Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 224, Issue 8, Pages 1383-1393Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiab081
Keywords
tuberculosis; virulence; secretion; PPiA; chaperone; integrin; matrix metalloproteinases
Categories
Funding
- JC Bose fellowship [SB/S2/JCB-012/2015, JCB/2019/000015]
- Indian Council of Medical Research, Senior Research Fellowship
- D. S. Kothari postdoctoral fellowship
- Science and Engineering Research Board
- Tuberculosis Aerosol Challenge Facility at International Centre for Genetic Engineering and Biotechnology
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PPiA not only assists in the survival of Mtb but also promotes disease progression by affecting host cell status through interaction with host-related factors.
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 alpha 5 beta 1 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.
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