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

Area of Science:

• Microbiology
• Immunology
• Pathogenesis

Background:

• Mycobacterium tuberculosis (Mtb) secretory gene mutants show reduced intracellular survival, highlighting their role as virulence factors.
• Mtb peptidyl prolyl isomerase A (PPiA) is known to assist protein folding via prolyl bond cis/trans isomerization.

Purpose of the Study:

• To investigate the role of Mtb PPiA in host-pathogen interactions and disease progression.
• To elucidate the mechanisms by which PPiA influences Mtb survival and host pathology.

Main Methods:

• Deletion and overexpression of PPiA in Mtb.
• Murine infection models to assess bacillary load, lesion formation, and host cell death (ferroptosis).
• Co-immunoprecipitation and surface plasmon resonance to study PPiA interaction with host integrin α5β1.
• Analysis of host matrix metalloproteinase (MMP) expression.

Main Results:

• PPiA deletion did not affect Mtb survival in vivo but impaired granuloma formation and induced ferroptosis.
• PPiA overexpression increased bacillary load and exacerbated lung pathology.
• PPiA directly interacts with host integrin α5β1 via an RGD motif.
• PPiA secretion and integrin interaction upregulate host MMPs, contributing to disease progression.

Conclusions:

• Mtb PPiA plays a critical non-chaperone role in facilitating host-pathogen interactions.
• PPiA promotes Mtb virulence by modulating host cellular processes and extracellular matrix remodeling.
• Targeting PPiA interactions could be a novel therapeutic strategy against tuberculosis.