From Infection to Death: An Overview of the Pathogenesis of Visceral Leishmaniasis

Abstract

Kala-azar, also known as visceral leishmaniasis (VL), is a disease caused by Leishmania infantum and L. donovani. Patients experience symptoms such as fever, weight loss, paleness, and enlarged liver and spleen. The disease also affects immunosuppressed individuals and has an overall mortality rate of up to 10%. This overview explores the literature on the pathogenesis of preclinical and clinical stages, including studies in vitro and in animal models, as well as complications and death. Asymptomatic infection can result in long-lasting immunity. VL develops in a minority of infected individuals when parasites overcome host defenses and multiply in tissues such as the spleen, liver, and bone marrow. Hepatosplenomegaly occurs due to hyperplasia, resulting from parasite proliferation. A systemic inflammation mediated by cytokines develops, triggering acute phase reactants from the liver. These cytokines can reach the brain, causing fever, cachexia and vomiting. Similar to sepsis, disseminated intravascular coagulation (DIC) occurs due to tissue factor overexpression. Anemia, hypergammaglobulinemia, and edema result from the acute phase response. A regulatory response and lymphocyte depletion increase the risk of bacterial superinfections, which, combined with DIC, are thought to cause death. Our understanding of VL's pathogenesis is limited, and further research is needed to elucidate the preclinical events and clinical manifestations in humans.

Keywords: Leishmania donovani; Leishmania infantum; clinical presentation; innate immunity; kala-azar; pathogenesis; systemic inflammation; visceral leishmaniasis.

Figure 1

Flowchart depicting the likely evolution of VL from infection to disease: After the infective sand fly bite, parasites are released into the skin. Some perish and thus are not expected to generate a cellular immune response. Viable parasites reach their host cells directly via phagocytosis by mononuclear phagocytes and/or via phagocytosis by neutrophils (Trojan host), followed by engulfment by mononuclear cells. After triggering Toll-like intracellular signaling in either case, the infection is controlled by Th1- and cell-mediated immunity. However, the parasites may overcome this host response to replicate by mediating the generation of Th2 and Treg responses, progressing to VL. The patients may die or be cured, leading to lasting immunity to reinfection. Some patients may suffer from relapsing VL due to suppression of cell-mediated immunity preventing a complete cure. ¹ Regulated cell death with the formation of neutrophil extracellular traps (NET). ² A mechanism of intracellular cell entry through the phagocytosis of neutrophils with engulfed microbe by mononuclear phagocytes. ³ T-regulatory cells.

Figure 2

Uncomplicated, complicated, and lethal VL. Top left: an uncomplicated disease with hepatosplenomegaly and paleness. Top center: extensive bruising. Top right: large hepatosplenomegaly, with ascites and edema of the scrotum. Bottom left: scleral jaundice. Bottom center and right: Pseudomonas aeruginosa secondary infection in the face and the ear.

Figure 3

Proposed evolution of VL to the death of the patients through leishmanial sepsis: After Leishmania infection, the progression of the disease can be exacerbated by interactions between parasite virulence and host factors. With the development of clinical signs and symptoms, leishmanial sepsis may ensue due to exaggerated innate immune response, which promotes increased tissue-factor expression by endothelium and monocytes, generating disseminated intravascular coagulation (DIC). At the end stage, DIC can trigger bleeding enhanced by acute phase reactions with elevation of procoagulant proteins and reduction in anticoagulant proteins, with liver function and bile retention being altered, reducing vitamin-K-dependent coagulation factors and thrombocytopenia secondary to hypersplenism. Simultaneously, prolonged hospital stays of the patients in conjunction with their lymphopenia and cachexia due to the production of IL-6, IL-1, and TNF-α and deprivation of amino acids, retinol, and zinc increase their susceptibility to bacterial infection and superimposed bacterial sepsis. These episodes of leishmanial sepsis fuel multiple organ dysfunction syndrome and death of the patients.