Identification of a genetic region linked to tolerance to MRSA infection using Collaborative Cross mice.

Autor: Nagarajan A; Interdisciplinary Program in Genetics and Genomics, Texas A&M University, College Station, Texas, United States of America.; Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America., Scoggin K; Interdisciplinary Program in Genetics and Genomics, Texas A&M University, College Station, Texas, United States of America.; Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America., Adams LG; Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America., Threadgill D; Interdisciplinary Program in Genetics and Genomics, Texas A&M University, College Station, Texas, United States of America.; Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, United States of America.; Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, Texas, United States of America.; Department of Biochemistry & Biophysics and Department of Nutrition, Texas A&M University, College Station, Texas, United States of America., Andrews-Polymenis H; Interdisciplinary Program in Genetics and Genomics, Texas A&M University, College Station, Texas, United States of America.; Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2024 Aug 23; Vol. 20 (8), pp. e1011378. Date of Electronic Publication: 2024 Aug 23 (Print Publication: 2024).
DOI: 10.1371/journal.pgen.1011378
Abstrakt: Staphylococcus aureus (S. aureus) colonizes humans asymptomatically but can also cause opportunistic infections, ranging from mild skin infections to severe life-threatening conditions. Resistance and tolerance are two ways a host can survive an infection. Resistance is limiting the pathogen burden, while tolerance is limiting the health impact of a given pathogen burden. In previous work, we established that collaborative cross (CC) mouse line CC061 is highly susceptible to Methicillin-resistant S. aureus infection (MRSA, USA300), while CC024 is tolerant. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice to generate F1 and F2 populations. Survival after MRSA infection in the F1 and F2 generations was 65% and 55% and followed a complex dominant inheritance pattern for the CC024 increased survival phenotype. Colonization in F2 animals was more extreme than in their parents, suggesting successful segregation of genetic factors. We identified a Quantitative Trait Locus (QTL) peak on chromosome 7 for survival and weight change after infection. In this QTL, the WSB/EiJ (WSB) allele was present in CC024 mice and contributed to their MRSA tolerant phenotype. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. C5ar1 and C5ar2 are receptors for the complement factor C5a, an anaphylatoxin that can trigger a massive immune response by binding to these receptors. We hypothesize that C5a may have altered binding to variant receptors in CC024 mice, reducing damage caused by the cytokine storm and resulting in the ability to tolerate a higher pathogen burden and longer survival.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Nagarajan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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