Shigella is the second leading cause of diarrheal disease-related death in young children in low and middle income countries. The mechanism of protection against
shigella infection and disease in endemic areas is uncertain. While historically LPS-specific
IgG titers have been associated with protection in endemic settings, emerging deeper immune approaches have recently elucidated a protective role for IpaB-specific antibody responses in a controlled human challenge model in North American volunteers. To deeply interrogate potential correlates of immunity in areas endemic for
shigellosis, here we applied a systems approach to analyze the serological response to shigella across endemic and non-endemic populations. Additionally, we analyzed shigella-specific antibody responses over time in the context of endemic resistance or
breakthrough infections in a high shigella burden location. Individuals with endemic exposure to shigella possessed broad and functional antibody responses across both
glycolipid and
protein antigens compared to individuals from non-endemic regions. In high shigella burden settings, elevated levels of OSP-specific FcαR binding
antibodies were associated with resistance to
shigellosis. OSP-specific FcαR binding
IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation and
reactive oxygen species production. Moreover,
IgA depletion from resistant serum significantly reduced binding of OSP-specific
antibodies to FcαR and antibody mediated activation of neutrophils and monocytes. Overall, our findings suggest that OSP-specific functional
IgA responses contribute to protective immunity against
shigella infection in high-burden settings. These findings will assist in the development and evaluation of
shigella vaccines.