A bioactive phlebovirus-like envelope protein in a hookworm endogenous virus.

Endogenous viral elements (EVEs), accounting for 15% of our genome, serve as a genetic reservoir from which new genes can emerge. Nematode EVEs are particularly diverse and informative of virus evolution. We identify Atlas virus-an intact retrovirus-like EVE in the human hookworm Ancylostoma ceylanicum, with an envelope protein genetically related to GN-GC glycoproteins from the family Phenuiviridae. A cryo-EM structure of Atlas GC reveals a class II viral membrane fusion protein fold not previously seen in retroviruses. Atlas GC has the structural hallmarks of an active fusogen. Atlas GC trimers insert into membranes with endosomal lipid compositions and low pH. When expressed on the plasma membrane, Atlas GC has cell-cell fusion activity. With its preserved biological activities, Atlas GC has the potential to acquire a cellular function. Our work reveals structural plasticity in reverse-transcribing RNA viruses.

The hookworm tissue inhibitor of metalloproteases (Ac-TMP-1) modifies dendritic cell function and induces generation of CD4 and CD8 suppressor T cells.

Hookworm infection is a major cause of disease burden for humans. Recent studies have described hookworm-related immunosuppression in endemic populations and animal models. A Tissue Inhibitor of Metalloproteases (Ac-TMP-1) has been identified as one of the most abundant proteins released by the adult parasite. We investigated the effect of recombinant Ac-TMP-1 on dendritic cell (DC) and T cell function. Splenic T cells from C57BL/6 mice injected with Ac-TMP-1 showed reduced proliferation to restimulation with anti CD3 or bystander antigens such as OVA. Incubation of bone marrow-derived DCs with Ac-TMP-1 decreased MHC Class I and, especially, Class II expression but increased CD86 and IL-10 expression. Co-incubation of splenic T cells with DCs pulsed with Ac-TMP-1 induced their differentiation into CD4+ and, particularly, CD8+ CD25+Foxp3+ T cells that expressed IL-10. These cells were able to suppress proliferation of naïve and activated CD4+ T cells by TGF-Beta-dependent (CD4+ suppressors) or independent (CD8+ suppressors) mechanisms. Priming of DCs with non-hookworm antigens, such as OVA, did not result in the generation of suppressor T cells. These data indicate that Ac-TMP-1 initiates the development of a regulatory response through modifications in DC function and generation of suppressor T cells. This is the first report to propose a role of suppressor CD8+ T cells in gastrointestinal helminthic infections.

A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18.

The chronic survival of many endoparasites is dependent on the ability of these organisms to escape the host immune response. Identification of the molecular mechanisms by which these organisms evade this response may yield novel approaches in the development of anti-inflammatory agents. We describe here the discovery and characterization of a novel 41-kilodalton glycoprotein from the canine hookwork (Ancylostoma caninum) that potently inhibits CD11/CD18-dependent neutrophil function in vitro. Neutrophil inhibitory factor (NIF) blocks the adhesion of activated human neutrophils to vascular endothelial cells as well as the release of H2O2 from activated neutrophils, over a similar concentration range (IC50 10-20 nM). Studies aimed at determining the nature of the NIF binding site on neutrophils revealed selective, high affinity binding of this protein to the integrin CD11b/CD18. A cDNA encoding NIF was isolated from a canine hookworm cDNA library. NIF comprises a mature polypeptide of 257 amino acids, preceded by a 17-amino acid leader. The mature protein has 10 cysteines and has seven potential N-linked glycosylation sites. NIF has no significant sequence homologies to any previously reported protein. As such, NIF represents a prototype of a novel class of leukocyte function inhibitors.

Changes in the adenylate energy charge of Nippostrongylus brasiliensis and Nematodirus battus during the development of immunity to these nematodes in their host.

Infection of rats with 2000 infective juveniles of Nippostrongylus brasiliensis and of lambs with 60 000 infective juveniles of Nematodirus battus results in a well-marked immunity to these nematodes in their respective host. There is a fall in the adenylate energy charge value of these nematodes during the course of these infections, reaching values of 0.37 in males and 0.27 in females of N. brasiliensis, and 0.31 in males and 0.23 in females of N. battus towards the end of the infections. In hosts given relatively small numbers of infective juveniles, the values for the nematodes removed from the hosts late in the infection remain at a relatively high level. These results indicate that the immune response of the host may affect the energy status of these nematodes, and this could help to explain their subsequent expulsion from the immune host.