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

Abstract 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 45% and followed a complex dominant-recessive inheritance pattern. Colonization in F2 animals was more extreme than in their parents, suggesting successful segregation of genetic factors. We identified a QTL peak on chromosome 7 for survival and weight change after infection. In this QTL, the 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. The complement factor, C5a , is an anaphylatoxin that can trigger a massive immune response by binding to its receptors, C5ar1 and C5ar2 . 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. Importance Staphylococcus aureus causes a wide range of diseases in humans. 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. Tolerance mechanisms are poorly understood in context of host-pathogen interaction. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice. The genetic factors controlling tolerance were well segregated in the F2 population. Using QTL mapping, we identified a significant peak on chromosome 7 for survival and weight change after infection. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. 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.