Endosymbiotic Wolbachia of parasitic filarial nematodes as drug targets.

The parasitic nematodes Wuchereria bancrofti, Brugia malayi and B. timori cause a dreadful disease in humans known as lymphatic filariasis, which afflicts more than 120 million people worldwide. As per recent epidemiologic estimates on prevalence of W. bancrofti and B. malayi, about 428 million people are at risk, with 28 million microfilaria carriers and 21 million clinical cases spread out in 13 States and 5 Union Territories of India. The Indian subcontinent that comprises Bangladesh, India, Maldives, Nepal and Sri Lanka harbours 50 per cent of the world's lymphatic filarial disease burden. Recently, an endobacterium of Wolbachia species that belongs to the family Rickettsiaceae was found in all life cycle stages of these nematodes and the transmission is exclusively vertical through the embryonic stages of the female worms. People with filariasis have been exposed to these Wolbachia bacteria or their proteins by the natural killing of parasites. Wolbachia have also been identified occasionally in body fluids of infected patients. Evidence suggests that these Wolbachia are mutualistic symbionts and can be cured from the nematodes by several antibiotics having antirickettsial properties. Treatment of nematodes with tetracyclines affect Wolbachia and they get cleared from worm tissues; and this elimination causes reproductive abnormalities in worms and affect worm's embryogenesis, resulting in sterility. Although it is impractical, prolonged treatment with doxycycline significantly reduces the numbers of microfilaria in circulation, which is an important strategy to control transmission of filariasis by mosquito vectors. In this review, the current knowledge of Wolbachia as a drug target and potential ways to reduce the infection through anti-Wolbachia treatments is discussed.

Transglutaminases, thioredoxins and protein disulphide isomerase: diverse enzymes with a common goal of cross-linking proteins in lower organisms.

Prokaryotes and various eukaryotes have remarkable ability to survive under adverse physiologic conditions and protect themselves from environmental stresses. An important mechanism by which they accomplish this is by synthesizing rigid and biochemically inert structures around them. In general, these structures are highly stable and resistant to mechanical and chemical insults. Biochemically, they are composed of complex carbohydrates, such as chitin and heavily crosslinked scaffold of proteins to form complex structures, such as sheath, cuticle, and epicuticle. Transglutaminases (TGases) are a family of enzymes that share catalytic function with thioredoxin and protein disulphide isomerases (PDI) and catalyze protein crosslink reaction by establishing epsilon-(gamma-glutamyl)lysine isopeptide bonds. The isopeptide bonds thus formed are of great physiologic significance because once formed, they cannot be hydorlysed by any known enzymes of the eukaryote system and exhibit high resistance to reducing agents, detergents, and chaotropic agents. Therefore, it is likely that protective structures viz., sheath, cuticle, epicuticle, and viral core proteins synthesized by microorganisms involve active participation of TGases. In this review, we briefly describe the current knowledge of non-mammalian TGases and their possible role in growth, development, and survival of small organisms. Special reference is made to filarial nematode and bacterial TGases since they are the most well-characterized and studied enzymes among non-mammalian TGases.