Innate responses following infection with enteric microbes

Abstract: As the rapidly unfolding COVID-19 pandemic claims its victims around the world, it has also inspired the scientificcommunity to come up with solutions to meet an urgent and unmet need -i.e., ameliorate the severity of Covid-19 and reduce mortality. Two obstacles make that task difficult-First, the pathophysiology of Covid-19 remainsa mystery; the emerging reports generally agree that the disease has a very slow onset and that those whosuccumb typically mount a 'cytokine storm', i.e., an overzealous immune response. However, despite beingimplicated as a culprit behind the observed mortality and morbidity in COVID-19, we know virtually nothing aboutwhat constitutes (nature, extent) or contributes to (cell or origin) such an overzealous response. A significantnumber of patients have GI symptoms. The treatment goals in COVID-19 have been formulated largely as a 'trialand error'-approach; this is reflected in the mixed results of the trials that have concluded. Second, the processof drug discovery is comprised of time-consuming steps; to avoid delays, we need to define the nature of thefatal cellular response before deciding how to model it in animals or matching therapeutics to curb it. Our preliminary work has helped us define the aberrant host cellular response in COVID-19. We usedmachine learning tools that can look beyond interindividual variability to extract underlying gene expressionpatterns within complex data across multiple cohorts of viral pandemics, including COVID-19. The resultantpattern, i.e., signature, was subsequently exploited as a predictive model to navigate COVID-19 for GIsymptoms. Surprisingly, the 166-gene signature was conserved in all viral pandemics, including COVID-19,inspiring the nomenclature-- (ViP)-signature. The ViP signature identified and predicted the disease severity ofSARS-CoV2-infected patients. We hypothesized that the ViP signature provides a quantitative and qualitativeframework for titrating the cellular response in viral pandemics and could serve as a powerful unbiased tool inour armamentarium to vet candidate drugs rapidly. In this proposal, our predicted model, experimental datasetsand the information from published literature will be used to screen drugs/nutritional components/probiotics inthe GI organoid derived monolayers in a semi-HTP format. We will experimentally validate the effect of thetherapeutics predicted in ViP gene signature of the host. The following two aims will provide a translational impacton the COVID-19 emergency.Aim 1: Identify the gastro-intestinal pathogenic pathways during COVID-19.Aim 2: Determine the impact of drugs, nutrients and supplements in gut-in-a-dish model of COVID-19.Impact: This proposal will identify the gastro-intestinal pathways (in healthy and patients with chronic diseases)involved in the GI symptoms of COVID 19 and provide new treatment options in COVID-19.