{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T07:13:10Z","timestamp":1772176390849,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011378","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T00:00:00Z","timestamp":1726531200000}}],"reference-count":113,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T00:00:00Z","timestamp":1724371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["D17AP00004"],"award-info":[{"award-number":["D17AP00004"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["D17AP00004"],"award-info":[{"award-number":["D17AP00004"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    ) 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\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    infection (MRSA, USA300), while CC024 is tolerant. To identify host genes involved in tolerance after\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    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,\n                    <jats:italic>C5ar1<\/jats:italic>\n                    and\n                    <jats:italic>C5ar2<\/jats:italic>\n                    , have high-impact variants in this region.\n                    <jats:italic>C5ar1<\/jats:italic>\n                    and\n                    <jats:italic>C5ar2<\/jats:italic>\n                    are receptors for the complement factor\n                    <jats:italic>C5a<\/jats:italic>\n                    , an anaphylatoxin that can trigger a massive immune response by binding to these receptors. We hypothesize that\n                    <jats:italic>C5a<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011378","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T14:11:14Z","timestamp":1724422274000},"page":"e1011378","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a genetic region linked to tolerance to MRSA infection using Collaborative Cross mice"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-3729","authenticated-orcid":true,"given":"Aravindh","family":"Nagarajan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6156-2224","authenticated-orcid":true,"given":"Kristin","family":"Scoggin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-1602","authenticated-orcid":true,"given":"L. Garry","family":"Adams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Threadgill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1818-1335","authenticated-orcid":true,"given":"Helene","family":"Andrews-Polymenis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,8,23]]},"reference":[{"issue":"19","key":"pgen.1011378.ref001","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21197061","article-title":"Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models.","volume":"21","author":"DM Mrochen","year":"2020","journal-title":"Int J Mol Sci."},{"issue":"8","key":"pgen.1011378.ref002","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"FD Lowy","year":"1998","journal-title":"N Engl J Med"},{"issue":"11","key":"pgen.1011378.ref003","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/nrmicro.2017.104","article-title":"The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota","volume":"15","author":"B Krismer","year":"2017","journal-title":"Nat Rev Microbiol"},{"issue":"10369","key":"pgen.1011378.ref004","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1016\/S0140-6736(22)02185-7","article-title":"Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019.","volume":"400","author":"GBD","year":"2022","journal-title":"Lancet"},{"issue":"6\u20137","key":"pgen.1011378.ref005","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.ijmm.2013.02.007","article-title":"Community-associated MRSA: what makes them special?","volume":"303","author":"M. 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