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Principal Investigator: Shao-Cong Sun
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2020
Award: $162,946
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causes coronavirus disease
2019 (COVID-19), which is characterized by acute inflammation in the lung and other organs, such as the
heart and intestine. It is increasingly clear that the pathogenesis of SARS-CoV2 involves suppression of
antiviral innate immunity and induction of inflammatory responses. SARS-CoV2 suppresses induction of the
antiviral type I interferons (IFNs) and, thereby, escapes from destruction by the early phase antiviral immunity.
Subsequent induction of inflammatory responses drives the development of COVID-19. Understanding how
SARS-CoV2 suppresses type I IFN expression and induces inflammatory responses, is crucial for designing
therapeutic approaches. Based on the studies of SARS-CoV, the close homolog of SARS-CoV2, several viral
proteins have been implicated in the interplay with host immune system, contributing to the suppression of type
I IFN responses and induction of proinflammatory cytokines. The major goal of this supplementary application
is to understand the mechanisms by which SARS-CoV2 proteins suppress antiviral innate immunity and
stimulate exacerbated inflammatory responses. We will perform two specific aims.
In Specific Aim 1, we will examine how SARS-CoV2 proteins suppress TBK1 signaling and antiviral innate
immunity. As described in the parent grant, TBK1 is a kinase that responds to signals from the toll-like
receptors (TLRs) and other pattern-recognition receptors (PRRs) during viral infections and mediates induction
type I IFNs. At the same time, TBK1 negatively regulates proinflammatory cytokine induction to prevent
exacerbated inflammation. Our parental grant focuses on the elucidation of how TBK1 regulates TLR signaling
and intestinal inflammation caused by gut microbes. In this supplementary application, we will specifically
address how SARS-CoV2 proteins modulate TBK1 signaling in the suppression of antiviral immunity and
stimulation of inflammation. We will examine our hypothesis that suppression of TBK1 signaling by SARS-
CoV2 proteins not only inhibits type I IFN production but also promotes inflammatory responses.
In Specific Aim 2, we will systematically define the mechanisms by which SARS-COV2 proteins induce
inflammatory responses using both cell culture and mouse models. We will examine the signaling pathways
involved in SARS-CoV2-induced expression of proinflammatory cytokines in macrophages and epithelial cells.
We will also examine how the Spike protein of SARS-CoV2 downregulates its cellular receptor, angiotensin-
converting enzyme 2 (ACE2). Since ACE2 is a pivotal anti-inflammatory factor, we hypothesize that Spike
protein-induced ACE2 downregulation critically contributes to the induction of lung and intestinal inflammation.
We believe that these proposed studies address novel mechanisms that mediate the pathogenesis of
COVID19 and will have important implications for COVID19 therapies.
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