Leishmania macropodum pathogenesis in mice and potential use as a live-attenuated vaccine against leishmaniasis

Leishmania (L.) parasites are protozoans from the Trypanosomatidae family able to infect a wide variety of vertebrates including humans. The disease is characterised by a broad range of clinical presentations including self-limited cutaneous lesions, destructive mucosal inflammation and disseminated visceral infection, which is fatal if untreated. For a long time, Australia was considered free of endemic Leishmania species and competent vectors for transmission. However, after the discovery of an endemic Leishmania species just over a decade ago, many questions and concerns arose, including the risk of human leishmaniasis becoming established in Australia. L. macropodum is the causative agent of cutaneous
leishmaniasis in several marsupial species in Australia, including kangaroos, wallaroos and wallabies. This Leishmania species can infect human cells in vitro but seems unable to cause disease in humans, and therefore considered non-human pathogenic. The use of non-human pathogenic Leishmania species as candidates for live-attenuated vaccines have shown promising results before. We investigated the infection of two naturally susceptible mouse strains (BALB/c and BALB/c nude mice) with L. macropodum and the possible use of L. macropodum as a candidate vaccine against human leishmaniasis. L. macropodum was able to transiently infect both mouse strains and to induce a type 1 T helper response in BALB/c mice. The initial survival in mice and the immunological response observed by a transient infection with L. macropodum prompted us to investigate whether the exposure to L. macropodum could confer protection against human-pathogenic Leishmania species. BALB/c mice were vaccinated with wild or mutant L. macropodum expressing an immunogenic antigen (thiol-specific antioxidant (TSA) from L. major), and subsequently, challenged with L. major. Vaccines were delivered using different regimens, including different routes of administration (intradermal or intravenous) and with or without a boost dose. Overall, the results indicated that both, wild and TSA L. macropodum, were safe
but unable to protect BALB/c mice against challenge with L. major. This initial data suggested that L. macropodum might not represent an effective vaccine candidate against leishmaniasis. However, the expression of other immunogenic antigens or use of adjuvants may improve L. macropodum effectiveness, as observed previously with several other attenuated Leishmania vaccine models.