Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model.
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.
Merck Research Labs, Merck and Co. Inc., West Point, PA, USA. amita_joshi@merck.com
Amita
A
Joshi
Greg
G
Pancari
Leslie
L
Cope
Edward P
EP
Bowman
Daniel
D
Cua
Richard A
RA
Proctor
Tessie
T
McNeely
D000818:Animals; D027682:Cation Transport Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D016219:Immunotherapy, Adoptive; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D018805:Sepsis / Q000276:immunology / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
D027682:Cation Transport Proteins; D020381:Interleukin-17; C510010:IsdB protein, Staphylococcus aureus; D013209:Staphylococcal Vaccines