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Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model

25 Jun 2008

Marcia Triunfol

Source: Proc Natl Acad Sci USA (see original article)

Citation: Gomes R, Teixeira C, Teixeira MJ, Oliveira F, Menezes MJ, Silva C, de Oliveira CI, Miranda JC, Elnaiem DE, Kamhawi S, Valenzuela JG, Brodskyn CI. (2008) Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model. Proc Natl Acad Sci USA 105(22):7845-50.

Several attempts have been made to develop vaccines against pathogens transmitted by the saliva of arthropods, such as sand flies and mosquitoes.

Most recently, it has been observed that the arthropod’s saliva may have the right target for drug design. In the case of Leishmania parasites, the arthropod’s saliva not only works as a vehicle for the pathogen but also enhances the effectiveness of the pathogen by carrying potent components that change the environment of the biting site, which may lead to more severe cutaneous leishmaniasis.

Previous studies have shown that pre-exposure to the saliva of pathogen-carrying arthropods can offer partial protection against Plasmodium berghei and Mycobacterium ulcerans infections in mice. Additionally, animals pre-exposed to the saliva of other transmitting insects also promote protection against tularaemia and borreliosis. These findings led a team of researchers from Brazil and from the US to look in the sand fly saliva for proteins that could be immunogenic or able to protect against visceral leishmaniasis.

The researchers had first to create an appropriate animal model so that the study could be carried out. For that they infected the ears of male hamsters with intradermal injections containing Leishmania infantum chagasi, together with the saliva of the transmitting vector, Lutzomya longipalpis. The group believes that this model mimics what happens in nature when the inoculation of the parasite takes place in the skin, when in the presence of the fly saliva.

The infected animals succumbed after 5-6 months, after showing clear signs of visceral leishmaniasis. This observation demonstrates that the animal model the group has created is indeed a good model for studying visceral leishmaniasis.

In a second phase of the study, researchers immunized the hamsters by injecting the animals’ ears with DNA plasmids carrying Lu. Longipalpis-secreted proteins known to induce either an antibody response or a delayed-type hypersensitivity (DTH) response. Among the four plasmids used, one of them (LJM19) was associated with a significant low number of parasites in the infected animal’s spleen and liver, five months post infection.

These animals showed no signs of visceral leishmaniasis and kept a low anti-Leshmania IgG antibody level, when compared to animals ‘immunized’ with other plasmids. This observation, added to the fact that no antibodies were detected after DNA immunization, indicates that the protective effect is caused by cellular immunity and not by a humoral response. Immunized animals had no signs of visceral leishmaniasis and lived for eight months after immunization, when they were then euthanized.

The researchers believe that immunization with LJM19 may create an unfavourable environment in which the parasite cannot survive, or it may prime the initial immune response that results in anti-Leishmania immunity. Regardless of what this mechanism might be specifically, the next step is to find the salivary molecules capable of triggering the same protective effect in human beings. Once found, these molecules may be good targets for a vaccine against visceral leishmaniasis.

Note: This article is published in a journal which is not open access. To see the full article a subscription to Proceedings of the National Academy of Sciences USA is therefore required. In some developing countries, readers who are based in institutions may be able to access it through the HINARI programme.

Source

Title:
Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model.

Authors:
Gomes R, Teixeira C, Teixeira MJ, Oliveira F, Menezes MJ, Silva C, de Oliveira CI, Miranda JC, Elnaiem DE, Kamhawi S, Valenzuela JG, Brodskyn CI

References:
Proc. Natl. Acad. Sci. U.S.A. 3 Jun 2008: Vol. 105 no. 22, pp. 7845-50

Abstract:
Visceral leishmaniasis (VL) is a fatal disease for humans, and no vaccine is currently available. Sand fly salivary proteins have been associated with protection against cutaneous leishmaniasis. To test whether vector salivary proteins can protect against VL, a hamster model was developed involving intradermal inoculation in the ears of 100,000 Leishmania infantum chagasi parasites together with Lutzomyia longipalpis saliva to mimic natural transmission by sand flies. Hamsters developed classical signs of VL rapidly, culminating in a fatal outcome 5-6 months postinfection. Saliva had no effect on the course of infection in this model. Immunization with 16 DNA plasmids coding for salivary proteins of Lu. longipalpis resulted in the identification of LJM19, a novel 11-kDa protein, that protected hamsters against the fatal outcome of VL. LJM19-immunized hamsters maintained a low parasite load that correlated with an overall high IFN-gamma/TGF-beta ratio and inducible NOS expression in the spleen and liver up to 5 months postinfection. Importantly, a delayed-type hypersensitivity response with high expression of IFN-gamma was also noted in the skin of LJM19-immunized hamsters 48 h after exposure to uninfected sand fly bites. Induction of IFN-gamma at the site of bite could partly explain the protection observed in the viscera of LJM19-immunized hamsters through direct parasite killing and/or priming of anti-Leishmania immunity. We have shown that immunity to a defined salivary protein (LJM19) confers powerful protection against the fatal outcome of a parasitic disease, which reinforces the concept of using components of arthropod saliva in vaccine strategies against vector-borne diseases.

PMID: 18509051
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