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Principal Investigator: Terry W Wright
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $535,156
Funding agency: National Institute of Allergy and Infectious Diseases
Pneumocystis pneumonia (PcP) remains a serious life-threatening respiratory fungal infection of
immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the
world. PcP-related mortality rates have changed little over the past two decades, likely due to our inability to
adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to
suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is
uncertain. The mechanisms by which Pc is recognized and cleared from the lung remain incompletely
understood. Alveolar macrophages (AMs) are at the frontline of the host-pathogen interaction, and serve as
important effectors of pulmonary host defense against Pneumocystis. Macrophages possess an array of PRR
that have the potential to recognize Pc, but they are typically ineffective for host defense when CD4+ T cell help
is not available. The reason for this is unknown, but it has been suggested that Pc may actively avoid or suppress
macrophage mediated host defense to insure survival and transmission. Our laboratory has identified an inbred
mouse strain which is unique in its ability to resist Pc infection in the absence of T cells. The resistance phenotype
requires the presence of AMs, and can be overridden by reprogramming the resistant AMs to a susceptible M1
biased phenotype. The identification of resistant and susceptible macrophage phenotypes will provide an
opportunity to explore the divergent host-pathogen interactions associated with either protection or infection. The
overarching hypothesis of this proposal is that differential macrophage polarization, phagocytic processing of Pc,
and antifungal effector production dictates the outcome of the Pc-AM interaction. To test this hypothesis we will
utilize the resistant and susceptible mouse models described in our Preliminary Studies. The identification of
new therapeutic strategies for the treatment of fungal diseases is an active area of drug-discovery research. Our
long-term goal is to understand the mechanisms regulating macrophage mediated innate immunity in the lung
to facilitate the rational design of therapeutic strategies to enhance host defense while limiting
immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) define functional differences
in the phagocytic machinery of resistant and susceptible AMs that dictate the outcome of infection; 2) explore
novel antifungal functions for chitinase-like proteins (Chi3l3) and TAM receptors (MerTK); and 3) map the Pc
resistance locus and identify resistance-associated effector molecules that contribute to protective antifungal
innate immunity. Our Preliminary Studies demonstrate that AMs can be programmed for innate protection against
this opportunistic fungal pathogen, and suggest that modifying macrophage function may represent a viable
strategy to enhance antifungal host defense.
Terms: <AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Address><Adrenal Cortex Hormones><Alveolar Macrophages><Antibiotic Therapy><Antibiotic Treatment><Area><Basic Research><Basic Science><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Candidate Disease Gene><Candidate Gene><Cell Body><Cells><Characteristics><Chitinase><Chromosome Mapping><Corticoids><Corticosteroids><Data><Death Rate><Disease><Disorder><Event><FVB Mouse><Failure><Fungus Diseases><Gene Localization><Gene Mapping><Gene Mapping Genetics><Generalized Growth><Genetic><Goals><Growth><Host Defense><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Immunity><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Impairment><In Vitro><Inbred Strains Mice><Inbreeding><Infection><Inflammatory><Ingestion><Injury><Innate Immunity><Interferon Gamma><Interferon Type II><Interstitial Plasma Cell Pneumonia><Knowledge><Laboratories><Life><Linkage Mapping><Lung><Lung Respiratory System><Macrophage><Maps><Mediating><Mice><Mice Mammals><Mission><Modeling><Mouse Strains><Murine><Mus><Mycoses><Mφ><NIH><National Institutes of Health><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Organism><Outcome><P jirovecii pneumonia><P. jirovecii Pneumonia><PTK Receptors><Patient Care><Patient Care Delivery><Pattern recognition receptor><Phagocytes><Phagocytic Cell><Phagocytosis><Phagosomes><Phenotype><Pneumocystis><Pneumocystis Infections><Pneumocystis Pneumonia><Pneumocystis carinii Infections><Pneumocystis carinii Pneumonia><Pneumocystis jirovecii pneumonia><Pneumocystosis><Predisposition><Production><Productivity><Proteins><Pulmonary Macrophages><QTL><Quantitative Trait Loci><Reagent><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Regulation><Research><Research Design><Resistance><Resistance to infection><Role><Sentinel><Study Type><Surface><Susceptibility><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Therapeutic Fungicides><Time><Tissue Growth><Total Human and Non-Human Gene Mapping><Transmembrane Receptor Protein Tyrosine Kinase><Transmission><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><United States National Institutes of Health><Work><adaptive immunity><amebocyte><anti-fungal><anti-fungal agents><anti-fungal drug><bacterial disease treatment><bacterial infectious disease treatment><candidate identification><care for patients><care of patients><caring for patients><drug discovery><fungal infection><fungal pathogen><fungi pathogen><fungus infection><gene locus><genetic locus><genetic mapping><genomic location><genomic locus><immune competent><immunosuppressed patient><improved><in vivo><infection resistance><ingest><inhibitor><injuries><insight><lFN-Gamma><living system><mortality rate><mortality ratio><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><pathogen><pathogenic fungus><programs><protein expression><pulmonary><rational design><receptor><resistance gene><resistance locus><resistant><resistant gene><respiratory><social role><study design><thymus derived lymphocyte><tool><translational study><transmission process><treatment strategy>