**5. Concluding remarks**

The leishmaniases are one of the most important groups of neglected tropical diseases estimated to affect 1 million people annually in nearly 100 countries [1]. The fact that an effective vaccine has yet to be developed reflects the gap in our understanding of host responses to *Leishmania* species, disease pathogenesis and what actually constitutes a protective immune response. The different *Leishmania* parasites inducing different host immune responses, which are further impacted by host genetics, have made it difficult to achieve consensus among experimental studies regarding the role of the different immune components in *Leishmania* infection. Furthermore, research to date highlights the inadequacies of small animal models in understanding human host responses to *Leishmania*. The increase in *in vitro*/*ex vivo* characterization of *Leishmania*specific immune responses using samples derived from human clinical studies has provided more information on human CL, however more efforts towards human clinical studies (cohort and case control-studies) including human *ex vivo* infection models should be emphasized to gain a better understanding of the human immune response to *Leishmania* parasites. An interesting recent focus has been the use of humanized mice to further examine the role of specific immune cells and responses in *Leishmania* infection; this could further inform the development of novel vaccine strategies [134].

Additionally, there are other important vector and parasite-derived components affecting host immune responses, which were outside the scope of this chapter but are important to consider in terms of host-parasite interactions. Recent experimental studies are providing new insights into host immune responses by employing a sandfly challenge model using the natural route of parasite inoculation via phlebotomine sandflies [46]. Vector-derived components have been shown to

contribute to early immune responses in infection [14]. For example, tissue damage caused by the phlebotomine sandfly's proboscis and the delivery of sandfly saliva triggers the rapid recruitment of neutrophils which induce inflammation [41]. *Leishmania*-derived components have also been shown to play a role during inoculation and *Leishmania* exosomes have been shown to modulate immune cells and host responses through direct and indirect contact [135].

This chapter has highlighted the complexity associated with CL and how host immune cells can both be protective and pathogenic depending on the interaction with *Leishmania* species parasite and host genetic. Employing a human CL model that provides a better understanding and more accurately represents parasite-host interactions will be critical for the development of an effective vaccine capable of inducing long-lasting protective immunity.
