The Caenorhabditis elegans p38 MAPK Gene plays a key role in protection from mycobacteria

Mitogen-activated protein kinases (MAPK) are critical mediators of cellular responses to pathogens and are activated in response to infection, but investigation is difficult in multi-cell hosts due to developmental lethality of mutations. Mycobacterium marinum (Mm) is an established model for tuberculosis, a disease afflicting nearly one-third of the world's population. We found that Mm-infected Caenorhabditis elegans display >80% mortality, but nonpathogenic M. smegmatis cause <15% mortality. C. elegans display pathological changes when infected with Mm, whereas Mm mutants produce lower mortality, suggesting that C. elegans is a promising virulence model for detailed genetic analysis. C. elegans MAPK mutants are hypersusceptible to mycobacterial infection; however, the C. elegans TOL-like, TGF-β and insulin-like pathway genes do not play important roles in susceptibility. We show that pathogenic mycobacteria inhibit MAPK-mediated protection through the MAPK phosphatase gene and demonstrate that C. elegans provide a genetically tractable pathogenicity model of both the host and pathogen.