The interplay between SARS-CoV-2 infection and dysregulated gut immunity

Abstract

An increasing number of sequelae and people suffering from the long-term debilitating effects of COVID-19 (long COVID-19 or post-acute COVID-19 syndrome - PACS) highlight the necessity of special attention to the interactions between SARS-CoV-2 and other organs such as intestine which, in addition to the lungs, are affected by the virus. Gastrointestinal (GI) symptoms such as abdominal pain and diarrhea have been reported during acute infection and can appear or persist as PACS. Another particular group of patients presents Inflammatory Bowel Diseases (IBD) such as Ulcerative Colitis (UC). These chronic GI disorders are treated with immunosuppressive therapies that may affect vaccines efficiency and effective anti-viral responses. Then, we speculate that IBD patients could be important long-term reservoirs of SARS-CoV-2 with maintenance of memory responses associated with post COVID-19 syndrome. Notably, IBD patients presenting persistence of SARS-CoV-2 antigens in the gut exhibit PACS, while those without virus' antigens are recovered after acute COVID-19. These findings suggested that PACS could be related to a possible immune dysregulation triggered by long-lasting SARS-CoV-2 antigens. Indeed, new COVID-19 sequelae are being increasingly recognized in the GI tract and in other body systems. Long-term consequences of the infection in patients genetically predisposed to IBD, as well as the role of SARS-CoV-2 as a trigger for a new onset colitis are still not totally clear. Otherwise, the susceptibility of UC patients to long COVID-19 as well as the later impacts of SARS-CoV-2 infection in the IBD clinical or endoscopic remission are still questionable. Here, we propose to investigate the complex interplay linking the breakdown of gut homeostasis and SARS-CoV-2 infection as a model to study the pathogenesis of long COVID-19, while exploring the reciprocal impacts between Ulcerative Colitis and COVID-19. Also, we expect to contribute to the management of patients affected by both UC and COVID-19, especially the virus sequelae in this IBD population who is previously prone to the breakdown of intestinal tolerance. To achieve our goals, first we will investigate the association of systemic dysregulated responses and GI manifestations in non-IBD patients presenting acute or post-acute COVID-19, as well as in subjects with UC who are either in disease remission or activity. We will also conduct in vitro tests using intestinal organoids to determine how circulating mediators that contribute to the worsening of both diseases, affect the intestinal responses to the virus, with or without gut bacteria products. Next, will use mice models of colitis and SARS-CoV-2 infection to unveil the mechanisms and effects of colitis on the virus infection, as well as the SARS-CoV-2 effects on a later intestinal inflammation. Additionally, UC patients who experience remission of intestinal inflammation will be monitored for an upcoming COVID-19 and long-term recovery of the infection, to elucidate if the disease sequelae or immunological memory to the virus could be related to colitis clinical and/or endoscopic relapses. The results from blood tests and transcriptome analysis, as well as metabolome assessment of plasma and feces, together with cellular and humoral responses, spatial transcriptomics of human gut biopsies, memory and TCR repertoire, bacteriome, PhIP-Seq detection of gut specific antibodies, quantification of virus, immune and endocrine mediators will be evaluated regarding the clinical progression of the diseases and analyzed integratively. This study holds crucial importance in comprehending the aftermaths and interplay between COVID-19 and IBD. Ultimately, it carries the potential to enhance the clinical approaches for treating patients with UC, COVID-19, or those with comorbid UC-COVID-19. (AU)