Pathogenesis of SARSCov2 infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Severe SARSCov2 disease occurs, predominantly, in humans with one of several preexisting conditions including cardiovascular disease, advanced age, obesity, and diabetes. These underlying conditions tend to have inflammation in common. Indeed, dexamethasone treatment is showing utility in COVID19. While the actual mechanisms underlying severe COVID19 are unclear increased coagulopathy seems to be common. Moreover, many individuals have evidence of GI tract involvement in their SARSCov2 infection with diarrhea and viral RNA being present in fecal samples. Individuals with high granulocyte to lymphocyte ratios also tend to be more common among groups with severe disease. We hypothesize the GI tract involvement of SARSCov2 infection leads to translocation of microbial products from the lumen of the GI tract into circulation and these lead to inflammation and coagulopathy. We aim to test the hypothesis that microbial translocation contributes to inflammation in SARSCov2 infection. We also aim to artificially elevate the granulocyte to lymphocyte ratio hypothesizing that this will exacerbate SARSCov2 disease. Finally, we aim to determine how, or if, preexisting immunity to common coronavirus (HKU1) influences subsequent SARSCov2 infection. These studies will involve longitudinal analysis of experimentally SARSCov2-infected Asian macaques. We will assess microbial translocation and the composition of the microbiome in animals and we will experimentally elevate the granulocyte to lymphocyte ratio with granulocyte stimulating factor prior to SARSCov2 infection. Finally, we will follow animals who had previously been experimentally infected with HKU1 and subsequently challenged with SARSCov2.