Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

Maren von Köckritz-Blickwede^*, Manfred Rohde, Sonja Oehmcke, Lloyd S. Miller, Ambrose L. Cheung^¶, Heiko Herwald, Simon Foster^|| and Eva Medina^*

From the Research Group Infection Immunology,^* and the Department of Microbial Pathogenesis, Helmholtz Centre for Infection Research, Braunschweig, Germany; the Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden; the Department of Microbiology, Immunology, and Molecular Genetics, Division of Dermatology, David Geffen School of Medicine, Los Angeles, California; the Department of Microbiology and Immunology,^¶ Dartmouth Medical School Hanover, New Hampshire; and the Department of Molecular Biology and Biotechnology,|| University of Sheffield, Sheffield, United Kingdom

Host genetic variations play a significant role in conferringpredisposition to infection. In this study, we examined theimmune mechanisms underlying the host genetic predispositionto severe Staphylococcus aureus infection in different mousestrains. Whereas C57BL/6 mice were the most resistant in termsof control of bacterial growth and survival, A/J, DBA/2, andBALB/c mice were highly susceptible and succumbed to infectionshortly after bacterial inoculation. Other strains (C3H/HeN,CBA, and C57BL/10) exhibited intermediate susceptibility levels.Susceptibility of mice to S. aureus was associated with an inabilityto limit bacterial growth in the kidneys and development ofpathology. Resistance to S. aureus in C57BL/6 mice was dependenton innate immune mechanisms because Rag2-IL2R ${gamma}$ ^–/–C57BL/6 mice, which are deficient in B, T, and NK cells, werealso resistant to infection. Indeed, neutrophil depletion orinhibition of neutrophil recruitment rendered C57BL/6 mice completelysusceptible to S. aureus, indicating that neutrophils are essentialfor the observed resistance. Although neutrophil function isnot inhibited in A/J mice, expression of neutrophil chemoattractantsKC and MIP-2 peaked earlier in the kidneys of C57BL/6 mice thanin A/J mice, indicating that a delay in neutrophil recruitmentto the site of infection may underlie the increased susceptibilityof A/J mice to S. aureus.