Sex-Specific Immune Responses Mediate Host Specificity in Hookworm Infections

Hookworm infections affect 500-700 million people worldwide and can lead to chronic conditions, such as malnutrition and anemia. The challenge of managing these infections is heightened by the absence of effective vaccines and the potential for anthelmintic resistance to develop. A comprehensive understanding of the molecular interactions between the parasite and host is vital for unraveling the complexities of infection dynamics. This study aimed to identify the immune system components responsible for host specificity in hookworms by infecting immunodeficient mouse models. Findings herein indicate that innate immunity is essential in protecting against Ancylostoma ceylanicum establishment in mice. Significant differences in parasite development were noted in mice lacking the signal transducer and activator of transcription 6 (Stat6^-), with female mice reliant on this Th2 pathway for protection. Secondary infections in female Stat6^- mice and an immunodeficient NSG mouse reached patency, demonstrating that immunodeficient mice fail to develop protective immunity against subsequent infections, similar to human hookworm infections. In contrast, no parasite development was observed in mice infected with A. caninum, highlighting that the survival strategies of this species are independent of the host immune landscape. These results underscore the complexity of host-parasite interactions and point to new directions for therapeutic strategies, which may differ between sex.