Immunization withStaphylococcus aureusiron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model

Abstract

We have previously shown that IsdB, a conserved protein expressed by Staphylococcus aureus, induces a robust antibody response which correlates with protection in a murine challenge model. Here we investigate the role of cellular immunity in IsdB mediated protection using lymphocyte deficient SCID mice. As opposed to WT CB-17 mice the CB-17 SCID mice were not protected against a lethal challenge of S. aureus after active and passive immunizations with IsdB. Adoptive transfer of in vitro isolated lymphocyte subsets revealed that reconstituting mice with IsdB specific CD3+ or CD4+ T-cells conferred antigen specific protection while CD8 + T-cells, CD19 + B-cells and plasma cells (CD138 high B220 int CD19 lo ) alone were not protective. A combination of CD3 + T-cells plus CD19 + B-cells conferred protection in CB-17 SCID mice, whereas bovine serum albumin (BSA) immune lymphocytes did not confer protection. Active immunization experiments indicated that IsdB immunized Jh mice (B-cell deficient) were protected against lethal challenge, while nude (T-cell deficient) mice were not. In vitro assays indicated that isolated IsdB specific splenocytes from immunized mice produced abundant IL-17A, much less IFN-γ and no detectable IL-4. IL-23 deficient mice were not protected from a lethal challenge by IsdB vaccination, pointing to a critical role for CD4 + Th17 in IsdB-mediated vaccination. Neutralizing IL-17A, but not IL-22 in vivo significantly increased mortality in IsdB immunized mice; whereas, neutralizing IFN-γ did not alter IsdB-mediated protection. These findings suggest that IL-17A producing Th17 cells play an essential role in IsdB vaccine-mediated defense against invasive S. aureus infection in mice.

Naturally occurring IgG antibody levels to theStaphylococcus aureusprotein IsdB in humans

“…Of the 50 hospital controls, 39 had sera from multiple time-points (median number of samples: 4, range: 2 to 8), and the mean time for final follow-up was 11.6 days post-diagnosis (range: 2 to 34 days). The mean time of followup was slightly longer for the hospital S. aureus cases compared deleted strain, 9,16 confirming the specificity of the vaccine. An observed rise in anti-IsdB titers induced by IsdB formulated on Merck aluminum adjuvant (MAA) correlated with protection against lethal S. aureus challenge, 9 indicating that antibody titers may be used as a nominal biomarker for vaccine efficacy.…”

“…Efficacy was mediated through an antigen specific IL17 response. 16 It should be noted that T-cell response to V710 (IsdB) in humans has not been evaluated.…”

“…8,11,12 Expression of IsdB was highly upregulated by essentially 100% of strain Becker grown under in vivo conditions in rats. 10 Multiple reports have demonstrated IsdB to be a potential vaccine candidate for the prevention of S. aureus infection 9,[13][14][15][16] in rodent challenge models. Importantly, enhanced protection from lethal sepsis in rodent models was mediated by both IsdB-specific CD4+ T cells, 16 and IsdB-specific mAb.…”

“…10 Multiple reports have demonstrated IsdB to be a potential vaccine candidate for the prevention of S. aureus infection 9,[13][14][15][16] in rodent challenge models. Importantly, enhanced protection from lethal sepsis in rodent models was mediated by both IsdB-specific CD4+ T cells, 16 and IsdB-specific mAb. 10,13,[17][18][19] The protection afforded by vaccination with IsdB in rodents was lost if the animals were challenged with an IsdB fluid (9), surgical tissue (22), synovial fluid (17), sputum (9), or other sites (5) during routine clinical care.…”

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…Neutralization of IL-17A and IL-22 resulted in significantly greater MRSA dissemination to kidneys in NDV-3-vaccinated mice. Interestingly, in nonvaccinated mice, Joshi et al observed that neutralization of IL-17A but not IL-22 increased mortality in S. aureus sepsis (69). In NDV-3-vaccinated mice, inhibition of both IL-17A and IL-22 was required to increase MRSA dissemination to the kidney.…”