Brugia malayi and Acanthocheilonema viteae: antifilarial activity of transglutaminase inhibitors in vitro

Abstract

The possible involvement of transglutaminase-catalyzed reactions in survival of adult worms, microfilariae (mf), and infective larvae of the Milarial parasite Brugia malayi was studied in vitro by using the specific pseudosubstrate monodansylcadaverine (MDC) and the active-site inhibitors cystamine or iodoacetamide. These inhibitors significantly inhibited parasite mobility in a dose-dependent manner. This inhibition was associated with irreversible biochemical lesions followed by filarial death. A. structurally related, inactive analog of MDC, dimethyldansylcadaverine, did not affect the mobility or survival of the parasites. Adult worms failed to release mf when they were incubated in the presence of MDC or cystamine, and this inhibitory effect on mf release was concentration dependent. Similar embryostatic and macrofilaricidal effects of MDC were observed in Acanthocheilonema viteae adult worms. These studies suggest that transglutaminase-catalyzed reactions may play an important role in the growth, development, and survival of filarial parasites.

Transglutaminase-catalyzed reaction is important for molting of Onchocerca volvulus third-stage larvae

“…Recently, an active TGase from an adult B. malayi worm was biochemically purified and characterized and its partial amino acid sequence was determined (37). In previous studies (29,31), it was reported that TGase inhibitors were lethal to B. malayi L3 and, in B. malayi and A. viteae, also affected other stages of development, microfilaria production, and microfilaria release by gravid female worms. In addition, an indirect support for the importance of TGase-catalyzed reactions for the molting of Onchocerca larvae could be derived from the report by Lok et al (24), showing that synthetic retinoids can inhibit the L3 to L4 molt of O. lienalis in vitro.…”

“…The presence of putative TGases and the products of TGase-catalyzed reactions was reported in other filarial nematodes (29,31,41). More recently, an active Brugia malayi TGase with a molecular mass of 56 kDa was purified (37).…”

“…Furthermore, embryos developing in utero contained very high amounts of the enzyme (29). Inhibition of enzyme activity in vitro by monodansylcadaverine (MDC) and cystamine (CS), two specific inhibitors of TGase (13,25,40), led to a time-and dose-dependent inhibition of microfilarial production and release by gravid female B. malayi and Acanthocheilonema viteae (29,31), thus indicating that in these parasites, TGase-catalyzed reac-tions play an important role during embryogenesis, the maturation of early embryonic stages to microfilariae, and survival of the parasites.…”

Molecular characterization of a Brugia malayi transglutaminase

“…The presence of transglutaminase in adult female B. malayi and its role in the in utero development of microfilariae was first reported by Mehta et al (1990). More recently, the presence of TGases in Dirofilaria immitis (Chandrashekar et al 1998), Onchocerca volvulus (Lustigman et al 1995), Acanthocheilonema viteae (Rao et al 1991), Caenorhabditis elegans (Natsuka et al 2001), and Plasmodium falciparum (Adini et al 2001) has been reported. The inhibitors of TGase enzyme have been found to inhibit the molting of L3 larvae to L4 stage larvae in O. volvulus and D. immitis (Lustigman et al 1995;Chandrashekar et al 2002).…”

Transglutaminase activity in equine strongyles and its potential role in growth and development

“…Simi larly, the highly insoluble complexes of larval or adult strongyle extracts reveal the presence of similar cross linking of isopeptide bonds. Recently, transglutaminase (TGase), a new type of protein cross linking enzyme, has been observed in lymphatic filarial nematodes (Mehta et al, 1990(Mehta et al, , 1992Rao et al, 1991), as well as Dirofilaria immitis and Onchocerca volvulus (Lustigman et al, 1995), and possibly plays a role in molting, growth, and development of these parasites. Moreover, TGase was also involved in covalent incorporation of host proteins into developing stages of Brugia malayi (Mehta et al, 1996).…”