An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosis H37 Rv and their potential as new drug targets.

Tuberculosis has long been the scourge of humanity, claiming millions of lives. The family of PE_PGRS gene has been attributed to the Mycobacterium tuberculosis pathogenesis over the past few decades. The gene of PE_PGRS family proteins are most often clustered in a region of the genome often as overlapping genes and role in cell surface markers, adhesion and invasion of defense cells of the host (macrophage and dendritic cells). The proline-glutamic acid (PE) domain is responsible for the cellular localization of these proteins on bacterial cells. This gene family shows immense genetic variability in terms of multiple insertion-deletions and single-nucleotide polymorphisms as seen in PE_PGRS9, PE_PGRS17, PE_PGRS18, and PE_PGRS33. In spite of variability, there are indications of shared epitopes in these proteins. Few of these gene sequences that have been studied from evolutionary perspective show indication of positive selection and also landmarks of recent evolutionary events. Many of these proteins show calcium-binding motifs and consequently seen to be responsible in inhibition of phagolysosome formation via a calmodulin-kinase-dependent pathway. A number of PE_PGRS genes were tested for its expression with different growth conditions in vitro and in vivo, among which the contrast in expressivity was seen vividly in PE_PGRS16 (upregulated) and PE_PGRS26 (downregulated) in bacteria persisting in macrophages. Similarly, PE_PGRS33 has been indicated in macrophagial necrosis by a tumor necrosis factor-α-induced pathway. These PE_PGRS family genes may be an interesting subject for research and development. Their fibronectin-binding and calcium-binding property may be strongly implicated in immunopathogenesis of virulent M. tuberculosis strain. In this review, an attempt has been made to evaluate and present data for better understanding of in vivo pathogen functions, for understanding the physiological significance of PE_PGRS gene family, and their potential as new drug targets.