An alternative mechanism for durable protective immunity to Staphylococcus aureus skin infection

Abstract The immune mechanisms for durable immunity against S. aureus skin infections are unclear as reinfections are common despite specific antibodies and Th1/Th17 cells. Using a CA-MRSA skin reinfection model in mice involving a primary infection (1°) in the lower back (cleared by 14 days) followed by a secondary infection (2°) in the upper back on day 28, we found that 1° and 2° wt mice had similar responses. In contrast, 1° IL-1β−/− mice had increased lesions and bacterial burden with impaired neutrophil recruitment whereas 2° IL-1β−/− mice were protected and resembled wt mice. Transfer of serum containing CA-MRSA specific antibodies did not confer protection to 1° IL-1β−/− mice and depletion of CD4+ T cells did not alter the protection of 2° IL-1β−/− mice, indicating a lack of a role of antibodies or CD4+ T cells. However, 2° IL-1β−/− mice were no longer protected if the egress of lymphocytes from lymph nodes was blocked in 2° IL-1β−/− mice (FTY720 treatment) and the immune impairment in naïve IL-1β−/− mice could be rescued by adoptive transfer of total lymph nodes cells from d28 IL-1β−/− mice. Moreover, transfer of only 50,000 γδ T cells from lymph nodes of day 28 IL-1β−/− mice conferred protection to 1° IL-1β−/− mice. These γδ T cells produced IFNγ/TNF-α, but not IL-17/IL-22, and neutralizing IFNγ/TNF-α activity resulted in loss of protection in 2° IL-1β−/− mice. In humans, similar IFNγ/TNF-α-producing γδ T cells were found in individuals with IRAK4 deficiency whose susceptibility to S. aureus skin infections improves with age but not from individuals with chronic granulomatous disease whose susceptibility is lifelong. These findings define an alternative mechanism to therapeutically target for long-term protection against CA-MRSA skin infections.