Innovative Strategies to Study the Pathogenesis of Elusive Spirochetes and Difficulties Managing the Chronic Infections They Cause.

The major human spirochetal pathogens (, , and ) are difficult to diagnose and lack vaccines to prevent infections. Infection by these spirochetes does not generate general protective immunity, allowing reinfection by different strains to occur. These stealth pathogens have uncommon physiology, pathogenesis, and clinical presentations and possess unique immune evasion mechanisms to facilitate their host adaptation and persistence. Collectively, host-spirochete interactions orchestrate systemic infections in a manner distinct from organ- and tissue-specific diseases caused by many bacterial pathogens. Difficulties in growing and genetic manipulation of infectious spirochetes have hindered the full understanding of their virulence factors despite decades to centuries of research. This article highlights the current understanding of the intricacies of spirochetal pathogenesis and diseases. Our comprehensive review of the progress versus gaps in knowledge lays a foundation for researchers to direct their studies toward the development of effective diagnostics and vaccines to protect patients from serious, chronic spirochetal diseases.