Parasitology Today, vol. 6, no 5, 1990 157 The Role of Vector Saliva in Transmission of Arthropod-Borne Blood-sucking arthropod diseasevectors all share one important feature: while probing for blood in the vertebrate, host's skin they salivate into the wound they create. Recent studies on the pharmacological properties of vector saliva have revealed an array of activities that are potentially beneficial to both the vector and to the pathogen. These observations may help explain why certain vectors and pathogens have co-evolved. In this article, Richard Titus and Jose Ribeiro discuss the role vector saliva may play in disease transmission, and the prospects for its use in the control of arthropod-borne pathogens. Many of the world's most serious infec- tious diseases, ranging from malaria, fila- riasis, trypanosomiasis and leishmaniasis to lyme disease, are l:ransmitted by blood-sucking arthropod vectors such as mosquitoes, tsetse flies, sand flies and ticks ~'2. In studies conducted using experimental animal mcdels, infections are initiated by injecting the pathogens via a syringe. However, it is now evident that blood-sucking arthropod vectors are not simply flying syringes and that administering pathogens to animals in this way does not mimic natural disease transmission. When arthropod ve,~ors bite the vertebrate host, they are probing for a blood meal. In the process of probing, the arthropod vector salivates into the skin. Vector saliva has been found to contain a large number of substances whose pharmacological effects include anti-hemostatic, vasodila.tory or anti- inflammatory/immunosuppressive ac- tivity 3'4. These effects of saliva would benefit the arthropod vector in its quest to locate blood and to maintain blood flow without inducing a host inflamma- tory response. In addition, the arthro- pod vector can deliver the pathogen it transmits into the site on the skin where it has salivated, so the pathogen encoun- ters, and possibly benefits from, a skin site that is profoundly altered by the effects of vector saliva. This would apply to pathogens that are delivered via the mouthparts, either by salivation or regur- gitation, and might also hold for those transmitted via the rectum (eg. Trypano- soma cruzi), since they may also invade the host through the bite wound. (~) 1990, Elsevier Science Publishers Ltd, (LJK)0169J~707/90/$02.00 Disease R.G. Titus and J.M,C. Ribeiro Components of Vector Saliva Arthropod-vector salivary glands contain a wealth of pharmacologically active substances 3'4. Anti-coagulant and anti-platelet activities are present in phlebotomine sandflies, mosquitoes, tsetse flies, triatomine bugs and ticks. The anti-platelet activity may be at- tributed, at least in part, to apyrase, a ubiquitous salivary enzyme that degrades ATP to AMP and orthophos- phate, thus destroying an important physiological mediator of platelet aggre- gation. In addition, other anti-platelet activities have been described: (I) anti- thromboxane in the bug Rhodnius pro- lixus s and (2) prostaglandin E2 (PGE2) and possibly prostacyclin in the tick Ixodes dammini 6. PGE2 and prostacyclin also promote vasodilation, a process that would provide more blood for the vec- tor at the feeding site. A nitrovasodilator from Rhodnius is currently under investigation, and a potent vasodilatory peptide has been described in the saliva of Lutzomyia sandflies, vectors of New World leishmaniasis7'8. Finally, we have observed that unsensitized individuals can exhibit erythema without swelling and itching after the bite of some fleas and Culicoides flies. This suggests that these arthropods may also secrete a salivary vasodilator during probing. Salivary anti-inflammatory agents, such as anti-histamine, anti-serotonin, kininase, anaphylatoxin-inactivating ac- tivity and anti-complement activity are present in the salivary glands of Rhodnius and in Ixodes ticks 3'4. These substances prevent the formation of edema. Edema probably impairs the arthropod's feed- ing success since it may disrupt blood flow and force the tick to feed on serous exudate instead of blood. An immuno- suppressive activity of tick saliva has been suggested by the work of Wikel 9'1°, who found that lymphocytes from tick-infested experimental animals showed a greatly reduced mitogenic response in vitro. In addition, saliva of the tick I. dammini has been shown to inhibit T-cell activation in vitro 6, a phenomenon that cannot be accounted for by the PGE2 present in the saliva6. I. dammini saliva also inhibits various neutrophil functions II. Thus it is possible that the immunosuppressive effect of tick saliva could enhance the feeding success of the tick and therefore the efficiency of trans- mission of pathogens. This phenomenon might not, however, apply to all tick hosts. The work of Trager 12 showed that guinea pigs infested with Dermo- center variabilis or I. scapularis upon repeated tick contact develop an ef- ficient immune response to the ticks. However, Trager ~2 also showed that such responses did not occur when the white-footed mouse, a natural host for such ticks, was used instead of the un- natural guinea pig host. It has been pro- posed that the key to successful tick infestation depends upon the tick's ability to resist pharmacological and immuno- logical attack by the host. Because differ- ent vertebrate species use different me- diators and mechanisms for promoting inflammation, a tick adapted to a particu- lar species may be able to feed to com- pletion on its natural host, but may be immunologically rejected when feeding on another, unnatural host species j3. Salivary gland lysates of the sandfly Lu. Iongipalpis (a vector of New World leish- maniasis) inhibit several macrophage functions. For example, macrophages preincubated for 3 h with Lu. Iongipalpis salivary gland lysates are unable to pro- duce hydrogen peroxide in response to activation with interferon-gamma (IFN-7) and are no longer able to present antigen (Ref. 12 and see below). Recent evidence suggests that the immuno- suppressive effect of Lu. Iongipalpis saliva may be mediated by the same peptide that is responsible for its vasodilatory effect 8,12 Sandfly Saliva and Leishmaniasis Since the sandfly injects the mam- malian host with Leishmania in the pres- ence of its saliva, and the salivary gland contains several molecules with potent pharmacological activities, we hypoth- esized that components of the saliva might influence the infectivity of the parasite for the vertebrate host. To test this hypothesis, we performed exper- iments in which mixtures of lysates of the salivary glands from the sandfly