Is Arthropod Saliva the Achilles’ Heel of Vector-Borne Diseases?

Abstract

Vector-borne pathogens are deposited into the skin of the vertebrate host animal during the process of blood feeding. The pathogen establishes an infection from this site rather than by having direct access to the host’s circulatory system. In an attempt to simplify the complex interactions between multiple species (vertebrate host, arthropod vector, and microbial pathogen) that occur during the blood meal and following the deposition of pathogen in the host, researchers routinely use artificial animal models, which do not account for a number of potential parameters. The delivery of isolated, purified pathogens by injection rather than natural infection by pathogen-carrying vectors introduces significant artifacts (1, 2). Therefore, insights gained from such models are somewhat limited and, not surprisingly, successes with experimental vaccines developed by using those models have been very difficult to replicate in field trials. In addition to the route of delivery, the immune and disease-status of the vaccinee (e.g., chronic infection with parasitic organisms), the heterogeneity of the pathogen (i.e., exposure to different pathogen strains in the field compared to the challenge with a defined pathogen strain in the laboratory), an important difference between vector-borne pathogens delivered by needle and syringe after their isolation from an infected vector (artificial) and by an arthropod vector (natural) is the presence of arthropod saliva in the latter scenario. The small amounts of vector-derived molecules in the infectious inoculum can significantly change the infectivity of the vector-borne pathogen as first described for Leishmania more than two decades ago (3). Saliva molecules delivered to the bite site together with a vector-borne pathogen have been shown to modulate or derail vertebrate immune responses resulting in a local microenvironment that favors the establishment of a vector-borne disease. For example, tick-derived saliva factors appear to inhibit inflammatory cytokine secretion thus preventing efficient immune responses against tick-borne Rickettsia (4); a defined molecule in the saliva of the Aedes aegypti mosquito (SAAG-4) has the potential to alter the Th-profile of the bite-induced immune response likely rendering the host unable to effectively eliminate vector-borne viruses (5); and sand fly saliva has a caspase-dependent, pro-apoptotic effect on neutrophils resulting in an infection of the host with increased numbers of Leishmania parasites (6). Vector saliva can even exhibit its effect on the course of an infection when delivered separately from the infectious inoculum, as demonstrated by the injection of purified Plasmodium parasites followed by the bite of a non-infected mosquito and thus the delivery of salivary proteins in “trans” (7). Finally, even a temporal separation of saliva- and pathogen-delivery cannot eliminate effects of arthropod saliva on a subsequent infection with a vector-borne disease (8).