Phlebotomine sand fly-borne pathogens in the Mediterranean Basin: Human leishmaniasis and phlebovirus infections

Abstract

Pathogens transmitted to humans by phlebotomine sand flies are neglected, as they cause infectious diseases that are not on the priority list of national and international public health systems. However, the infections caused by protozoa of the Leishmania genus and viruses belonging to the Phlebovirus genus (family Phenuiviridae)-the most significant group of viruses transmitted by sand flies-have a relevant role for human pathology. These infections are emerging in the Mediterranean region and will likely spread in forthcoming decades, posing a complex threat to human health. Four species and 2 hybrid strains of Leishmania are pathogenic for humans in the Mediterranean Basin, with an estimated annual incidence of 239,500-393,600 cases of cutaneous leishmaniasis and 1,200-2,000 cases of visceral leishmaniasis. Among the phleboviruses, Toscana virus can cause neuroinvasive infections, while other phleboviruses are responsible for a typical "3-day fever"; the actual incidence of Phlebovirus infections in the Mediterranean area is unknown, although at least 250 million people are exposed. Here, we reviewed the current literature on epidemiology of sand fly-borne infections in the Mediterranean Basin, with a focus on humans. Our analysis indicates the need for increased public health activities directed to determine the disease burden of these infections as well as to improve their surveillance. Among the emerging challenges concerning sand fly-borne pathogens, the relationships between sand fly-borne protozoa and viruses should be considered in future studies, including epidemiological links between Leishmania and phleboviruses as well as the conditional capacity for these pathogens to be involved in interactions that may evolve towards increased virulence.

Fig 1. Phleboviruses phylogeny reconstruction.

Phylogenetic relationships between selected Old World sand fly–borne phleboviruses based on partial large (L) RNA sequences; phylogenetic relationships of selected amino acid sequences were inferred by using the maximum likelihood method based on the Jones-Taylor-Thornton (JTT) model gamma distributed with invariant sites [35]. A discrete gamma distribution was used to model evolutionary-rate differences among sites [5 categories]. The analysis involved 44 sequences. All positions with less than 95% site coverage were eliminated so that there was a total of 55 positions in the final dataset. Evolutionary analysis was conducted in MEGA6 using 500 bootstrap pseudoreplications [35].

Fig 2. Distribution of human infections caused by sand fly–transmitted pathogens in the Mediterranean region using spatial methods.

(a) Autochthonous human leishmaniasis in the Mediterranean area. Countries where human leishmaniasis was diagnosed by serological tests and/or Leishmania isolation and/or PCR method are depicted in yellow. Diagrams show Leishmania species identified and/or isolated in human cases. (b) Autochthonous human phlebovirus infection in the Mediterranean area. Countries where human phlebovirus infection was diagnosed by serological tests and/or Phlebovirus isolation and/or PCR method are depicted in yellow, while white areas represent countries where human phlebovirus infection was never observed. Diagrams show Phlebovirus species identified and/or isolated in human cases; where no diagram is present, identification of phleboviruses species was not performed. Maps were created using the open source software, QGIS 2.12.