Mycobacterium tuberculosis PPiA interacts with host integrin receptor to exacerbate disease progression.

Attenuated intracellular survival of Mycobacterium tuberculosis (Mtb) secretory gene mutants exemplifies their role as virulence factors. Mtb peptidyl prolyl isomerase A (PPiA) assists in protein folding through cis/trans isomerization of prolyl bonds. Here, we show that PPiA abets Mtb survival and aids in the disease progression by exploiting host-associated factors. While the deletion of PPiA has no discernable effect on the bacillary survival in a murine infection model, it compromises the formation of granuloma-like lesions and promotes host cell death through ferroptosis. Overexpression of PPiA enhances the bacillary load and exacerbates pathology in mice lungs. Importantly, PPiA interacts with the integrin α5β1 receptor through a conserved surface-exposed RGD motif. The secretion of PPiA as well as interaction with integrin contributes to the disease progression by upregulating multiple host matrix metalloproteinases. Collectively, we identified a novel non-chaperone role of PPiA that is critical in facilitating host-pathogen interaction ensuing disease progression.