Parasitological and Immunological Studies on the Effects of Immunization with Filarial Worm Fraction on Subsequent Infection in Rodent Host

Abstract

Filariasis, a group of diseases caused by filarial nematode parasites, is prevalent in many parts of the tropics and sub-tropics of the world and 150-200 million people suffer from filarial diseases: lymphatic filariasis (caused by Wuchereria bancrofti, Brugia malayi and B. timori), onchocerciasis or river blindness (caused by Onchocerca volvulus) and loiasis (caused by Loa loa). Lymphatic filariasis (LF) is by far the most prevalent and most debilitating disease of the filarial infections. Globally around 128 million are infected with LF, 74 million with asymptomatic microfilaraemia; around 54 million suffer from filarial disease manifestations and 1.25 billion people at risk in about 83 countries (WHO, 2005; 2009). In India, more than 500 million people in 261 districts are at risk (this is almost 50% of the global risk) for bancroftian and malayan LF, more than 22 million suffer from elephantiasis and/or hydrocoele, and 27 million carry the infection (WHO, 2001; 2002). The most debilitating manifestations are the grotesque deformities of limbs (elephantiasis), breast and genitalia, particularly the scrotal sac where it causes ‘hydrocoele’, which are largely irreversible and cause huge loss of useful man-hours (5.5 million Disability Adjusted Life Years (DALYs)). In addition, the psychological and social stigma associated with the deformities is immense. The filarial adult worms live for about six years or more in the human lymphatic system, and female worms release millions of microfilariae (mf; 1st stage larva) that circulate in the blood and are picked up by mosquitoes during a blood meal. In the mosquito, the mf undergoes two molts to become 3rd stage infective larvae (L3) which then enter human host during a blood meal of the vector. L3 secretes certain proteases and other enzymes that facilitate their penetration through local connective tissue and migrate to local lymphatic vessels where they take 2 to 12 months to develop into adult worms through two molts. Sexually mature male and female adult worms residing in afferent lymphatic vessels copulate, and the female worms subsequently release the mf which then enter the bloodstream and are picked-up by mosquitoes; and the infection cycle continues. Filarial parasites modulate the host’s immune system in such a way that the host tolerates the parasites for a long time. Such host’s tolerance which is immune mediated plays an important role in modulating the dynamics of infection and disease (Maizels and Lawrence, 1991; Maizels and Yazdanbakhsh, 2003; Maizels et al., 2004). Several investigators have proposed a number of possibilities regarding the development of immune tolerance (Nutman et al., 1987; Piessens et al., 1980; 1982). Apoptotic cell death of exposed T cells was recently considered as one of the mechanism underlying immune suppression and the cells that survive cell death produce high levels of anti-inflammatory cytokines such as IL-4 and IL-10 suggesting a mechanism that may prolong in vivo tolerance. However, neither the identity of antigen(s) evoking such reaction nor the type of immune responses responsible has been clearly delineated. One of the major obstacles to the study of parasite specific immune responses has been the lack of well-defined parasite antigens. Studies conducted in this laboratory revealed that of the two major Sephadex G-200 eluted fractions of B. malayi adult worm extract, BmAFII was protective against both adult worms and L3 in vivo and stimulates predominantly pro-inflammatory cytokines (Dixit et al., 2004; 2006) while BmAFI facilitates parasite survival and stimulates predominantly IL-10 (Dixit et al., 2004). The proposed study is therefore, aimed at characterizing the host immune response to BmAFI in vivo and to determine the significance of these responses on the establishment and course of subsequently introduced infection into the peritoneal cavity, a non-physiological site of Mastomys coucha for development of L3.