Sand flies and Leishmania: specific versus permissive vectors

In her recent review in Trends in Parasitology [1], Kamhawi highlighted the role of sand fly midgut receptors of lipophosphoglycan (LPG) in Leishmania attachment. This attachment is a critical step in Leishmania development as it enables the parasite to avoid expulsion from the midgut when the fly defecates. Two sand fly species, Phlebotomus papatasi and P. sergenti, display remarkable specificity for the Leishmania species they transmit in nature. In these specific vectors the attachment is controlled by LPG receptors that bind to terminal carbohydrates of the parasite LPG. In P. papatasi the galactose-specific lectin PpGalec was identified as the LPG receptor [2].

It is understandable that the review deals primarily with the best studied and straightforward parasite-vector system L. major - P. papatasi but it should be also acknowledged that a more complex picture of attachment is emerging for most other species. We feel that it should be stressed that most sand fly species tested to date support development of multiple Leishmania species and thus fall into a second group called “permissive vectors”. A typical example is P. arabicus, a sand fly recently identified as a vector of L. tropica [3]. The broad vectorial competence of P. arabicus was demonstrated by its high susceptibility to both L. major and L. infantum [4], as well as by the cyclical transmission of L. tropica to hyraxes Procavia capensis [5] that serve as natural reservoir hosts for this parasite [3].

The mechanism of Leishmania attachment in permissive vectors is very different; unexpectedly, it was shown that another lectin-like mechanism, independent of LPG, exists in these sand flies. LPG-deficient mutants of L. mexicana and L. major grew well in permissive vectors Lutzomyia longipalpis and P. arabicus producing heavy infections, fully comparable with those caused by the wild type parasites [4, 6]. Similarly, L. tropica with modified LPG [7] is not able to grow in P. sergenti but successfully develops in a permissive vector P. arabicus [8]. Clear correlation was found between permissivity and the type of glycosylation of the midgut proteins; O-glycosylated proteins with N-acetylgalactosamine (GalNAc) epitopes were present in permissive flies but not in the specific vectors [4, 8]. The hypothesis about the role of O-glycosylated proteins in Leishmania attachment in permissive vectors is supported by two further observations: molecules with GalNAc epitopes bind to Leshmania surface [4] and are present on microvillar surface of the midgut, the very place of the attachment of Leishmania promastigotes [4, 8, 9]. It follows that GalNAc-specific lectin activity found on promastigote surface [10] serves as a receptor for this binding.

The classification of sand fly species into specific or permissive vectors is likely to be an oversimplification of the true complexity of parasite-sand fly interactions. Indeed, some sand fly species may be of an ‘intermediate’ type, since they support development of many but not all Leishmania species. Whether the LPG-independent paradigm seen with L. longipalpis or P. arabicus will apply generally to all permissive sand flies remains to be determined; in a single study on P. argentipes the LPG deficient L. donovani mutants failed to survive [11]. However, while the concept of specific versus permissive vectors may be further refined, at present it provides a useful model to work with.

The broad vectorial competence of permissive sand flies also has important epidemiological consequences as it enables successful adaptation of Leishmania to new vectors. This explains some unexpected findings from the field such as the circulation of LPG-impaired L. tropica through P. arabicus [3, 8] and the introduction of L. infantum (syn. L. chagasi) from the Mediterranean to Latin America [12], where it adapted to the local permissive sand fly L. longipalpis. Presently, changes of climate, expansion of human settlements and accelerated movements of humans and animals around the world lead all to an increased risk of the spread of vector-borne diseases including leishmaniases. The high susceptibility of permissive sand fly species thus may represent an important aspect in the establishment of new foci of leishmaniases.