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.
PLoS Genet. 2024 Aug 23;20(8):e1011378. doi: 10.1371/journal.pgen.1011378. eCollection 2024 Aug.
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.
金黄色葡萄球菌（S. aureus）无症状地定植于人体，但也可引发机会性感染，从轻症皮肤感染到严重危及生命的病症均有涉及。抵抗和耐受是宿主在感染中得以存活的两种方式。抵抗是限制病原体负担，而耐受是限制给定病原体负担对健康的影响。在之前的工作中，我们建立了合作交叉（CC）小鼠品系 CC061 对耐甲氧西林金黄色葡萄球菌（MRSA，USA300）感染高度易感，而 CC024 具有耐受性。为了鉴定金黄色葡萄球菌感染后涉及耐受的宿主基因，我们将 CC061 小鼠和 CC024 小鼠进行杂交，以产生 F1 和 F2 群体。F1 和 F2 代在 MRSA 感染后的存活率分别为 65%和 55%，并表现出 CC024 增加的生存表型的复杂显性遗传模式。F2 代动物的定植比其父母更为极端，这表明遗传因素成功分离。我们在染色体 7 上鉴定出一个与感染后存活和体重变化相关的数量性状基因座（QTL）峰。在这个 QTL 中，CC024 小鼠中存在 WSB/EiJ（WSB）等位基因，这有助于它们的 MRSA 耐受表型。该区域存在两个基因，C5ar1 和 C5ar2，它们具有高影响的变异体。C5ar1 和 C5ar2 是补体因子 C5a 的受体，C5a 是一种过敏毒素，通过与这些受体结合可引发大规模免疫反应。我们假设 C5a 可能与 CC024 小鼠中变体受体的结合发生改变，从而减少细胞因子风暴造成的损害，并使它们能够耐受更高的病原体负担和更长的存活时间。
