In late 2019, a novel human betacoronavirus emerged in Wuhan, China and subsequently led to pandemic spread. Designated Severe Acute Respiratory Virus 2 (SARS CoV-2), this virus has spawned a coronaviral infection (COVID-19) that has threatened world populations and overwhelmed healthcare systems globally. Host immune responses during COVID-19 clearly play a significant role in viral clearance as well as pulmonary progression, but these responses are yet to be characterized. Most notably, the innate immune responses required for viral clearance and resistance to repeated infections are not yet known. Recent studies also suggest that these innate immune responses can also form immunologic memory (?trained immunity?) that occurs independently of B and T cells and results from epigenetic reprogramming of monocytes, macrophage and NK cell functions that alters their intracellular signaling and cellular metabolism patterns. This reprogramming allows them to acquire enhanced capability to respond to secondary stimulation by related or unrelated infectious agents. Because data from related coronaviruses suggest that innate immune responses are fundamentally important to pathogenesis, we hypothesize that NK/monocyte responses to viral proteins are necessary to maximize host immune responses. In this proposal, we will comprehensively investigate the importance of innate immune cells in the development of anamnestic adaptive responses to SARS CoV-2 antigen, and the role of NK and monocytes/macrophages in trained innate immune responses to viral antigen, from a clinically characterized cohort of COVID-19 patients following recovery.
In aim 1, we will determine the importance of innate immune responses in responding to repeat exposure to viral antigens following COVID-19 recovery by 1) assessing the necessity of innate immune cells in generating anamnestic adaptive cellular responses to SARS CoV-2, and 2) characterizing the cross-reactivity of betacoronaviral antigens in inducing NK/monocyte responses including phenotypic changes, activation, proliferation, and cytokine expression, in COVID-recovered subjects.
In aim 2, we identify innate trained immune responses to SARS CoV-2 antigens following COVID-19 recovery by examining if either NK cells or monocytes/macrophages from COVID-19 recovered subjects exhibit innate immune memory to SARS CoV-2 as assayed by functional, metabolic, and epigenetic changes These novel translational studies will produce key, relevant data on host immunity to COVID-19 infection, informing vaccine design and enhancing our understanding of innate immune memory and the correlates of protective immunity.

Public Health Relevance

Severe Acute Respiratory Virus 2 (SARS CoV-2) has spawned a coronaviral infection (COVID- 19) that has threatened world populations and overwhelmed healthcare systems globally. The immune system responds to viral infections with fundamental, innate immune responses mediated primarily by natural killer (NK) cells and monocyte/macrophages, and these responses appear important to the pathogenesis of COVID-19. In addition, recent studies suggest that these innate immune cells have immunologic memory of prior infection. In this proposal, we will employ COVID-19-recovered patients to isolate NK cells and monocytes and examine their responses to re-exposure to SARS CoV-2 and other coronavirus antigens, focusing on their ability to activate the adaptive immune system and to generate immunologic memory of COVID- 19 infection. These studies are key to understanding SARS CoV-2 pathogenesis and informing vaccine design strategies.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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James H Quillen VA Medical Center
Mountain Home
United States
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