My research program focuses on SARS-CoV, MERS-CoV and SARS-CoV-2, three highly pathogenic coronaviruses emerged into the human population in the 21st century. While genetically quite distinct, these viruses can cause a similar end stage lung disease including diffuse alveolar damage and acute respiratory distress syndrome. By comparing and contrasting virus systems we aim to identify common and unique regulators of disease; focusing on virus-host interactions and how these interactions can promote virus-induced, immune-mediated disease or conversely, protect the infected host.
Our research can be divided into 3 major topics:
- The role of natural genetic diversity in susceptibility to coronavirus infection. Host genetic variation contributes to susceptibility or resistance to many infectious diseases, including human coronaviruses. Using the Collaborative Cross (CC) genetic reference population — in conjunction with collaborators in the UNC Genetics Department and Systems Genetics Core — we examine the role of host genetic variation in contributing to the severity of SARS-CoV and SARS-CoV-2 infection. This non-biased approach allows for discovery of novel host genes that contribute to disease including TRIM55 and Ticam2. Importantly, through the identification of causative mutations, this genetics approach can also provide insight into the molecular mechanisms of disease development.
- Coagulapathies and COVID-19. A particularly challenging aspect of COVID-19 is the variable patient response to SARS-CoV-2 infection. While the majority of patients are asymptomatic or experience mild disease, others display severe disease such as hypoxia, acute respiratory distress syndrome (ARDS), and multi-organ involvement. COVID-19 autopsy studies have uniformly documented the presence of intravascular thrombi and extravascular fibrin deposits with inflammatory cell infiltrates in the lung, heart, and other organs. High rates of thrombosis have been reported in COVID-19 patients, and treatment with low molecular weight heparin (LMWH) has become standard of care for COVID-19 patients. Evidence suggests that dysregulation of the fibrinolytic system and fibrin(ogen)-driven inflammation may constitute a ‘molecular switch’ between mild and severe COVID-19. Working with colaborators in the UNC Blood Research Center we are using the MA10 mouse model of COVID-19 to dissect the role of plasminogen and fibrin/inflammatory cell networks and the provoking mechanisms of failed fibrinolysis are simply a by-product of COVID-19 or whether they actively contribute to the pathogenesis of severe CoV2-driven disease.
- The host immune response to coronavirus infection. Both SARS-CoV and SARS-CoV-2 infections can lead to Acute Respiratory Distress Syndrome (ARDS), an immune mediated, end stage lung disease. ARDS is characterized by high levels of inflammatory cells, surfactant deficiency, vascular leakage and edema, hyaline membrane formation and hypoxia. Mouse models of SARS and COVID-19 accurately reflect the human disease state and are incredibly useful tools for dissecting the mechanisms of disease development. Our group has shown that some host signaling pathways such as complement and IL1 contribute to disease progression, while others such as the TLR3 and TLR4 pathways are essential for protection from disease. Our goal is to understand how these and related pathways get stimulated in response to coronavirus infection to 1) better understand disease progression and 2) identify targets for therapeutic treatment.
Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury. Sims AC, Mitchell HD, Gralinski LE, Kyle JE, Burnum-Johnson KE, Lam M, Fulcher ML, West A, Smith RD, Randell SH, Metz TO, Sheahan TP, Waters KM, Baric RS. mBio. 2021 Aug 31;12(4
Coagulation and wound repair during COVID-19. Menachery VD, Gralinski LE. J Heart Lung Transplant. 2021 Jun 12:S1053-2498(21)02359-7.
SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung. Routhu NK, Cheedarla N, Bollimpelli VS, Gangadhara S, Edara VV, Lai L, Sahoo A, Shiferaw A, Styles TM, Floyd K, Fischinger S, Atyeo C, Shin SA, Gumber S, Kirejczyk S, Dinnon KH 3rd, Shi PY, Menachery VD, Tomai M, Fox CB, Alter G, Vanderford TH, Gralinski L, Suthar MS, Amara RR. Nat Commun. 2021 Jun 11;12(1):3587.
SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd, Liu H, Madden VJ, Krzystek HM, De C, White KK, Gully K, Schäfer A, Zaman T, Leist SR, Grant PO, Bluemling GR, Kolykhalov AA, Natchus MG, Askin FB, Painter G, Browne EP, Jones CD, Pickles RJ, Baric RS, Garcia JV. Nature. 2021 Mar;591(7850):451-457.
Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection in Collaborative Cross mice. Graham JB, Swarts JL, Leist SR, Schäfer A, Menachery VD, Gralinski LE, Jeng S, Miller DR, Mooney MA, McWeeney SK, Ferris MT, Pardo-Manuel de Villena F, Heise MT, Baric RS, Lund JM. PLoS Pathog. 2021
Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody. Rappazzo CG, Tse LV, Kaku CI, Wrapp D, Sakharkar M, Huang D, Deveau LM, Yockachonis TJ, Herbert AS, Battles MB, O’Brien CM, Brown ME, Geoghegan JC, Belk J, Peng L, Yang L, Hou Y, Scobey TD, Burton DR, Nemazee D, Dye JM, Voss JE, Gunn BM, McLellan JS, Baric RS, Gralinski LE, Walker LM. Science. 2021 Feb 19;371(6531):823-829.
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Hou YJ, Chiba S, Halfmann P, Ehre C, Kuroda M, Dinnon KH 3rd, Leist SR, Schäfer A, Nakajima N, Takahashi K, Lee RE, Mascenik TM, Graham R, Edwards CE, Tse LV, Okuda K, Markmann AJ, Bartelt L, de Silva A, Margolis DM, Boucher RC, Randell SH, Suzuki T, Gralinski LE, Kawaoka Y, Baric RS. Science. 2020 Dec 18;370(6523):1464-1468.
A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice. Leist SR, Dinnon KH 3rd, Schäfer A, Tse LV, Okuda K, Hou YJ, West A, Edwards CE, Sanders W, Fritch EJ, Gully KL, Scobey T, Brown AJ, Sheahan TP, Moorman NJ, Boucher RC, Gralinski LE, Montgomery SA, Baric RS. Cell. 2020 Nov 12;183(4):1070-1085.
A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Dinnon KH 3rd, Leist SR, Schäfer A, Edwards CE, Martinez DR, Montgomery SA, West A, Yount BL Jr, Hou YJ, Adams LE, Gully KL, Brown AJ, Huang E, Bryant MD, Choong IC, Glenn JS, Gralinski LE, Sheahan TP, Baric RS. Nature. 2020 Oct;586(7830):560-566.
Return of the Coronavirus: 2019-nCoV. Gralinski LE, Menachery VD. Viruses. 2020 Jan 24;12(2):135.
Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. mBio. 2018 Oct 9;9(5):e01753-18.
Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice. Gralinski LE, Menachery VD, Morgan AP, Totura AL, Beall A, Kocher J, Plante J, Harrison-Shostak DC, Schäfer A, Pardo-Manuel de Villena F, Ferris MT, Baric RS. G3 (Bethesda). 2017 Jun 7;7(6):1653-1663.
Department of Epidemiology
Department of Microbiology & Immunology