Dubey Neha, Khan Mehak Zahoor, Kumar Suresh, Sharma Aditya, Das Lahari, Bhaduri Asani, Singh Yogendra, Nandicoori Vinay Kumar
Department of Zoology, University of Delhi, Delhi, India.
Department of Molecular Microbiology, Washington University in St Louis, St Louis, Missouri, USA.
J Infect Dis. 2021 Oct 28;224(8):1383-1393. doi: 10.1093/infdis/jiab081.
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.
结核分枝杆菌（Mtb）分泌基因突变体在细胞内生存能力的减弱例证了它们作为毒力因子的作用。Mtb肽基脯氨酰异构酶A（PPiA）通过脯氨酰键的顺式/反式异构化协助蛋白质折叠。在此，我们表明PPiA通过利用宿主相关因子来促进Mtb的存活并助力疾病进展。虽然在小鼠感染模型中PPiA的缺失对细菌存活没有明显影响，但它会损害肉芽肿样病变的形成，并通过铁死亡促进宿主细胞死亡。PPiA的过表达会增加小鼠肺部的细菌载量并加重病理状况。重要的是，PPiA通过一个保守的表面暴露RGD基序与整合素α5β1受体相互作用。PPiA的分泌以及与整合素的相互作用通过上调多种宿主基质金属蛋白酶来促进疾病进展。总体而言，我们确定了PPiA一种新的非伴侣蛋白作用，它在促进宿主 - 病原体相互作用及随后的疾病进展中至关重要。
