Elucidating the role played by bone marrow in visceral leishmaniasis

Abstract

Leishmaniasis is a widespread group of infectious diseases that significantly impact global health. Despite high prevalence, leishmaniasis often receives inadequate attention in the prioritization of measures targeting tropical diseases. The causative agents of leishmaniasis are protozoan parasites of the Leishmania genus, which give rise to a diverse range of clinical manifestations, including cutaneous and visceral forms. Visceral leishmaniasis (VL), the most severe form, can be life-threatening if left untreated. Parasites can spread systemically within the body, infecting a range of organs, such as the liver, spleen, bone marrow and lymph nodes. Natural reservoirs for these protozoa include rodents, dogs, foxes, jackals, and wolves, with dogs serving as the primary urban reservoir for Leishmania infantum. Dogs exhibit clinical and pathological similarities to human VL and are valuable models for studying disease progression. Both human and canine VL provoke clinical symptoms, such as organ enlargement, fever, weight loss and abnormal gamma globulin levels. Hematologic abnormalities have also been observed, including anemia, leukopenia with lymphocytosis, neutropenia, and thrombocytopenia. Studies in dogs have linked these hematologic changes in peripheral blood to alterations in the bone marrow. Mouse models of VL have also contributed significantly to our understanding of the mechanisms underlying these hematologic and bone marrow abnormalities. This review consolidates information on hematological and immunological changes in the bone marrow of humans, dogs, and mice infected with Leishmania species causing VL. It includes findings on the role of bone marrow as a source of parasite persistence in internal organs and VL development. Highlighting gaps in current knowledge, the review emphasizes the need for future research to enhance our understanding of VL and identify potential targets for novel diagnostic and therapeutic approaches.

Keywords: Leishmania; bone marrow; canine visceral leishmaniasis; human visceral leishmaniasis; visceral leishmaniasis.

Figure 1

Life-cycle of L. infantum and L. donovani. Leishmaniasis transmission occurs through the bite of female phlebotomine sand flies that are carrying parasites. In the Old World, visceral leishmaniasis (VL) is anthroponotic, with L. donovani circulating among humans. However, in Europe, West Africa, and the Americas, VL is a zoonosis, primarily caused by L. infantum, which affects humans and dogs, which are considered as the main parasite reservoir. The transmission process begins when sand flies feed on blood (1) and inject the infective metacyclic form of Leishmania promastigotes (2) into the host’s dermis. Once inside the body, promastigotes are engulfed by macrophages (3) and other types of mononuclear phagocytic cells. Within these cells, promastigotes transform into amastigotes (4), the tissue stage of the parasite. Amastigotes multiply through simple division (5) and proceed to infect other mononuclear phagocytic cells, leading to the development and manifestation of the infection.

Figure 2

Hematological alterations in bone marrow and peripheral blood during CVL. This image depicts the common hematological changes observed in the peripheral blood of dogs infected with L. infantum. Although the underlying causes appear to differ from those in humans, dogs with CVL commonly exhibit anemia along with thrombocytopenia, eosinopenia, and lymphopenia. By contrast, leukocytosis associated with neutrophilia and monocytosis in CVL was also described in CVL.

Figure 3

Hematological alterations in bone marrow and peripheral blood during VL. This illustration highlights the main hematological abnormalities observed in the peripheral blood of humans affected by VL. These include anemia, which can result from various causes, thrombocytopenia, and pancytopenia due to reduced counts of monocytes, neutrophils, eosinophils, and lymphocytes. The reduction in cell counts coexists in bone marrow with an increase in cells from different lineages, such as myelopoietic stem cells, erythroid precursors, neutrophilic precursors, and monocytic precursors. Additionally, common alterations observed in the bone marrow of VL patients include erythrophagocytosis and leukophagocytosis.