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).
Highlights
Numerous reports have documented the potent and pleiotropic effects of the saliva of blood-feeding arthropods, which include anti-coagulation, vasodilation anti-inflammation [reviewed by [9]], calling into question how minute amounts of proteins in the inoculum that is delivered during a blood meal could significantly alter the host’s immune response against the vector-delivered pathogen
The main effect of immunomodulatory saliva components in regard to infection appears to be temporary and local, altering immune responses at the bite site in the skin long enough to allow the vector to feed and for small numbers of pathogenic organisms to establish an infection. In addition to these indirect effects, certain salivary proteins, such as Salp15 in ticks, can be used by the pathogen (Borrelia burgdorferi in this case) to directly protect it from antibody-mediated killing when the pathogen coats itself with the vectorderived protein [10]. These findings explain why only a small number of Plasmodium parasites injected by a mosquito and in the presence of arthropod saliva causes malaria infection, but large numbers of isolated sporozoites have to be injected by needle and syringe to accomplish the same task
Using vector saliva rather than pathogen-derived antigens as vaccine candidates has a number of attractive advantages, including: [1] protective immunity might be independent of the pathogen strain; [2] vaccine efficacy might not be abrogated by escape mutants, www.frontiersin.org
Summary
Numerous reports have documented the potent and pleiotropic effects of the saliva of blood-feeding arthropods, which include anti-coagulation, vasodilation anti-inflammation [reviewed by [9]], calling into question how minute amounts of proteins in the inoculum that is delivered during a blood meal could significantly alter the host’s immune response against the vector-delivered pathogen. This observation is puzzling considering that vector saliva primarily evolved to assist the arthropod in obtaining a blood meal and not to facilitate the infection of the vertebrate host with a vector-borne pathogen.
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