UC San Diego

A crucial stage in the transmission of diseases that are caused by intracellular pathogens is the exit of these pathogens from their replicative host cell niche. Leaving the host cell allows the pathogen to disseminate to new cells or organisms not yet compromised by infection. Microsporidia are a poorly understood group of intracellular pathogens that must carry out a host cell exit process. A species of microsporidia called Nematocida parisii is a naturally occurring intracellular pathogen of the laboratory model organism Caenorhabditis elegans. Using this host-pathogen pair, we have discovered many interesting details of a carefully orchestrated microsporidian host cell exit strategy. N. parisii forms spores that exit by exocytosis from the apical side of C. elegans intestinal cells. Even prior to spore formation, a dramatic restructuring of the host cytoskeleton occurs, including ectopic localization of actin filaments and gaps in the intermediate-filament dense terminal web structure. Through a genetic screen we found that intracellular membrane-bound spores co-opt the host endocytic recycling system and become coated in C. elegans RAB-11 protein. RAB -11 is necessary for spores to fuse with the host apical membrane and thus for exocytosis of spores into the intestinal tract of the host animal. In addition to RAB-11 and other key members of the endocytic recycling system, an isoform of host actin called ACT-5 is strongly required for spore exit. We believe that ACT-5 plays several roles in spore exit, including forming a distinctive coat on spores fused with the apical membrane. Together these findings comprise the bulk of what is known about microsporidia exit from any host cell and illustrate the complexity and intimacy of interactions between intracellular pathogens and their hosts