Use of In Vivo Imaging System Technology in Leishmania major BALB/c Mouse Ear Infection Studies

Abstract

Novel treatments for cutaneous leishmaniasis (CL) are needed, due to current lack of effective universal treatments, increasing resistance among the parasite, and toxic effects or impracticality of the current therapeutics. Models of direct infection with high number of Leishmania parasites in the current research of CL involving the BALB/c mouse or Golden Syrian Hamster are considered not suitable for the assessment of antileishmanial drug efficacy because of the lack of disease similarities with humans. The saliva of the sand fly vector is known to affect the host response to infection by the Leishmania parasite. Here, we build upon a previous BALB/c model infected with luciferase-expressing Leishmania major parasites. In the present study, we infect the ear dermis instead of the foot pad or base of the tail, and compare multiple methods of infection, using parasites alone or mixed with either bites from uninfected sand flies (Phlebotomus duboscqi Diptera Psychodidae:Neveu-Lemaire) or salivary gland sonicate from sand flies. Our data show a dose-response of bioluminescent signal (which represents the parasite load at the infection site), dermal lesion development, and Leishmania Donovan Units in liver and spleen. This in vivo L. major ear infection model, once optimized, can be used for assessing the efficacy of drug compounds that have been determined as very effective in the other, high inoculum CL models.

Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis

“…Salivary proteins have a strong effect on the immune system of the host, which includes but is not limited to, inhibition of T cell and macrophage activation, diminishing the ability of dentritic cells to present antigens, and reducing neutrophil migration during specific antigen-induced inflammation (Abdeladhim et al, 2014). Therefore, whenever possible, animal infection should mimic the natural transmission by the sand-fly bite of a small inoculum of Leishmania metacyclic promastigotes and saliva in the infection site (Mears et al, 2015), (Croft et al, 2006), (Abdeladhim et al, 2014), (Kimblin et al, 2008), (Belkaid et al, 1998), (Belkaid et al, 2000), (Cawlfield et al, 2018). Humanized mice models have also been used with some success to study the human immune response against the Leishmania pathogen, conduct drug discovery studies, and predict possible side effects of new drugs in humans (Wege et al, 2012).…”