Complex host genetic susceptibility to Staphylococcus aureus infections

• Great care is needed to select cases and controls for genetic studies of Staphylococcus aureus infection.
• Infection susceptibility involves cell adhesion, invasion, and innate and adaptive immunity.
• Genetics of S. aureus carriage and severe infection involves different host factors.
• Susceptibility to S. aureus infections is polygenic due to pathogen versatility.
• S. aureus infection severity, trajectory, and tissue specificity are polygenic.

Understanding of the host genetic susceptibility to carriage of, and infections, due to Staphylococcus aureus, a nosocomial pathogen, is still in its nascent stages. Mouse models show variable susceptibility to S. aureus infections across mouse strains and disease models with roles for signaling pathways involving Toll-like receptors (TLR-1, TLR-2, and TLR-6), interleukins (IL-4, IL-6, IL-10, and IL-13), chemokines [CXC ligand (CXCL)-1 and CXCL-2], and T helper (Th)1/Th2 responses. Genome-wide association studies (GWASs) for carriage in humans identified SNPs in IL4, DEFB1, CRP, and VDR for persistent nasal carriage. NR3C1 haplotypes may either enhance risk or provide protection from colonization. GWASs for all S. aureus diseases have suggested roles for DAPK3, a kinase, and XRN1, a nuclease, while CDON could have a role in complicated bacteremia. More studies are needed to identify host susceptibility genes along with confirmation from functional assays.