Immune Evasion Genes from Parasitic Nematodes

We have identified an array of parasite molecules for which we postuate a role in immunomodulation, or which may promote parasite survival in other ways. Further proteins are implicated in invasion or evasion by virtue of the time and site of expression, and some have now been tested as vaccine targets. A summary of the major immune evasion genes which we have now identified are as follows

The first group of potential immunomodulatory genes are cytokine-like molecules such as transforming growth factor-beta (TGF-b) homologues. As early as 1997, a B. malayi TGH-1 was cloned using a degenerate primer strategy by PCR (Gomez-Escobar et al 1998), and a second (TGH-2) emerged from ESTs produced by the Filarial Genome Project (Gomez-Excobar et al 2000). Subsequently, we have isolated homologues from a set of trichostrongyloid nematodes (McSorley et al 2009), including two species (H. polygyrus and Teladorsagia circumcincta) for which we have found active TGF-beta like activity in ES products. We have also reported the sequence and expression patterns of a TGF-b receptor kinase from B.malayi.

B. malayi also expresses two homologues of macrophage migration inhibitory factor, the second of which (MIF-2) was isolated in our laboratory (Zang et al 2002). Like human MIF, Bm-MIF displays an unusual enzyme activity, dopachrome tautomerase. Bm-MIF is highly soluble and we have successfully crystallized Bm-MIF-2.  Parasite expression of MIF was considered a surprising finding, because MIF has generally been found to act in a pro-inflammatory manner, for example promoting septic shock following bacterial exposure. However, we have recently determined that the action of MIF on macrophages is highly context-dependent. In the presence of IL-4, which will be elevated during helminth infections, MIF induces the alternative activation of macrophages which, following combined IL-4-MIF treatment, adopt a profoundly suppressive phenotype (Prieto-Lafuente et al 2009).

A second series of candidate immune evasion molecules are protease inhibitors. Two cystatins from B. malayi have been identified, one of which (CPI-2) provides an exciting example of direct intereference with antigen presentating cysteine proteases by human cells (Manoury et al 1998). Interesting results have also emerged with the serine protease inhibitor (serpin) SPN-2 of B.malayi, which is expressed exclusively by the blood-stage microfilariae and shows specific inhibition of two key blood leukocyte proteases, cathepsin G and neutrophil elastase (Zang et al 1999).

Recently, from proteomic analysis of B. malayi adult ES, we found high levels of a functional galectin that is secreted. The filarial galectin binds host cells, in a lactose-inhibitable manner, and we hypothesise that (like mammalian galections) this protein is engaged in modulating activity of the T cell compartment.

Each of these potential immune evasion products are being tested for efficacy as vaccines, using the rationale that a heightened host antibody response to a parasite immunomodulator may block its activity and permit a stronger, natural, anti-parasite effector response to ensue.