LJM19, a salivary protein from the sand fly vector that transmits leishmaniasis, is a novel inhibitor of the classical pathway of complement

AbstractApart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.

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A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates

Science Translational Medicine ◽

10.1126/scitranslmed.aaa3043 ◽

2015 ◽

Vol 7 (290) ◽

pp. 290ra90-290ra90 ◽

Cited By ~ 66

Author(s):

Fabiano Oliveira ◽

Edgar Rowton ◽

Hamide Aslan ◽

Regis Gomes ◽

Philip A. Castrovinci ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Nonhuman Primates ◽

Mononuclear Cells ◽

Rhesus Macaques ◽

Parasite Burden ◽

Salivary Protein ◽

Sand Fly ◽

Protein Vaccine ◽

Peripheral Blood Mononuclear ◽

Phlebotomus Duboscqi

Currently, there are no commercially available human vaccines against leishmaniasis. In rodents, cellular immunity to salivary proteins of sand fly vectors is associated to protection against leishmaniasis, making them worthy targets for further exploration as vaccines. We demonstrate that nonhuman primates (NHP) exposed to Phlebotomus duboscqi uninfected sand fly bites or immunized with salivary protein PdSP15 are protected against cutaneous leishmaniasis initiated by infected bites. Uninfected sand fly–exposed and 7 of 10 PdSP15-immunized rhesus macaques displayed a significant reduction in disease and parasite burden compared to controls. Protection correlated to the early appearance of Leishmania-specific CD4+IFN-γ+ lymphocytes, suggesting that immunity to saliva or PdSP15 augments the host immune response to the parasites while maintaining minimal pathology. Notably, the 30% unprotected PdSP15-immunized NHP developed neither immunity to PdSP15 nor an accelerated Leishmania-specific immunity. Sera and peripheral blood mononuclear cells from individuals naturally exposed to P. duboscqi bites recognized PdSP15, demonstrating its immunogenicity in humans. PdSP15 sequence and structure show no homology to mammalian proteins, further demonstrating its potential as a component of a vaccine for human leishmaniasis.

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Genetic variation in the sand fly salivary protein, SP-15, a potential vaccine candidate against Leishmania major

Insect Molecular Biology ◽

10.1111/j.1365-2583.2004.00539.x ◽

2005 ◽

Vol 14 (2) ◽

pp. 145-150 ◽

Cited By ~ 33

Author(s):

D.-E. A. Elnaiem ◽

C. Meneses ◽

M. Slotman ◽

G. C. Lanzaro

Keyword(s):

Genetic Variation ◽

Leishmania Major ◽

Vaccine Candidate ◽

Salivary Protein ◽

Sand Fly ◽

Potential Vaccine Candidate ◽

Potential Vaccine

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Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0004322 ◽

2016 ◽

Vol 10 (1) ◽

pp. e0004322 ◽

Cited By ~ 25

Author(s):

Jacqueline Araújo Fiuza ◽

Ranadhir Dey ◽

Dwann Davenport ◽

Maha Abdeladhim ◽

Claudio Meneses ◽

...

Keyword(s):

Immune Response ◽

Leishmania Donovani ◽

Salivary Protein ◽

Protective Immune Response ◽

Sand Fly ◽

Knock Out ◽

Intradermal Immunization

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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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0712153105 ◽

2008 ◽

Vol 105 (22) ◽

pp. 7845-7850 ◽

Cited By ~ 156

Author(s):

R. Gomes ◽

C. Teixeira ◽

M. J. Teixeira ◽

F. Oliveira ◽

M. J. Menezes ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Fatal Outcome ◽

Salivary Protein ◽

Sand Fly ◽

Hamster Model

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

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1112042.568012 ◽

2008 ◽

Author(s):

Barbara Papadopoulou

Keyword(s):

Visceral Leishmaniasis ◽

Fatal Outcome ◽

Salivary Protein ◽

Sand Fly ◽

Hamster Model

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The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B

Frontiers in Immunology ◽

10.3389/fimmu.2017.01065 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 4

Author(s):

Antonio F. Mendes-Sousa ◽

Vladimir Fazito do Vale ◽

Naylene C. S. Silva ◽

Anderson B. Guimaraes-Costa ◽

Marcos H. Pereira ◽

...

Keyword(s):

Alternative Pathway ◽

Salivary Protein ◽

Sand Fly ◽

Direct Binding ◽

Alternative Pathway Of Complement

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Protective Efficacy in a Hamster Model of a Multivalent Vaccine for Human Visceral Leishmaniasis (MuLeVaClin) Consisting of the KMP11, LEISH-F3+, and LJL143 Antigens in Virosomes, Plus GLA-SE Adjuvant

Microorganisms ◽

10.3390/microorganisms9112253 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2253

Author(s):

Laura Fernández ◽

Jose Carlos Solana ◽

Carmen Sánchez ◽

Mª Ángeles Jiménez ◽

Jose M. Requena ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Process Development ◽

Protective Efficacy ◽

Humoral Response ◽

Cost Effective ◽

Salivary Protein ◽

Sand Fly ◽

Vaccine Formulation ◽

Hamster Model ◽

Nucleoside Hydrolase

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the Leishmania membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with Leishmania infantum. Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble Leishmania antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against L. infantum infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trials.

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Phlebotomus papatasi sand fly salivary protein diversity and immune response potential in Egypt and Jordan populations

10.1101/649517 ◽

2019 ◽

Author(s):

Catherine M. Flanley ◽

Marcelo Ramalho-Ortigao ◽

Iliano V. Coutinho-Abreu ◽

Rami Mukbel ◽

Hanafi A. Hanafi ◽

...

Keyword(s):

Immune Response ◽

Genetic Variability ◽

Salivary Protein ◽

Sand Fly ◽

Delayed Type Hypersensitivity ◽

Salivary Proteins ◽

Human Populations ◽

Phlebotomus Papatasi ◽

Study Sites ◽

Pharmacologically Active

AbstractPhlebotomus papatasi sand flies inject their hosts with a myriad of pharmacologically active salivary proteins to assist with blood feeding and to modulate host defenses. These salivary proteins have been studied for their role in cutaneous leishmaniasis disease outcome with different salivary proteins attenuating or exacerbating lesion size. Studies have shown that while co-administered sand fly saliva exacerbates Leishmania major infections in naïve mice, animals pre-exposed to saliva are protected, with the infection attenuated via a delayed-type hypersensitivity immune reaction. These studies highlight the potential of the salivary components to be used as a vaccine. One protein in particular, P. papatasi salivary protein 15 (PpSP15) has been intensively studied because of its ability to protect mice against Le. major challenge. The number of antigenic molecules included in vaccines is restricted thus emphasizing the role of population genetics to identify molecules, like PpSP15, that are functionally significant, conserved across populations and do not experience selection. Three distinct ecotope study sites, one in Egypt (Aswan) and two in Jordan (Swaimeh and Malka), were chosen based on their elevation, rainfall, vegetation, differing reservoir species, and the presence or absence of Le. major. The objective of this work was to analyze the genetic variability of nine of the most abundantly expressed salivary proteins including PpSP12, PpSP14, PpSP28, PpSP29, PpSP30, PpSP32, PpSP36, PpSP42, and PpSP44 and to predict their ability to elicit an immune response. Two proteins, PpSP12 and PpSP14, demonstrated low genetic variability across the three sand fly populations represented in this study, with multiple predicted MHCII epitope binding sites, identified by alleles present in the human populations from the study sites. The other seven salivary proteins revealed greater allelic variation across the same sand fly populations indicating that their use as vaccine targets may prove to be challenging.

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