Emergence of antibiotic resistant strains
Emergence of antibiotic resistant strains of Mtb alongwith the inefficacy of widely used Bacillus Calmette-Guerin (BCG) vaccine in adults are major challenges in the treatment and prevention of TB. Elucidation and characterization of new vaccine and drug candidates are therefore required in order to design a multi-pronged strategy to prevent and treat this disease. Mtb produces a variety of virulence factors that aid in its extracellular and intracellular survival within the macrophages. A formidable and unusually lipid-rich D-erythro-Sphingosine (synthetic) is by far its most effective virulence factor, contributing to its intrinsic resistance to a number of therapeutic agents . With respect to the secretion system, virulent phenotype in Mtb is associated with its ESX-1 secretion system that exports ESAT-6 and CFP-10 in the extracellular environment, which in turn are majorly responsible for regulating many of the anti-bacterial responses of the host and cell to cell spread of Mtb infection . Recruitment of plasminogen on to the bacterial surface has long been acknowledged as a mechanism involved in bacterial attachment and tissue invasion , , . Plasminogen is a proenzyme which can be proteolytically activated by host tissue plasminogen activator (tPA) and urokinase into fibrinolytic plasmin. It is a glycoprotein abundant in plasma and extracellular fluids , . Some bacteria like Streptococcus pyogenes, Staphylococcus aureus and Yersinia pestis also express their own versions of plasminogen activators like streptokinase, staphylokinase and plasminogen activator (pla), respectively , . Plasmin is a broad spectrum serine protease which can degrade components of the ECM like fibronectin and laminin, dissolve fibrin clots and indirectly activate certain MMPs . Plasmin can activate procollagenase into collagenase which in turn can degrade collagen, a major component of basement membranes, and also activate certain complement mediators . Binding of plasminogen to bacterial surface followed by its activation to plasmin, converts the bacteria into a proteolytic organism, wherein plasmin also gets sequestered away from its circulating inhibitor α2-antiplasmin , enriching the protease activity associated with the circulating pathogen. A number of microorganisms are known to express surface components for binding to host plasminogen, which enables them to interact with the host fibrinolytic system and ECM components to initiate invasion and dissemination . Glycolytic enzymes form one of the classes of these proteins that are exported to the surface of many microorganisms , , , , . These surface localized enzymes because of their non-glycolytic functions are termed as moonlighting proteins. Enolase is one of the most widely studied moonlighting proteins in pathogenic microorganisms, which is exported to the surface of Streptococcus pneumoniae, Staphylococcus aureus, Aeromonas hydrophila, Borrelia burgdorferi, Bacillus anthracis, Group A streptococci, Candida albicans etc. , , , , , , , , , . It is also found on the surface of commensal bacteria like Lactobacillus plantarum and species of Bifidobacterium, . For most of these microorganisms, binding to host plasminogen has been characterized as the moonlighting function of enolase. Two other glycolytic enzymes Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoglycerate kinase (PGK) are also found on the surface of several streptococcal species that bind to plasminogen , . Apart from glycolytic enzymes, there are a number of other plasminogen binding receptors which have been reported from many organisms like M-like proteins from streptococcal species, PavB (pneumococcal adherence and virulence factor B) from S. pneumoniae and Epf (Extracellular Protein Factor) from S. pyogenes. Notably, streptococcal species code for a variety of plasminogen binding proteins .