Genome-led reverse vaccinology for visceral leishmaniasis: establishment of a bioluminescent murine infection model and candidate evaluation


H B Ong1; S Clare1; G J Wright1
1 Wellcome Sanger Institute, UK


Visceral leishmaniasis (VL) is an infectious parasitic disease caused by the protozoan parasites Leishmania donovani and Leishmania infantum. These parasites primarily infect the host liver and spleen macrophages resulting in hepatosplenomegaly and the disease is fatal if left untreated. Currently, the disease is managed by drugs but they are highly toxic causing harmful side effects, and are not widely accessible. A better solution would be an effective vaccine but none exist for VL. To identify potential vaccine candidates, we have assembled a library of 93 L. donovani proteins that are predicted to be exposed on the parasite cell surface or secreted by searching the genome for proteins containing features such as signal peptides and transmembrane regions. The entire extracellular regions were expressed as secreted recombinant proteins in HEK293 mammalian cells to increase the chances that structurally critical posttranslational modifications such as disulphide bonds were faithfully added. To evaluate their efficacy as vaccine candidates, we have established a bioluminescent murine infection model of L. donovani to quantitatively determine the parameters of infection. Our model allowed us to longitudinally visualise the initial infection of livers and their resolution during the first 4-6 weeks, followed by parasite-dissemination and persistence in the spleens. These observations were consistent with other L. donovani murine infection models that relied on impression smears for parasite quantification. Using our model, we have identified five potential candidates that altered infection dynamics of the livers and spleens of infected mice. We have also used our protein library together with sera from infected mice, dogs and humans to identify serological markers of infection. We identified four potential biomarkers that could be developed for diagnostics purposes.

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