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

• Grant number: 23/03257-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2024
• End date: August 31, 2029
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Cristina Ribeiro de Barros Cardoso
• Grantee: Cristina Ribeiro de Barros Cardoso
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Antonio Ricardo Khouri Cunha ; Arno Rolf Bourgonje ; Atila Alexandre Trapé ; Carlos Arterio Sorgi ; Daniela Carlos Sartori ; Elaine Cristina Pereira de Martinis ; Eurico de Arruda Neto ; Fernanda de Freitas Anibal ; Gerard Dijkstra ; Gislane Lelis Vilela de Oliveira ; Gustavo Cabral de Miranda ; Jelle Matthijnssens ; Johan van Weyenbergh ; José Joaquim Ribeiro da Rocha ; Kelen Cristina Ribeiro Malmegrim de Farias ; Klaas Nico Faber ; Lúcia Helena Faccioli ; Manoel Barral Netto ; Marcelo Dias Baruffi ; Marley Ribeiro Feitosa ; Murillo Duarte Silva ; Omar Feres ; Rafael Luís Luporini ; Rogerio Serafim Parra ; Scott Snapper ; Viviane Sampaio Boaventura de Oliveira
• Associated research grant(s): 25/03689-7 - Multi-user equipment approved in grant 2023/03257-4: endoscopy system for mice (Karl Storz): TELE PACK + VET, AP.EMU
• Associated scholarship(s): 25/12298-1 - Immune Dysregulation and Barrier Dysfunction in COVID-19 and Ulcerative Colitis: Shared Mechanisms and Comparative Insights, BP.IC; 25/01984-1 - Unraveling the Interplay between SARS-CoV-2 Infection and Ulcerative Colitis: An Integrated Analysis of Immune Responses and Gut Microbiome, BP.DD; 25/01983-5 - Deciphering the interplay between immunoendocrine responses and gastrointestinal manifestations in the worsening of COVID-19, BP.DD; 24/22179-7 - Investigation of SARS-CoV-2 Impact on Ulcerative Colitis and Long-term Consequences of COVID-19, BP.PD; 24/20758-0 - Impact of sexual dimorphism on experimental colitis, BP.IC

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)