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Principal Investigator: William Clark Gause
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $773,368
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT:
Infections of the lung significantly impact health worldwide, with non-tuberculosis lower respiratory infections
causing 2.7 million deaths annually and chronic infections significantly contributing to impaired lung function and
morbidity. Pulmonary macrophages are critical, front-line mediators of host protection against helminth parasites,
fungi, and viruses. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse
sets of pathogens, our understanding of the cellular and molecular events that regulate macrophage responses
in the lung remain poorly defined. For example, the precise mechanisms that allow pulmonary macrophages to
eliminate both intracellular and extracellular pathogens while simultaneously mitigating tissue injury and
preserving lung function remain elusive. Further, an emerging body of literature has now revealed that
macrophage populations in the lung are more heterogeneous than originally appreciated. Specifically, it is now
understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue-
derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages-
Mo-AMs). Despite this important advance, it is currently unclear whether these ontologically distinct pulmonary
macrophage populations perform comparable or distinct functions in mediating protection (reduction in pathogen
burdens and/or maintenance of tissue integrity). Also, whether these distinct macrophage populations initiate
similar or unique effector functions in the context of helminth, fungal, or viral challenges remains unknown.
Finally, our understanding of how a previous exposure to one pulmonary pathogen alters the responsiveness of
lung macrophages to a subsequent challenge with a distinct pathogen is poorly understood. This important gap
in knowledge has become extremely evident during the COVID-19 pandemic where individual outcomes vary
dramatically and we have a poor understanding of how one’s infectious past may contribute to these differences.
The leaders of this project will employ their combined expertise to address these critical questions. The central
hypothesis of this application is that infection with diverse pathogens program TD-AMs and Mo-AMs to perform
distinct functions against heterologous pathogens while mitigating tissue injury. We further hypothesize that the
pathogen-induced response of TD-AMs and Mo-AMs is critically shaped by neutrophil-derived signals and type
I and III interferons. In three distinct and complementary aims we will use a combination of discovery-based
studies combined with targeted in vitro and in vivo approaches to define the overlapping and unique contributions
of tissue-derived macrophages and recruited monocyte-derived cells to host protective responses following
helminth, fungal or viral infections. This thorough and comprehensive approach will allow us to gain an
unprecedented understanding of fundamental innate immune functions. This novel insight may inform
therapeutic strategies to target lung macrophage populations in a manner that will allow for the fine tuning of
inflammation and pulmonary infection outcomes.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Affect><Alveolar Macrophages><Antigens><Basic Research><Basic Science><Biology><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><CoV-2><CoV2><Communicable Diseases><Coronavirus Infectious Disease 2019><Data><Death><Defect><Embryo><Embryonic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Experimental Models><Exposure to><Fungus Diseases><Gene Targeting><Goals><Health><Helminths><History><IFN><IFNAR><IFNAR1><IFNAR1 gene><Immune><Immune response><Immunes><Immunity><Immunological response><Impairment><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Innate Immunity><Interferons><Intracellular Communication and Signaling><Knowledge><Literature><Lower Respiratory Tract Infection><Lower respiratory infection><Lung><Lung Respiratory System><Lung infections><Macrophage><Maintenance><Maps><Marrow Neutrophil><Marrow monocyte><Mediating><Mediator><Memory><Mice><Mice Mammals><Modification><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Mycoses><Mφ><Native Immunity><Natural Immunity><Nature><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><Ontology><Outcome><Parasites><Parasitic Worms><Pathway interactions><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Primary Infection><Publishing><Pulmonary Macrophages><Recording of previous events><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><STAT1><STAT1 gene><STAT91><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Standardization><Stimulus><Testing><Therapeutic><Therapeutic Fungicides><Tissue Preservation><Tissues><Training><Viral><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><anti-fungal><anti-fungal agents><anti-fungal drug><anti-microbial><antimicrobial><biological signal transduction><chronic infection><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><embryo cell><epigenetically><experience><extracellular><fungal infection><fungal pathogen><fungi pathogen><fungus><fungus infection><gain of function><global gene expression><global transcription profile><hCoV19><helminth infection><helminthic infection><histories><host response><human disease><immune system response><immunogen><immunoresponse><in vivo><infected with helminth><injury to tissue><innate immune function><insight><instructor><loss of function><lung function><lung pathogen><monocyte><mortality><mouse model><murine model><nCoV2><neutrophil><novel><pathogen><pathogenic fungus><pathogenic virus><pathway><persistent infection><programs><pulmonary><pulmonary function><pulmonary infections><pulmonary pathogen><recruit><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><tissue injury><transcriptome><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease>