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.

Public Health Relevance

The pathogenesis of COVID-19 involves exacerbated inflammation in the lung and other organs, which in turn due to responses of host immune cells to the infection of the COVID-19-causative virus SARS-CoV2. The proposed project addresses innovative questions regarding how SARS-CoV2 induces inflammatory responses and will lead to high-impact findings with therapeutic implications.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Vazquez-Maldonado, Nancy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Shi, Jian-Hong; Sun, Shao-Cong (2018) Tumor Necrosis Factor Receptor-Associated Factor Regulation of Nuclear Factor ?B and Mitogen-Activated Protein Kinase Pathways. Front Immunol 9:1849
Shi, Jian-Hong; Xie, Xiaoping; Sun, Shao-Cong (2018) TBK1 as a regulator of autoimmunity and antitumor immunity. Cell Mol Immunol 15:743-745
Zhu, Lele; Xie, Xiaoping; Zhang, Lingyun et al. (2018) TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival. Nat Commun 9:2812
Jie, Zuliang; Yang, Jin-Young; Gu, Meidi et al. (2018) NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis. Nat Immunol 19:1224-1235
Yang, Jie; Zhang, Siya; Zhang, Lingyun et al. (2018) Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cell Mol Immunol :
Zhang, Huiyuan; Li, Haiyan S; Hillmer, Emily J et al. (2018) Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis. Proc Natl Acad Sci U S A 115:E2311-E2319
Sun, Shao-Cong (2017) The non-canonical NF-?B pathway in immunity and inflammation. Nat Rev Immunol 17:545-558
Liu, Ting; Zhang, Lingyun; Joo, Donghyun et al. (2017) NF-?B signaling in inflammation. Signal Transduct Target Ther 2:
Hu, Hongbo; Sun, Shao-Cong (2016) Ubiquitin signaling in immune responses. Cell Res 26:457-83
Jin, Jin; Xie, Xiaoping; Xiao, Yichuan et al. (2016) Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 17:259-68

Showing the most recent 10 out of 56 publications