Molecular negotiations at the host-parasite interface

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The success or failure of an infection depends on the outcome of a molecular dialog between host and pathogen. This is especially true for large metazoan parasites such as nematodes, which infect the gastrointestinal tract and internal tissues. Hosts resist infection by almost all parasite species, and host-parasite interactions are typically quite specific. How this fundamental aspect of nematode parasitism is determined at the molecular level remains a mystery. Our driving hypothesis is that molecules secreted by parasitic nematodes selectively and specifically modulate host immune responses that would normally prevent infection. Parasite molecules interact with host immune cells at the receptor level and at the level of gene regulation. These interactions are specific for permissive hosts and establish the molecular basis of host-parasite specificity. Understanding the molecules used by parasites to accomplish this immunomodulation will reveal the molecular basis for host-parasite specificity and illuminate the evolutionary processes involved in parasitism. Parasitic nematodes secrete exosomes, small vesicles that deliver molecular information to cells. Exosomes deliver proteins, mRNAs and microRNAs (miRNAs) as part of their cargo. For tissue-dwelling filariae, hundreds of parasite miRNAs appear in host blood during an infection. Nematode miRNAs repress gene expression and affect the function of host immune cells in culture. These preparations include multiple parasite miRNAs, and we have used bioinformatics analyses to identify candidate host immune response gene targets for several of them. We will identify parasite miRNAs that act on dendritic cells, key regulators of immune responses. Our top priority is to identify those miRNAs that act in a host species-specific manner and thus may play a role in the evolution of host-parasite specificity. A single nucleotide change in the recognition seed sequence of miRNAs or their mRNA target can dramatically alter their effects. The 6-8 nucleotide seed region must match perfectly to the target mRNA. Nucleotide sequences in this region of mRNAs are typically variable across species; we have identified parasite miRNAs that have high-quality mRNA targets in host immune pathways that are species-specific. Using bioinformatics, dendritic cell functional assays and qPCR, we will characterize the species specificity of these parasite miRNAs. We will characterize miRNAs from six species of parasitic nematodes to that selectively infect three mammalian hosts to determine if these molecules act on immune response pathways that are targeted by convergent evolution among phylogenetically distinct pathogens, but that restrict infection by these parasites only to their permissive hosts.