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ANTI-SALIVA ANTIBODY PRODUCTION IN NAIVE DOGS EXPOSED TO UNINFECTED LUTZOMYIA LONGIPALPIS BITES
Autor
Afiliación
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil.
Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, MD, United States.
Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, MD, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil.
Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil.
Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, MD, United States.
Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, MD, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de interação parasita-hospedeiro e epidemiologia. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Veterinária. Salvador, BA, Brasil.
Resumen en ingles
Canine visceral leishmaniasis (CVL) is caused by Leishmania infantum and transmitted to dogs and humans by sandflies. In Brazil, Lutzomyia longipalpis is the primary vector of this disease. When feeding, infected sandflies inoculate metacyclic promastigote forms of Leishmania and their saliva and other components into the hosts. Anti-saliva antibodies were associated with increased visceral leishmaniasis severity in naturally infected dogs. Although these compounds introduced by the vector favor the establishment of Leishmania, the early events that occur at the bite site are not fully understood. A better understanding of these initial events is essential to the development of better therapeutics and prophylactic strategies. Studies have demonstrated that sandfly saliva promotes Leishmania infection. Leishmania major co-injected with Lu. longipalpis or Phlebotomus papatasi saliva resulted in more severe disease manifestations in mice, as reflected by larger lesions compared to animals that received only parasites. This initial observation was further supported by additional studies demonstrating the enhanced infectivity of L. major when co- inoculated with saliva from the sandfly Lu. longipalpis. Apart from antihemostatic properties, sand fly saliva promotes chemotactic activity in a variety of immune cells, such as macrophages, neutrophils, dendritic cells and lymphocytes. In addition, many other cell types, including monocytes, interact with sandfly saliva, thereby modifying inflammatory processes at the blood feeding site. It has been proposed that the resulting effects on the host immune system contribute to increased parasite loads in mice exposed to sandfly bites compared to animals infected through needle injection7. Moreover, it has also been demonstrated that other vector-derived factors can additionally contribute to Leishmania infection, such as the microbiota of the vector, exosomes and the promastigote secretory gel. In recent years, our group has contributed compelling data linking the differential production of lipid mediators to inflammatory factors involved in the establishment of infection. Specific levels of lipid mediators, mainly the eicosanoids leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), are important components of the inflammatory response to, and outcome of infection by intracellular pathogens. Previous in vitro studies have demonstrated the role of LTB4 as a factor that participates in parasite killing, while PGE2 was shown to favor Leishmania survival. More recently, lipid mediators were identified as biomarkers of cutaneous and visceral leishmaniasis severity. Anti-sandfly saliva antibodies could also represent an essential epidemiological tool to assess vector exposure in endemic areas. LJM11 and LJM17 recombinant proteins are present in the vector's saliva and have already been used for this purpose. Our goal was to follow up anti-saliva antibodies (anti-LJM11 and anti-LJM17) production in naïve dogs experimentally exposed to Lu. longipalpis sandflies. We also assessed the persistence of anti-saliva antibodies titers for one year, and after re- exposure to the sandfly vectors. Blood samples from the dogs were collected weekly to assess the production of anti-LJM11 and anti-LJM17 IgG by ELISA. Six healthy naïve dogs were exposed weekly to 35 Lu. longipalpis female sandflies until at least 80% of the female were fed. Dogs were exposed to the sandflies until anti-saliva antibody production reached a plateau and remained elevated for at least three consecutive weeks. Afterward, we ceased sandflies exposures; we followed the dogs weekly until the animals tested negative for anti-saliva antibodies for three consecutive weeks. Then, we re-exposed the dogs to the sandflies and evaluated the time-period it took for the animals to resume anti-saliva antibody production. The Reactivity Index (RI) was calculated by dividing the optical density by the cut-off point obtained in each ELISA plate to compare antibody production. Soon after the first exposures, there was an immediate increase in the production of anti-saliva antibodies (between the first and the third week). On the twenty-eighth day after the first exposure (with a median of 10.5 days), all six animals showed detectable anti-saliva IgG titers. Dogs were exposed to sandflies for six to nine weeks (with a median of 52.5 days). After the initial rising of anti-saliva antibody production post-exposure, anti- saliva antibody titers fluctuated, remaining detectable for over a year. We found a statistically significant difference comparing anti-saliva antibodies titers before exposure and five weeks after the exposure (p<0,05). Despite the variations in titration, four dogs remained positive for 41 weeks (290 days) on average, two animals are still positive after 460 days. After the first week of re-exposure, dogs demonstrated antibody titers rising significantly. Throughout the evaluation, there was a considerable variation in antibody production among the six animals, especially concerning the time of seroconversion, time to reach the plateau, and titer decay. Although we observed differences among the animals, we can detect a similar pattern during the follow-up. Currently, studies evaluating the cellular immune response of these animals are being carried out. We have collected peripheral blood mononuclear cells (PBMC) in different time points after exposure and re-exposure and we intend to stimulate these cells with salivary gland homogenate and measure the cytokines production with LUMINEX specific canine kit. Moreover, we will measure canine serum cytokines produced during the follow-up after exposure and re-exposure to sand flies. This experimental approach allows us to better understand the early events among vector and host after exposure to sand flies and to delineate better strategies to control infection establishment.
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