Abstract
BackgroundSaliva is a key element of interaction between hematophagous mosquitoes and their vertebrate hosts. In addition to allowing a successful blood meal by neutralizing or delaying hemostatic responses, the salivary cocktail is also able to modulate the effector mechanisms of host immune responses facilitating, in turn, the transmission of several types of microorganisms. Understanding how the mosquito uses its salivary components to circumvent host immunity might help to clarify the mechanisms of transmission of such pathogens and disease establishment.MethodsFlow cytometry was used to evaluate if increasing concentrations of A. aegypti salivary gland extract (SGE) affects bone marrow-derived DC differentiation and maturation. Lymphocyte proliferation in the presence of SGE was estimated by a colorimetric assay. Western blot and Annexin V staining assays were used to assess apoptosis in these cells. Naïve and memory cells from mosquito-bite exposed mice or OVA-immunized mice and their respective controls were analyzed by flow cytometry.ResultsConcentration-response curves were employed to evaluate A. aegypti SGE effects on DC and lymphocyte biology. DCs differentiation from bone marrow precursors, their maturation and function were not directly affected by A. aegypti SGE (concentrations ranging from 2.5 to 40 μg/mL). On the other hand, lymphocytes were very sensitive to the salivary components and died in the presence of A. aegypti SGE, even at concentrations as low as 0.1 μg/mL. In addition, A. aegypti SGE was shown to induce apoptosis in all lymphocyte populations evaluated (CD4+ and CD8+ T cells, and B cells) through a mechanism involving caspase-3 and caspase-8, but not Bim. By using different approaches to generate memory cells, we were able to verify that these cells are resistant to SGE effects.ConclusionOur results show that lymphocytes, and not DCs, are the primary target of A. aegypti salivary components. In the presence of A. aegypti SGE, naïve lymphocyte populations die by apoptosis in a caspase-3- and caspase-8-dependent pathway, while memory cells are selectively more resistant to its effects. The present work contributes to elucidate the activities of A. aegypti salivary molecules on the antigen presenting cell-lymphocyte axis and in the biology of these cells.
Highlights
Saliva is a key element of interaction between hematophagous mosquitoes and their vertebrate hosts
A. aegypti salivary gland extract (SGE) does not interfere with dendritic cell differentiation or maturation Bone marrow-derived dendritic cell (BMDC) from BALB/c mice were cultured with GM-CSF in the presence of different concentrations of A. aegypti saliva and their differentiation was evaluated by flow cytometry through the percentage of CD11c+/CD11b+ cells
Because cells from Bim−/− mice are as susceptible to apoptosis as cells from Bim+/− mice (Figure 4C), and it is well known that this differential resistance is considerably dependent on the neutralization of Bim-mediated apoptosis by increased levels of Bcl-2 [29,30], we investigated whether the A. aegypti salivary components would have an effect on memory cells
Summary
Saliva is a key element of interaction between hematophagous mosquitoes and their vertebrate hosts. The key interaction element between A. aegypti and its vertebrate host is the mosquito saliva and a successful blood meal is achieved by the action of salivary anti-hemostatic and immunomodulatory molecules present in this pharmacological cocktail The former are responsible for anticoagulant, anti-platelet aggregation and vasodilatory activities [5,6], while the latter is thought to modulate immune functions, which in turn, facilitates pathogen transmission. As a result of their strategic location in the skin, dendritic cells (DCs) interact directly with the mosquito salivary components during and after the blood meal They are among the first cells to encounter pathogens transmitted by these vectors and initiate the adaptive immune response against them. Recent literature has demonstrated an important functional relationship between coagulation and immunity [21,22,23] and, some of the salivary anti-hemostatic molecules described in hematophagous arthropods are involved in the modulation of host inflammation and immune responses through different mechanisms and pathways [20,24,25,26]
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