Project Details
Description
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.
Status | Active |
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Effective start/end date | 7/14/23 → 6/30/25 |
Funding
- National Institute of Allergy and Infectious Diseases: $773,368.00
- National Institute of Allergy and Infectious Diseases: $779,547.00
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