Proteins><Published Comment><Reactive Oxygen Species><Regulation><Research><Resected><Respiratory Infections><Respiratory Tract Infections><Rhesus Macaque><Rhesus Monkey><Role><SCYB8><SIS cytokines><Small Inducible Cytokine A11><Staining method><Stains><Surface><Susceptibility><System><T Helper Factor><TB infection><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Time><Tissues><Torula><Tuberculosis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Type A Influenza><Vaccine Design><Vaccines><Viewpoint><Viral><Whole Blood><Wound Repair><adaptive immunity><adipose><amebocyte><anti-microbial><antimicrobial><arm><autoimmune disorder><autoinflammatory><b-ENAP><bacteria infection><bacterial disease><bactericidal><bactericide><chemoattractant cytokine><chemokine><chronic disorder><chronic infection><cytokine><cytotoxic><developmental><disseminated TB><disseminated tuberculosis><eosinophil><eotaxin-1><flow cytophotometry><fungal infection><fungus infection><granule><granulocyte><heavy metal Pb><heavy metal lead><host response><immune modulation><immune regulation><immune regulator><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><infection due to Mycobacterium tuberculosis><insight><interferon beta 2><lipid mediator><lymphocyte activating factor><mRNA><macrophage><malignancy><migration><model of animal><model organism><mouse model><mtb><murine model><necrocytosis><neoplasm/cancer><neutrophil><non-tuberculosis mycobacteria><non-tuberculosis mycobacterial><non-tuberculous mycobacteria><non-tuberculous mycobacterial><nontuberculosis mycobacterial><nontuberculous mycobacteria><nontuberculous mycobacterial><novel><pathway><persistent infection><plasmocyte><programs><pulmonary><pulmonary infections><respiratory><response><social role><translational pipeline><translational spectrum><treatment strategy><tuberculosis infection><tuberculous spondyloarthropathy><white adipose tissue><wound healing><wound resolution><yellow adipose tissue>