Journal of Cytology & Tissue Biology Category: Clinical Type: Mini Review
Interactions between Parasite and Host in Human Visceral Leishmaniasis
- Harizanov R1*, Rumen N1, Kaftandjiev Iskren T2
- 1 Department Of Parasitology And Tropical Medicine, National Center Of Infectious And Parasitic Diseases, Sofia, Bulgaria
- 2 Department Of Parasitology And Tropical Medicine, National Center Of Infectious And Parasitic Diseas, Sofia, Bulgaria
*Corresponding Author:Harizanov R
Department Of Parasitology And Tropical Medicine, National Center Of Infectious And Parasitic Diseases, Sofia, Bulgaria
Received Date: Jul 03, 2014 Accepted Date: Jul 31, 2014 Published Date: Aug 14, 2014
Leishmaniasis is one of the most important Neglected Tropical Diseases (NTDs) affecting mainly the poorest social groups in many countries of the world. Visceral form of the disease is caused by protozoa belonging to Leishmania donovani complex. The clinical manifestations arise from a number of complex interactions between cells of the causative agent and the host. Our aim is briefly to introduce some of the pathogenetic mechanisms in visceral leishmaniasis with a belief that detailed study and understanding of the disease pathology could lead to more effective methods for rapid diagnosis and effective treatment.
Visceral leishmaniasis is a protozoan, vector born disease characterized by a chronic course, undulating fever, splenic and hepatic enlargement and anemia to complete secondary pancytopenia and immunosuppression.
In 1900 William Leishman performed pathological examination of the body of a British soldier who died from dum-dum fever (Dum Dum is an area in north Kolkata, formerly known as Calcutta). The deceased suffered from febrile episodes, anemia, muscle atrophy and enlargement of the spleen. Examining spleen specimens Leishman discovered a huge number of oval bodies measuring 2-3 µm. He published his findings in British Medical Journal on 11 May 1903. A month later, similar finding in a material from enlarged spleen of a patient who died of suspected malaria in Madras (India), described Charles Donovan. Laveran and Mesnil classified this parasite as protozoa. Subsequently, Ronald Ross, using Leishmans staining technique named these protozoan microorganisms "Leishman bodies", and Manson named them "Leishman-Donovan bodies"-in memory of the two English scientists. The name, "kala-azar" (black disease) was given by McNaught, who described the disease in India. Swaminath et al., using volunteers proved that the disease is transmitted to humans by insects and found those specific biological carriers are bloodsucking insects from genus Phlebotomus. For first time Rogers was able to cultivate the parasite in citrated blood, but his attempts to maintain the strain by passaging were unsuccessful. Later, Ch. Nicolle was able to cultivate and maintain Leishmania strain by passaging and also to induce experimental disease in dogs and monkeys. He first highlights the epidemiological link between man and dog [1,2].
Genus Leishmania belongs systematically to Kingdom Protista; Subkingdom Protozoa; Family Tripanosomatidae . Taxonomic identification of the different species Leishmania is based on two types of features-external (clinical manifestations, geographical distribution, epidemiological cycle) and internal (morphological and molecular structure) [4,7].
Parasite classification at genus level has been based on global taxonomics derived in the 1990s using isoenzyme technique in comparison with reference strains. Identification depends on the employed method, e.g. zymodemes (parasite populations with common isoenzyme patterns identified electrophoretically) or schizodemes (parasite populations defined by shared 'fingerprint patterns' obtained by a process involving digestion of kinetoplast DNA by restriction enzymes). The results are relevant in descriptive epidemiology and allows grouping of the parasites into hierarchies that suggest their evolutionary relations .
In the Mediterranean basin, L infantum displays a broad enzymatic polymorphism with 20 different zymodemes, of which 18 have been found in humans. L. infantum MON-1 is the most frequent zymodeme in humans and is usually responsible for VL along the Mediterranean, region more rarely for CL .
Morphology and life cycle
When taking a blood meal from human or animal carrier the female sand fly ingest with the blood also hosts cells invaded by amastigotes. Then the amastigotes are released into the midgut of the digestive tract of the insect where are transformed into elongated flagellate promastigotes (procyclic promastigotes) and in a few days later their number increases significantly. The promastigotes migrate to the front section of the digestive tract where are transformed into short, spherical, non-dividing promastigotes (metacyclic promastigotes) and when the phlebotomine sand fly takes another blood meal it will inoculate 10 to 200 promastigotes (Figure 2) in the dermis of a vertebrate host [8,10,11]. From there they fall into the phagocytic cells of the immune system, including macrophages, dendritic cells and neutrophils where will transform again to amastigotes and begin cycle of reproduction . The infected macrophages spread from the dermis to other tissues and organs such as spleen, liver and bone marrow. Different species Leishmania possess specific tropism, and some of them are dermatotropic (causing cutaneous and mucocutaneous leishmaniasis), while others are viscerotropic (causing visceral leishmaniasis). The reasons for existence of specific tropism are not clear yet, but it is assumed that depends on some genetic features of the host and the parasite, as well as some external factors such as temperature. For example dermatotropic Leishmania spp. can not realize their biological cycle at the ambient temperature of the internal organs of a vertebrate host as are able the viscerotropic Leishmania spp.
In South-East Asia visceral leishmaniasis is the main form of the disease. Transmission most often occurs in rural areas below 600m above sea level, with a heavy annual rainfall, mean humidity above 70%, a temperature range of 15-38°C, abundant vegetation, subsoil water and alluvial soil. The disease is most common in agricultural villages where houses are frequently constructed with mud walls and earthen floors, and livestock is living close to humans [4,8,27].
In East Africa there are frequent outbreaks of visceral leishmaniasis in in the northern Acacia-Balanite savanna and the southern savanna and forest areas where sandflies live around termite mounds [4,8,27].
Americas-visceral leishmaniasis is very similar to that found in the Mediterranean Basin [4,8,27].
The disease is highly endemic in the Indian subcontinent and in East Africa. An estimated 200, 000 to 400, 000 new cases of VL occur worldwide each year. Over 90% of new cases occur in six countries: Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan .
PATHOGENESIS AND PATHOLOGY
Pathogenesis and histological changes in individuals with uncompromised immunity
Macrophages, the primary target of intracellular Leishmania infection, may take on distinct phenotypes in response to parasite signals and inflammatory stimuli within the infected microenvironment. Classically activated (M1) macrophages respond to IFN? and microbial products by generating antimicrobial molecules that effectively kill Leishmania and other intracellular pathogens. Central to the killing of intracellular parasites is the production of nitric oxide by the action of inducible nitric oxide synthase 2 on the substrate L-arginine. In contrast, alternatively activated or M2 macrophages, which are typically generated by exposure to type 2 cytokines (IL-4, IL-13), fail to produce antimicrobial effector molecules to kill intracellular pathogens and serve to dampen inflammation and promote wound healing [33,34]. However, as other infectious agents, most Leishmania species have evolved effective strategies to evade the innate immune response during the early moments of infection, and this is by rapidly blocking the induction and regulation of key host cell functions including production of nitric oxide, tumour necrosis factor-alpha, interleukin-12, and radical oxygen species . Peripheral blood mononuclear cells from patients with manifested VL typically do not proliferate or produce IFNγ in response to Leishmanial Antigen (LAg). A few months after completion of therapy, following cure, proliferative and cytokine responses to LAg are usually detectable . Leishmania parasites have been shown to alter host-cell signaling pathways to promote their survival. Activation of host Src homology 2 domain containing tyrosine phosphatases by Leishmania infection results in global dephosphorylation of tyrosine residues, leading to deactivation of a variety of signaling pathways including JAK/STAT, NF-?B, IRF-1, and MAP kinases. Increased concentrations of secondary messengers including Calcium (Ca2+), inositol lipids, inositol phosphatases, and protein kinase C have also been observed following Leishmania infection. Induction of the negative regulatory proteins, suppressors of cytokine signaling, have been characterized following Leishmania infection and interfere with cytokine signaling and host cell activation .
On the sites of inoculations are formed small granulomas (leishmaniomas), which consists of histiocytes containing parasites. They are surrounded by epithelioid cells, which are gradually transformed into giant cells. Subsequent development depends on the host immune response, ranging from missing to a response that leads to a full eradication of the parasite. From the site of inoculation, and after transformation into amastigotes the leishmania parasites localize in the regional lymph nodes, from where they pass into the blood stream and through it to other cells of the reticuloendothelial system of the end host. It develops hyperplasia of the reticuloendothelial cells of the liver, spleen, bone marrow, lymph nodes, lining of the small intestine, and other lymphoid tissues. Increase of the spleen size is due to reticuloendothelial proliferation and, in some cases can be so extreme that its caudal part may reach the iliac fossa. The spleen is with dense consistency and full with congested blood. In the acute stage of the disease its capsule is smooth, within the pulp are observed multiple infarct areas and massive intracellular invasion of the histiocytes by amastigotes. Histologic studies of liver changes in visceral leishmaniasis showed that the Kupffer cells in the portal areas contain numerous parasites [4,8,10,16,20,24]. In most cases, efficient immune responses to L. donovani in the liver depend on the formation of granulomas, a process influenced by chemokine production, subsequent recruitment of monocytes, neutrophils, CD4+ T cells and CD8+ T cells, production of inflammatory cytokines and activation of infected cells . Lymph nodes may be enlarged and contain histiocytes infected with amastigotes. Bone marrow is poor in cellular elements as myelocytes and promyelocytes predominate. At the beginning hematopoiesis is normal, but in the course of illness the life of erythrocites and leukocytes shortens and that leads to anemia and granulocytopenia with relative lymphoid and monocytosis. Subsequently is reduced the synthesis of prothrombin. This in combination with growing thrombocytopenia can lead to severe bleeding from mucous membranes. The course of the disease may be complicated with diarrhea, ulceration of the intestinal mucosa, and enteritis in untreated cases. In the late stage may develop secondary infections such as pneumonia and tuberculosis, which often lead to death. Activation of the complement system may enhance developing anemia due to circulating immune complexes, but complications such as development of glomerulonephritis have been reported rarely. Reticuloendothelial massive proliferation induces enlargement of the liver and spleen, which upon proper treatment may restore their original size [4,8,20,24,38,39].
Pathogenesis in leishmania/HIV co-infection
T-cells immune response in visceral leishmaniasis
B-cells immune response in visceral leishmaniasis
Target of the humoral immune response are some heat shock proteins (Hsp). Antibodies against Hsp 70 have been detected in 92% of patients with VL . In blood sera of the patients can be found circulating immune complexes with immunoglobulins of classes A, G and M. Skin patch delayed hypersensitivity reaction is suppressed or even absent. After recovery this sensitivity is restored [40,52].
CLINICAL PRESENTATION AND COMPLICATIONS
Visceral leishmaniasis is a kind of reticuloendotheliosis and is directly related to the immune status of infected individuals. Clinical manifestations of VL can range from asymptomatic subclinical carrier to manifested, severe forms of the disease. After incubation period ranging from 10 days to more than a year (mean of 2 and 4 months) appear the first symptoms of the disease. Depending on the species of viscerotropic leishmaniae the beginning may be indolent or noticeable-protracted or severe. In the first case the symptoms can be vague, with a sense of discomfort, while acute onset disease resembles typhoid fever or malaria. Described are several clinical forms of VL .
Light subclinical (oligosymptomatic) form of VL
Classical form of VL
Initial stage: The earliest clinical symptom is development of primary lesion-ulcer at the site of inoculation, which can be detected in the prodromal period prior general clinical manifestations to appear. Typically, in the initial stage the first manifestation of VL is increased body temperature, which is constant or remitting, and later can become intermittent with two or three peaks a day [20,24,57-60].
Stage of splenohepatomegaly: Gradually, amid prolonged febrile condition develops enlargement of the spleen and liver, lymphadenopathy, accompanied in some cases by acute abdominal pain. Darkening of the skin of the face, hands, feet and abdomen is observed in the Indian version of VL (kala-azar). Clinical examination reveals that splenic enlargement is more pronounced than hepatomegaly. The spleen is usually palpable at about 5-15 cm below the left rib arc. According to some authors, splenomegaly may be absent in about 5% of the cases . Anemia, weight loss and pronounced splenohepatomegaliy occur with disease progression. Anemia is a symptom, almost always accompanying visceral leishmaniasis, and in some cases may be of high grade. It is usually normocytic and normochromic, and is caused by various factors, including bone marrow damage by the parasites, signs of hypersplenism, haemorrhage and hemolysis. Leukopenia is common, and in some cases on this background develop secondary infections. Thrombocytopenia may lead to bleeding (haemorrhagic) diathesis [57,58]. In some cases of VL can be found hypergammaglobulinemia, circulating immune complexes and positive rheumatoid factor. Seldom, the circulating immune complexes can cause development of glomerulonephritis in the kidneys . Also have been described cases of combination of VL with acute hepatitis , bacteremia , Guillain-Barre syndrome . Malabsorption is a significant problem in children with VL and is a consequence of adverse effects of the cell-mediated immunity . In cases of disease in India and Sudan have been observed Post-kala-azar Dermal Leishmaniasis (PKDL). These nodular or papular skin lesions contain large number of amastigotes and are of great epidemiological importance for the spread of VL.
Stage of cachexia: Usually develops because of delayed diagnosis and/or improper treatment. In patients in this stage is observed a significant reduction of body weight. This is accompanied by aggravation of the haematological changes with development of hemorrhagic diathesis. Without treatment, the clinically manifested VL is usually fatal [8,20,57,58,67].
Sudanese clinical variation of VL (Sudanese disease; Killing disease)
VL associated with AIDS
Diagnosis and Treatment options
In most cases visceral leishmaniasis is curable disease. Several treatment options are available but their usage and efficacy depend on a variety of factors. These factors include parasite species, severity of the symptoms and the immune status of the host. The only treatment currently available for visceral leishmaniasis relies on chemotherapy [12,77]. Classical, first-line drug treatments include pentavalent antimonials compounds, stibogluconate (Pentostam) or meglumine antimonite (Glucantime). Pentavalent antimonials have been in use for more than 50 years and are the recommended treatment by the World Health Organization (WHO) [4,8]. Other common drugs include amphoterecin B, lipid formulations of amphoterecin B, including liposomal amphotericin B, amphotericin B lipid complex and amphotericin B colloidal dispersion, pentamidine, miltefosine (Impavido or Miltex) and imidazoles, allopurinol (Zyloric), or paromomycin among others.
However, several obstacles remain in the treatment of visceral leishmaniasis Most treatments require extensive (weeks to months) and invasive (intramuscular or intravenous) modes of administration and there is a high rate of significant drug-related toxic side effects. The cost of treatment is often well beyond the means of many patients and severe toxicity may require secondary treatment, adding to the already high cost of therapy [12,69].
Host-parasite interactions are many and various in nature. In the review we have tried to present briefly some interactions between the agents of visceral leishmaniasis and hosts cells. Their further study could lead to improved diagnostic methods and development of new therapeutic formulations and vaccines which to introduce in the clinical practice.
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Citation:Harizanov, Rumen N, Kaftandjiev Iskren T (2014) Interactions between Parasite and Host in Human Visceral Leishmaniasis. J Cytol Tissue Biol 1: 001.
Copyright: © 2014 Harizanov R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.