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Comparison of gamma variant tropism and pathogenicity versus original SARS CoV-2 in humanized K18-ACE2 mice: role of gut microbiota

Grant number: 19/14342-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2019
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Marco Aurélio Ramirez Vinolo
Grantee:Patrícia Brito Rodrigues
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation, AP.JP2
Associated scholarship(s):22/02058-5 - Clinical aspects and host-microbiota interactions of emerging SARS-CoV-2 variants infection in hamsters, BE.EP.DR


Gastrointestinal symptoms during COVID-19 have been associated with a worse prognosis. Infection with the P.1 variant has a higher mortality rate when compared to ancestral virus infection. In addition, the influence of gastrointestinal disorders, such as dysbiosis of the intestinal microbiota on the physiopathogenesis of COVID-19, especially about the P.1 variant, remains unknown. The objective of this work will be to compare the effects on the composition of the intestinal microbiota during infection with the gamma variant (P.1.) versus the ancestral SARS CoV-2 infection (B.1), in addition to verifying the effects of modulation of the intestinal microbiota via inulin or butyrate ingestion in the immune response profile during SARS-CoV-2 infection. K18-hACE2 mice were infected with ancestral SARS-CoV-2 (B.1) or with the P.1 variant, evaluated clinically for 5 days, and then euthanized for collection of biological materials or maintained for 10 days for survival rate analysis. Viral load will be measured by qRT-PCR in the lung, heart, duodenum, colon, spleen, and whole blood. Inflammatory parameters will be verified by cytokines quantification of the TNF-±, IL-6, IL-1², IL-17, CXCL1 (KC), CXCL-2, and IFN-². by ELISA. In addition, transcripts from apoptosis (BCL-2 and BAX), anti-viral (IFN-³, IFN-², IFN-», OAS1, and ISG15), and inflammatory pathways (CXCL11, CXCL10, TNF-±, IL-6, IL-1², IL-17, IL-22, and RANK-1) will be evaluated by qRT-PCR in lung and isolated intestinal epithelial cells. To verify the microbiota composition, 16S ribosomal RNA sequencing of colonic luminal content will be analyzed. All parameters evaluated will be repeated in experimental models of microbiota depletion by use of antibiotics in drinking water, in addition to models of treatment with a diet supplemented with 5% inulin or treatment via water intake with 150 mM of butyrate. Therefore, the work seeks to contribute information on the pathogenesis of the infection caused by the P.1 variant, especially regarding intestinal and microbiota issues, given their importance in the disease severity. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FACHI, JOSE LUIS; SECCA, CRISTIANE; RODRIGUES, PATRICIA BRITO; PINHEIRO DE MATO, FELIPE CEZAR; DI LUCCIA, BLANDA; FELIPE, JAQUELINE DE SOUZA; PRAL, LAIS PASSARIELLO; RUNGUE, MARCELLA; ROCHA, VICTOR DE MELO; SATO, FABIO TAKEO; et al. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. JOURNAL OF EXPERIMENTAL MEDICINE, v. 217, n. 3, . (17/06577-9, 19/14342-7, 12/10653-9, 18/02208-1, 17/16280-3)
PASCOAL, LIVIA BITENCOURT; RODRIGUES, PATRICIA BRITO; GENARO, LIVIA MOREIRA; DOS SANTOS PEREIRA GOMES, ARILSON BERNARDO; TOLEDO-TEIXEIRA, DANIEL AUGUSTO; PARISE, PIERINA LORENCINI; BISPO-DOS-SANTOS, KARINA; SIMEONI, CAMILA LOPES; GUIMARAES, PAULA VERI; BUSCARATTI, LUCAS ILDEFONSO; et al. Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples. GUT MICROBES, v. 13, n. 1, p. 1-9, . (20/04558-0, 20/04583-4, 20/02448-2, 20/02312-3, 19/14342-7, 20/04746-0, 17/26908-0, 20/04579-7, 20/04919-2, 19/06372-3, 13/07607-8, 20/02159-0)

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