Background: Natural immunity to Streptococcus pyogenes (StrepA) is slow to develop and its role in preventing subsequent infections is poorly understood. Current efforts are yet to define a vaccine to protect against a diverse range of StrepA serotypes in addition to preventing both skin and upper respiratory tract (URT) mucosal infections.
Methods: Through multiple non-lethal, intranasal infections with StrepA M1 strain, we modelled repeated URT natural exposure to StrepA in mice to interrogate site-specific and “cross-compartment” protection at the skin site. We further deciphered the humoral and cellular immune mechanisms governing protection based on ELISA, ELISpot, flow cytometry and IHC analysis.
Results: Mice pre-exposed intranasally to a homologous StrepA isolate generated a cumulative, site-specific protective effect on subsequent infections, characterised by reduction of bacterial burden in NALT (analogue to human tonsil) and lungs. Protection was induced in the URT after a single infection and endured for at least 9 weeks. However, at least four repeated homologous intranasal infections were needed to induce significant cross-compartment protection at the skin site.
URT immunity was associated with an increase of M1-specific salivary IgG and IgA, higher infiltration of neutrophils and effector memory CD4+ T cells into the lungs and increased IL-17A secretion by lung immune cells. The importance of IL-17 for site-specific protection was confirmed in IL-17 KO mice, which did not develop a protective response in the URT following StrepA challenge, even when previously infected multiple times. Repeated URT mucosal infections generated cross-compartment immunity at the skin site that was not associated with changes in IL-17 levels, but correlated with germinal centre activity , as detected by increased levels of sera CXCL13 and expansion of CD4+ T cells in the splenic follicles.
Conclusion: Altogether, our data show that different immune mechanisms operate at different sites of StrepA infection. Induction of local immune response is the key to protective immunity and therefore must be taken into consideration for vaccine designing and delivery strategies.