Fatal progression of experimental visceral leishmaniasis is associated with intestinal parasitism and secondary infection by commensal bacteria, and is delayed by antibiotic prophylaxis

Abstract

Leishmania donovani causes visceral leishmaniasis (VL), which is typically fatal without treatment. There is substantial variation between individuals in rates of disease progression, response to treatment and incidence of post-treatment sequelae, specifically post-kala-azar dermal leishmaniasis (PKDL). Nevertheless, the majority of infected people are asymptomatic carriers. Hamsters and mice are commonly used as models of fatal and non-fatal VL, respectively. Host and parasite genetics are likely to be important factors, but in general the reasons for heterogeneous disease presentation in humans and animal models are poorly understood. Host microbiota has become established as a factor in cutaneous forms of leishmaniasis but this has not been studied in VL. We induced intestinal dysbiosis in mice and hamsters by long-term treatment with broad-spectrum antibiotics in their drinking water. There were no significant differences in disease presentation in dysbiotic mice. In contrast, dysbiotic hamsters infected with L. donovani had delayed onset and progression of weight loss. Half of control hamsters had a rapid progression phenotype compared with none of the ABX-treated animals and the nine-month survival rate was significantly improved compared to untreated controls (40% vs. 10%). Antibiotic-treated hamsters also had significantly less severe hepatosplenomegaly, which was accompanied by a distinct cytokine gene expression profile. The protective effect was not explained by differences in parasite loads or haematological profiles. We further found evidence that the gut-liver axis is a key aspect of fatal VL progression in hamsters, including intestinal parasitism, bacterial translocation to the liver, malakoplakia and iron sequestration, none of which occurred in non-progressing murine VL. Diverse bacterial genera were cultured from VL affected livers, of which

Non-human primates and Leishmania immunity

“…Moreover, mice and humans differ in number of effector molecules such as defensin [5] , [6] and granulysin [7] and the capacity of human phagocytic cells to produce NO appears to be under much tighter regulation [8] , [9] . Furthermore, no infection of intestine is observed in mouse model [10] .…”

Leishmaniasis Beyond East Africa

“…VL is characterized by presence of an enlarged liver and spleen, anemia, weight loss, and irregular fevers ( 2 ). Patients with VL often die within 2 years of contracting the disease if left untreated, commonly from subsequent infections or severe anemia ( 30 , 31 ). Although not seen in all VL species it is expected that darkening of the skin, particularly in India, is caused by the cytokine-induced production of adrenocorticotrophic hormone ( 32 ).…”

Resistance Against Leishmania major Infection Depends on Microbiota-Guided Macrophage Activation

“…The dysbiosis is marked by increased specific groups of bacteria that were related to the outcome of disease ( 38 ). Gut microbiota composition seems to be relevant in visceral leishmaniasis since it was recently shown that gut microbiota modulation by an antibiotic cocktail can improve the disease outcome in hamsters infected with L. donovani ( 39 ).…”