IL-17A-Producing Neutrophils Play a Critical Role in Lethal Infection Induced by an Emerging Ultra-Virulent Streptococcus suis Serotype 5 Strain

Streptococcus suis (S. suis) is an important emerging zoonotic pathogen. In recent years, ultra-virulent serotype 5 clinical strains have emerged in China, characterized by causing high mortality in mice at early infection, even at low inoculation doses. In this study, we investigated the characteristics of lethal infection induced by the ultra-virulent S. suis serotype 5 strain SC2022MYS167 isolated from a patient with Streptococcal toxic shock-like syndrome (STSLS) and severe pneumonia. The lethal infection was associated with excessive bacterial loads and pro-inflammatory cytokines in peripheral blood and organs. Blocking IL-17A activity effectively reduced mouse mortality at infection stages 1 and 2. The lung tissues exhibited significantly higher levels of pro-inflammatory cytokines compared to liver and spleen tissues, with elevated IL-17A levels observed exclusively in the lung tissues of moribund mice at infection stage 1. A significant increase in IL-17A-producing CD11b+ Ly6G+ neutrophils recruited from peripheral blood was identified within lung tissues. The inflammatory cascade in lung associated with infiltration of neutrophils accelerated mortality in infected mice. Post-infection depletion of neutrophils rescued mice from lethal SC2022MYS167 infection and was accompanied by substantial reductions in bacterial burdens and IL-17A levels in peripheral blood at 5 h post-infection. A dose-dependent relationship between neutrophil-depleting antibody and protection from lethal infection was observed. These findings reveal the critical roles of IL-17A-producing neutrophils in STSLS development, pulmonary inflammation and pathological lesions, and subsequent acute host death induced by ultra-virulent serotype 5 strains, while providing a promising therapeutic target for reducing patient mortality.