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Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections

Award Number: R01HL165259
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Pneumonia is an important global health problem 1. Influenza A virus (IAV) leads to an estimated 500,000 deaths annually, and these numbers can be even higher during IAV pandemic years 2. A complication following infection with IAV is bacterial pneumonia, and this can lead to a more severe disease 3- 21. To survive a given infection hosts must be able to not only clear the pathogen, but also tolerate to the effects of the pathogen or the host response. The latter processes are referred to as disease tolerance. Normally, a balance between these two processes is reached, and the infection resolves 2223. My research lab has been at the forefront of exploring the concept of host disease tolerance in deadly complex respiratory infections 242322 • 25 • 26. We have shown that during pulmonary IAV/bacterial coinfection this balance between resistance and tolerance is disrupted causing increased lethality 22,24. Regulated cell death (RCD) plays important roles in both resistance and tolerance to infection. Cell death can be broadly categorized as membrane permeable (e.g. necroptosis and pyroptosis) or membrane impermeable (e.g. apoptosis). During infection several different types of cell death can be induced each inducing a unique response. Macrophages are responsible for both resistance mechanisms such as coordination of the immune response, and they contribute to tolerance in the form of the tissue repair responses after damage. This proposal aims to bridge gaps in our current understanding of complex respiratory infections by investigating the role of Caspase-8. a key regulator of RCD. in relevant in vitro and in vivo models of IAV/bacterial coinfection. We will focus on understanding how Caspase-8 pathways in lung macrophages during IAV/bacterial coinfection contributes to resistance and tolerance. Our preliminary data has demonstrated that Caspase-8 deficiency in macrophages leads to increased host resistance at the expense of host tolerance in the early stages of coinfection. This is most likely due to increased necroptosis and anti-microbial responses. We hypothesize that during severe lung infections such as those that occur with bacterial infection following IAV infection macrophage cell death controlled by Caspase-8 plays an important role in regulating the balance between resistance and tolerance. In this study we will determine the role that Caspase-8 in macrophages plays throughout the course of infection. We will use relevant in vitro models using human primary macrophages, as well as in vivo models. These studies will lay the foundation for future studies on understanding the impact of RCD in macrophages during complex pulmonary infections, which may ultimately lead to improved treatment options for patients with complex and severe lung infections.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $56,400 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	2	12/11/2024	SUPPLEMENT FOR EXPANSION	$56,400
														Subtotal = $56,400

Issue Date FY: 2024 ( Subtotal = $757,662 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	2	5/29/2024	NON-COMPETING CONTINUATION	$757,662
														Subtotal = $757,662

Issue Date FY: 2023 ( Subtotal = $797,454 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	1	8/2/2023	NEW	$797,454
														Subtotal = $797,454

Grand Total All Awards = $1,611,516

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Central role of Caspase-8 in control of host tolerance and resistance mechanisms in pulmonary macrophage populations during severe respiratory infections

Award Number: R01HL165259

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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