Mycobacterium tuberculosis Peptidyl Prolyl Isomerase A Interacts With Host Integrin Receptor to Exacerbate Disease Progression

• Published in: The Journal of infectious diseases Vol. 224; no. 8; pp. 1383 - 1393
• Main Authors: Dubey, Neha, Khan, Mehak Zahoor, Kumar, Suresh, Sharma, Aditya, Das, Lahari, Bhaduri, Asani, Singh, Yogendra, Nandicoori, Vinay Kumar
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 28-10-2021
• Subjects: Animals; Cell death; Disease Progression; Ferroptosis; Granuloma; Host-Pathogen Interactions; Integrins; Isomerization; Matrix metalloproteinase; Mice; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Peptidylprolyl isomerase; Peptidylprolyl Isomerase - metabolism; Protein folding; Tuberculosis; Virulence factors; secretion; virulence; chaperone; tuberculosis; integrin; PPiA; matrix metalloproteinases
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiab081

Abstract
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 disease progression by exploiting host-associated factors. While the deletion of PPiA has no discernable effect on 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 disease progression by upregulating multiple host matrix metalloproteinases. Collectively, we identified a novel nonchaperone role of PPiA that is critical in facilitating host–pathogen interaction and ensuing disease progression.
Mycobacterium tuberculosis encodes for a Peptidyl prolyl isomerase A (PPiA) that is secreted through its N-terminal secretion signal. Secreted PPiA interacts with host integrin via arginine-glycine-aspartic acid motif, resulting in the upregulation of matrix metalloproteinases facilitating intracellular bacillary survival.