Granuloma Formation around Filarial Larvae Triggered by Host Responses to an Excretory/Secretory Antigen

Abstract

In previous studies using a murine model of filarial infection, granuloma formation was found to be a most important host-protective mechanism. We have also shown that in vitro cytoadherence is a surrogate for the formation of antifilarial granulomas in vivo and that it requires "alternatively activated" host cells and a source of antifilarial antibody. We show here that antibodies against L3 excretory/secretory (E/S) products can facilitate in vitro cytoadherence. We generated a set of hybridomas reactive with filarial E/S products and screened them for their ability to mediate in vitro cytoadherence. One clone (no. 1E9) was positive in this assay. We then screened a novel expression library of filarial antigens displayed on the surface of T7 bacteriophage for reactivity with 1E9. Phage expressing two filarial antigens (TCTP and BmALT-2) reacted with 1E9. Immunization of mice showed that the cohort immunized with BmALT-2 cleared a challenge infection with infective Brugia pahangi L3 in an accelerated manner, whereas cohorts immunized with TCTP cleared larvae with the same kinetics as in unimmunized mice. These data confirm that BmALT-2 is the antigenic target of granuloma-mediated killing of B. pahangi L3. Our findings also confirm previous studies that BmALT-2 is a potential vaccine candidate for filarial infection. Our data reinforce the work of others and also provide a possible mechanism by which immune responses to BmALT-2 may provide host protection.

Large Extracellular Loop of Tetraspanin as a Potential Vaccine Candidate for Filariasis

“…These findings were similar to those reported after vaccination of mice with Sm TSP-2 [52]. Presence of antigen-specific IFN-γ secreting cells together with IL-10 secreting cells in the spleen suggest a balanced Th1/Th2 immune responses that may be important for regulating the inflammation caused by the host-protective mechanism in the filarial infections or for preventing the development of highly polarized Th1 responses [53,54]. Increase in the levels of IFN-γ suggests the activation of macrophages that may be important in the ADCC mediated killing of parasites observed in our studies [35] and others [55].…”

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

“…Repeated infections shorten the clearance time in immunocompetent mice (110,(117)(118)(119)128). As this is a nonpermissive model, repeat infections are not a direct measure of concomitant immunity.…”

“…Previous infection is protective regardless of the method of inoculation (117), and as few as 2 worms can mediate this effect (117). The transfer of CD4 and CD8 T cells from previously infected mice to naive mice is sufficient to induce an accelerated immune response (128).…”

“…Irradiated larvae (129,130), L3 cuticles (128), BmALTII (128), and L3 ES products (128) have all been shown to be effective vaccines in the B. pahangi-mouse model, showing accelerated clearance after challenge infections. Efficacy of the L3 ES vaccine is mediated at least partially by antibodies, as the transfer of sera from vaccinated to naive mice is sufficient to induce a protective immune response (128).…”

“…Efficacy of the L3 ES vaccine is mediated at least partially by antibodies, as the transfer of sera from vaccinated to naive mice is sufficient to induce a protective immune response (128). ES products from other stages of worm development (MF, L4, or adult) were not effective vaccine candidates (128).…”