Variation in Maxadilan and Its Consequences

RO1 AI39540 (Lanzaro, PI)

NIH/NIAID

Sand Fly. (Photo by Greg Lanzaro)

Our observation that the sand fly salivary protein, maxadilan is highly polymorphic was surprising.  It would seem that the amino acid sequence of such a protein, with functions presumably vital to the sand fly, would be conserved.  We hypothesize that hyper-variation in maxadilan has evolved as a mechanism for the avoidance of host immune response mounted against it. 

To test this hypothesis we propose studies aimed at determining amino acid sequence polymorphism for the salivary protein, maxadilan from Lutzomyia longipalpis (Aim #1).  Population genetics studies will be conducted at field sites in Colombia, Nicaragua and Brazil.  If variation in maxadilan does represent antigenic polymorphism and is adaptive, then it must be true that anti-maxadilan antibodies have a negative effect on vector fitness. 

In Aim #2 we propose a series of experiments to test this hypothesis.  We will immunize hamsters with recombinant maxadilan. Flies will be fed on immunized and control animals and effects on sand fly fitness evaluated. 

In Aim #3 we will examine the impact of maxadilan on leishmanial infections.  There is compelling evidence that the immunomodulatory activities of sand fly saliva, and maxadilan itself, enhances the establishment of parasite infections.  The effects of vector saliva and specific maxadilan proteins on the pathogenesis of Leishmania chagasi will be evaluated by experimental infections (Aim #3).  We have discovered that natural Lu. longipalpis populations differ dramatically in the amount of maxadilan present in their saliva.  As part of Aim #3 we will conduct epidemiological field studies to determine the distribution of “high” and “low” maxadilan fly populations in relation to the distribution of visceral or atypical cutaneous disease caused by Le. chagasi. 

In Aim #4, we will study immunological variation and receptor binding properties of different maxadilan variants.  The goal of these experiments is to determine if different maxadilan proteins illicit specific antibodies and to evaluate if these cross react (antigenic specificity).  The receptor binding studies are designed to evaluate if variants differ in their ability to bind to the PACAP receptor, which is related to their vasodilatory activity.