The Hamster as a Model of Human Visceral Leishmaniasis: Progressive Disease and Impaired Generation of Nitric Oxide in the Face of a Prominent Th1-Like Cytokine Response

Abstract

Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia. In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease. Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function. Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L. donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model. Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-γ, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function. Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice. The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-β. Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster.

Studies in a co-infection murine model of Plasmodium chabaudi chabaudi and Leishmania infantum: interferon<FONT FACE=Symbol>-g</FONT> and interleukin-4 mRNA expression

“…Although some authors point out to the importance of IFN-γ in the resolution of leishmaniasis infection (Kaye et al 1991, Carvalho et al 1994, the IFN-γ expression levels detected at day 7, when Leishmania parasites were inoculated, apparently did not restrain the progression of L. infantum infection in co-infected mice. According to Melby et al (2001), syrian hamsters infected with L. donovani are not able to control parasite replication despite the high levels of Th 1 cytokine expression, namely IFN-γ, as observed in this study. In fact, co-infected mice presented an evident splenomegaly on day 56, which is a typical clinical symptom of visceral leishmaniasis, and positive cultures with high values of parasite density were observed.…”

Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis

“…Studies in the classical hamster model of VL also showed decreased expression of iNOS mRNA, accounting for defective parasite elimination, thereby enhancing disease progression (47). Indeed serum nitrite levels are also decreased in active VL (48), and our study corroborated that intracellular NO in macrophages of patients with VL (n 5 6) are significantly decreased as compared to healthy individuals (n 5 5), GMFC being 38.88 AE 25.44 vs. 212.70 AE 15.71 (P \ 0.05, Fig.…”

Preliminary study towards a novel experimental model to study localized cutaneous leishmaniasis caused bY Leishmania (Leishmania) mexicana

“…This situation led to the experimental infection of the deer mouse Peromyscus maniculatus, a primary reservoir of the SNV 8 . However as in the golden hamster experimental model to study visceral leishmaniasis research is hindered by the lack of commercially available immunological and molecular reagents to investigate mechanisms of disease 25 .…”