Immunity to Sand Fly Salivary Protein LJM11 Modulates Host Response to Vector-Transmitted Leishmania Conferring Ulcer-Free Protection

Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 06/2012; 132(12). DOI: 10.1038/jid.2012.205
Source: PubMed


Leishmania vaccines that protect against needle challenge fail against the potency of a Leishmania-infected sand fly transmission. Here, we demonstrate that intradermal immunization of mice with 500 ng of the sand fly salivary recombinant protein LJM11 (rLJM11) from Lutzomyia longipalpis, in the absence of adjuvant, induces long-lasting immunity that results in ulcer-free protection against Leishmania major delivered by vector bites. This protection is antibody independent and abrogated by depletion of CD4(+) T cells. Two weeks after challenge, early induction of IFN-γ specifically to rLJM11 correlates to diminished parasite replication in protected animals. At this time point, Leishmania-specific induction of IFN-γ in these mice is low in comparison with its high level in non-protected controls. We hypothesize that early control of parasites in a T-cell helper type 1 environment induced by immunity to LJM11 permits the slow development of Leishmania-specific immunity in the absence of open ulcers. Leishmania-specific immunity observed 5 weeks after infection in rLJM11-immunized mice shows a twofold increase over controls in the percentage of IFN-γ-producing CD4(+) T cells. We propose LJM11 as an immunomodulator that drives an efficient and controlled protective immune response to a sand fly-transmitted Leishmania somewhat mimicking "leishmanization"-induced protective immunity but without its associated lesions.Journal of Investigative Dermatology advance online publication, 28 June 2012; doi:10.1038/jid.2012.205.

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Available from: Jesus G. Valenzuela, Oct 13, 2015
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    • " response against sali - vary antigens that protected them against L . major infection ( Belkaid et al . 1998 , 2000 , Kamhawi et al . 2000 ) . Importantly , immun - ization of mice with defined molecules from saliva of vector species also conferred a strong protection against L . major infection ( Valenzuela et al . 2001 , Oliveira et al . 2008 , Gomes et al . 2012 ) . This suggests that sand fly salivary components may be considered as candidates for a cocktail vaccine against Leish - mania infection . In the Esfahan hyperendemic focus of ZCL , the most abundant sand fly species is P . papatasi ( Yaghoobi - Ershadi and Javadian 1997 , 1999 ) . Of relevance , antibod - ies against saliva of this v"
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    ABSTRACT: Background: Sand fly saliva helps parasite establishment and induce immune responses in vertebrate hosts. In the current study, we investigated the modulation of Phlebotomus papatasi salivary gland antigen expression by seasonal and biological factors. Methods: Sand flies were grouped according to physiological stages such as unfed, fed, semi-gravid, gravid, parous, nulliparous, infected or non-infected with Leishmania major and based on the season in which they were collected. Salivary gland antigens (SGAs) were analyzed using SDS-PAGE and the antibody response against SGAs in Rhombomys opimus was determined by ELISA and Western blot. Results: The highest protein content was found in the salivary glands of unfed sand flies. The saliva content was higher in parous compared to nulliparous, in summer compared to spring, and in Leishmania-infected compared to non-infected flies. The salivary gland lysate (SGL) electrophoretic pattern variations were observed among sand flies with various physiological stages particularly from 4–9 protein bands of 14–70 kDa. The SGL of unfed and gravid flies had extra protein bands compared to fed and semi-gravid sand flies. There was missing protein bands in SGL of parous compared to nulliparous; and in summer compared to spring collected flies. Rhombomys opimus serum reacted strongly with an antigenic band of around 28 kDa in the SGL of all sand fly groups. Conclusion: Certain biological and environmental characteristics of wild populations of vector sand flies affect the protein content and antigenicity of saliva. This might have an important implication in the design of vector-based vaccines.
    Iranian Journal of Arthropod-Borne Diseases 04/2016; 10(1):39-49. · 0.88 Impact Factor
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    • "The initial saliva-specific immune response is observed as early as 2–6 h after bite up to 1 week post-challenge (29–31, 35). By 2-weeks post-infection, animals vaccinated with a salivary protein mount a stronger Leishmania-specific immunity with minimized pathology (28, 31). This supports our hypothesis that the initial immune response to a salivary protein in the skin can potentially alter the nature of the immune response to the parasites long-term and is therefore relevant for protection against both CL and VL. "
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    ABSTRACT: Visceral leishmaniasis (VL) is a vector-borne disease transmitted by phlebotomine sand flies and remains the most serious form of the disease with no available human vaccine. Repeatedly, studies have demonstrated the immunogenicity and protective efficacy of a number of sand fly salivary proteins against cutaneous and visceral leishmaniasis. All Leishmania species including agents of VL are co-deposited into the skin together with vector saliva. Generally, the immune response to a protective salivary protein in vaccinated animals is rapid and possibly acts on the parasites soon after delivery into the skin by the bite of an infective sand fly. This is followed by the development of a stronger Leishmania-specific immunity in saliva-vaccinated animals compared to controls. Considering that several of the most efficacious protective molecules were identified from a proven vector of VL, we put forward the notion that a combination vaccine that includes a Leishmania antigen and a vector salivary protein has the potential to improve vaccine efficacy by targeting the parasite at it most vulnerable stage just after transmission.
    Frontiers in Public Health 08/2014; 2:99. DOI:10.3389/fpubh.2014.00099
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    • "Additionally, lymphocytes from immunized dogs effectively killed parasites in vitro. In a recent study, mice immunized with recombinant LJM11, present in L. longipalpis saliva, in the absence of an adjuvant, were challenged by L. major-infected sand-fly bites (36). Authors detected IFN-γ being produced in response to LJM11 vaccination, which correlated with decreased numbers of parasites. "
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    ABSTRACT: Leishmaniases are worldwide diseases transmitted to the vertebrate host by the bite of an infected sand-fly. Sand-fly biting and parasite inoculation are accompanied by the injection of salivary molecules, whose immunomodulatory properties are actively being studied. This mini review focuses on how the interactions between sand-fly saliva and the immune system may shape the outcome of infection, given its immunomodulatory properties, in experimental models and in the endemic area. Additionally, we approach the recent contributions regarding the identification of individual salivary components and how these are currently being considered as additional components of a vaccine against leishmaniasis.
    Frontiers in Immunology 11/2013; 4:375. DOI:10.3389/fimmu.2013.00375
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