92-857: L. aethiopica L. amazonensis L. arabica L. archibaldi (starus species) L. aristedesi (status disputed) L. (Viannia) braziliensis L. chagasi (syn. L. infantum ) L. donovani L. (Mundinia) enriettii L. forattinii (status disputed) L. garnhami (status disputed) L. gerbili L. (Viannia) guyanensis L. infantum L. killicki (status disputed) L. (Viannia) lainsoni L. major L. (Mundinia) macropodum L. (Mundinia) martiniquensis L. mexicana L. (Viannia) naiffi L. (Viannia) panamensis L. (Viannia) peruviana L. pifanoi (status disputed) L. (Viannia) shawi L. tarentolae L. tropica L. turanica L. waltoni L. venezuelensis Leishmania / l iː ʃ ˈ m eɪ n i ə , - ˈ m æ n -/
184-520: A Palearctic origin. Such migrations would entail subsequent migration of vector and reservoir or successive adaptations along the way. A more recent migration is that of L. infantum from Mediterranean countries to Latin America (known as L. chagasi ), since European colonization of the New World , where the parasites picked up their current New World vectors in their respective ecosystems. This
276-457: A RNA virus in LS, the co-infecting parasite with LD i.e. the "LD-LS-Lepsey NLV1 triple pathogen" phenomenon. The life cycle of Leishmania is completed in two hosts, humans and sandflies. The adult female sandfly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an individual infected with Leishmania , the pathogen is ingested along with the prey's blood. The protozoan
368-466: A city in West Bengal] fever". The causative parasite for the disease was identified in 1901 as a concurrent finding by William Boog Leishman and Charles Donovan . They independently visualised microscopic single-celled parasites (later called Leishman-Donovan bodies) living within the cells of infected human organs. The parasitic genus would later be classed as trypanosomatid protozoans under
460-502: A decade of use 2) it is potentially embryotoxic, fetotoxic and teratogenic , and thus cannot be used without anticonception in women of child-bearing age for three months (in some cases, five months ) after treatment. Incomplete treatment has been cited as a major reason of death from visceral leishmaniasis. The nonprofit Institute for OneWorld Health has adopted the broad spectrum antibiotic paromomycin for use in treating VL; its antileishmanial properties were first identified in
552-526: A few months with African kala-azar, or as much as several years with the Indian strain—a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy , and occasionally causing blindness if they spread to
644-417: A group of proteins which bind different glycans, are often used to detect these lipophosphoglycan variants. For example, peanut agglutinin binds a particular lipophosphoglycan found on the surface of the infective form of L. major . Lipophosphoglycan is used by the parasite to promote its survival in the host and the mechanisms by which the parasite does this center around modulating the immune response of
736-508: A hybrid between Leishmania (V.) guyanensis and Leishmania (V.) shawi shawi . The genus is presently divided into 4 subgenera: Leishmania , Sauroleishmania , Mundinia and Viannia . The division into the two subgenera ( Leishmania and Viannia ) was made by Lainson and Shaw in 1987 on the basis of their location within the insect gut. The species in the Viannia subgenus develop in the hind gut: L. (V.) braziliensis has been proposed as
828-517: A lipid domain, a neutral hexasaccharide, and a phosphorylated galactose-mannose, with a termination in a neutral cap. Not only do these parasites develop postphlebotomus digestion, but it is also thought to be essential to oxidative bursts, thus allowing passage for infection. Characteristics of intracellular digestion include an endosome fusing with a lysosome , releasing acid hydrolases which degrade DNA , RNA , proteins and carbohydrates . Leishmania aethiopica Leishmania aethiopica
920-503: A mixed T helper cell and regulatory T cell response. Both CD4+ and CD8+ T cells contributed to IFN-γ production. Studies of Leishmania antigen specific T cell clones from cured patient PBMC confirm that cured patients have a mixed T cell response that involves both CD4+ helper T cells and CD4+ and CD8+ regulatory T cells. Two studies of asymptomatic T cell clones show that most have Type 1 profiles and secrete more IFN-γ than T cell clones from cured patients. Neither study revealed
1012-413: A phagocytotic immune cell like a macrophage will ingest a pathogen within an enclosed endosome and then fill this endosome with enzymes which digest the pathogen. However, in the case of Leishmania , these enzymes have no effect, allowing the parasite to multiply rapidly. This uninhibited growth of parasites eventually overwhelms the host macrophage or other immune cell, causing it to die. Transmitted by
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#17327795419651104-456: A slightly different strain of the pathogen, L. chagasi , is responsible for leishmaniasis in the new world. Several species of canines serve as reservoir hosts of L. infantum (chagasi) . Contemporary life has made itself felt even here, however—not as "progress" but in the form of the many small wars of Africa's post-colonial era. In the Sudan , where civil war has been continuous since 1983,
1196-450: A well-screened or air-conditioned area, use a bed net and tuck it under your mattress. If possible, use a bed net that has been soaked in or sprayed with a pyrethroid-containing insecticide. The same treatment can be applied to screens, curtains, sheets, and clothing (clothing should be retreated after five washings). As with many diseases in developing nations, (including trypanosomiasis and malaria ) effective and affordable chemotherapy
1288-747: Is L. infantum , also known as L. chagasi . The insect vectors are species of sandfly of the genus Phlebotomus in the Old World, and of Lutzomyia in the New World. Sandflies are tiny flies, measuring 3–6 mm long by 1.5–3 mm in diameter, and are found in tropical or temperate regions throughout the world. The sandfly species Lutzomyia longipalpis is the primary vector of this disease. The larvae grow in warm, moist organic matter around human habitations (such as old trees, house walls, or waste) making them hard to eradicate. Visceral Leishmaniasis/kala-azar samples from India revealed
1380-399: Is a Leishmania species. It is associated with cutaneous leishmaniasis also called "oriental sore". It comes under the old world group of Leishmania species, along with L. major and L. tropica which are other agents causing oriental sore. Black fever Visceral leishmaniasis ( VL ), also known as kala-azar ( Hindi : kālā āzār , "black sickness") or " black fever ",
1472-1233: Is a 9.6 fold increase in IL-10 expressing CD8+ T cells among PBMC lymphocytes from PKDL patients. In the one study of T cell clones from VL patients, the clones isolated from VL PBMC were 100% CD8+. When mixed with self PBMC one or three years after successful treatment the CD8+ T cells decreased Leishmania antigen specific proliferation and IFN-γ secretion and increased IL-10 secretion. Depletion of CD8+ T cells from VL PBMC stopped endogenous IL-10 secretion but increased Leishmania antigen specific IL-10 secretion, suggesting that CD8+ regulatory T cells are responsible for endogenous IL-10 secretion. CD4+ clones could only be isolated from VL PBMC after CD8+ T cell depletion. The CD4+ clones had little effect on IL-10 secretion but decreased IFN-γ secretion when mixed with self PBMC collected after successful treatment. Regulatory B cells are known to favor development of regulatory T cells and suppress development of Type 1 T helper cells by producing IL-10 and other down-regulatory cytokines. IL-10 levels are elevated in B cells from VL PBMC. A study of dogs with naturally acquired VL showed that
1564-654: Is a parasitic protozoan , a single-celled organism of the genus Leishmania that is responsible for the disease leishmaniasis . They are spread by sandflies of the genus Phlebotomus in the Old World , and of the genus Lutzomyia in the New World . At least 93 sandfly species are proven or probable vectors worldwide. Their primary hosts are vertebrates ; Leishmania commonly infects hyraxes , canids , rodents , and humans . Members of an ancient genus of Leishmania -like parasites, Paleoleishmania , have been detected in fossilized sand flies dating back to
1656-419: Is considered a zoonosis . Leishmania species are unicellular eukaryotes having a well-defined nucleus and other cell organelles including kinetoplasts and flagella . Depending on the stage of their life cycle, they exist in two structural variants, as: The details of the evolution of this genus are debated, but Leishmania apparently evolved from an ancestral trypanosome lineage. The oldest lineage
1748-549: Is derived from kala which means black in Sanskrit , as well as in the languages descended from it, including Assamese , Hindi and Urdu ; the word azar is a Persian loanword in Hindustani that means "fever"; as such the disease is named for the darkening of the skin on the extremities and abdomen that is a symptom of the Indian form of the disease. It is also pronounced kālāzar (कालाज़ार کالا زار). The agent of
1840-414: Is endemic. A 2014 Cochrane review evaluated different rapid diagnostic tests. One of them (the rK39 immunochromatographic test) gave correct, positive results in 92% of the people with visceral leishmaniasis and it gave correct, negative results in 92% of the people who did not have the disease. A second rapid test (called latex agglutination test ) gave correct, positive results in 64% of the people with
1932-560: Is exposed on the surface of dead parasites, L. major switches off the oxidative burst , thereby preventing killing and degradation of the viable pathogen. In the case of Leishmania , progeny are not generated in PMNs, but in this way they can survive and persist untangled in the primary site of infection. The promastigote forms also release Leishmania chemotactic factor (LCF) to actively recruit neutrophils, but not other leukocytes , for instance monocytes or NK cells . In addition to that,
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#17327795419652024-414: Is in the smaller of its two forms, called an amastigote , which is round, non-motile, and only 3–7 micrometers in diameter. Inside the stomach of the sandfly, the amastigotes quickly transform into elongated and motile forms called the promastigotes . Promastigote is spindle-shaped, triple the size of the amastigote, and has a single flagellum that allows mobility. The promastigotes live extracellularly in
2116-521: Is inversely correlated with antigen specific IFN-γ secretion but Leishmania antigen specific IL-10 and IFN-γ secretion are not correlated, suggesting that endogenous secretion is more important in pathology. Addition of anti-IL-10 increases proliferation and IFN-γ secretion by PBMC from some patients. Both CD4+ and CD8+ T cells have been shown to contribute to IL-10 secretion by VL PBMC. The high level of immune complexes characteristic of VL have also been shown to increase IL-10 levels. More than 90% of
2208-488: Is much more cumbersome to use and appears not to have any advantages over the K39 test. There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment. Conversely, because serological tests look for an immune response and not for
2300-759: Is now amphotericin B in its various liposomal preparations. In East Africa, the WHO recommended treatment is SSG&PM (sodium stibogluconate and paromomycin) developed by Drugs for Neglected Diseases initiative (DNDi) in 2010. Miltefosine is the first oral treatment for this disease. The cure rate of miltefosine in Phase III clinical trials is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of
2392-467: Is often used as a marker of non-protective immunity in VL. Elevated levels of IL-10 in the plasma, infected tissues, and PBMC of VL patients accompany the anergy of VL. PKDL patients also have elevated IL-10 levels. VL patients with the highest IL-10 levels are more likely to be unresponsive to treatment and progress to PKDL. PBMC secretion of IL-10 without the addition of Leishmania antigen (endogenous)
2484-726: Is often used as a marker of protective immunity. Cured PBMC generally secrete less IFN-γ and more interleukin 10 (IL-10) in response to Leishmania antigens than asymptomatic PBMC. IL-12 is important in the development and maintenance of Type 1 T helper cell responses and protective immunity so its role in VL has also been studied. Addition of IL-12 to some VL PBMC increases proliferation and IFN-γ secretion in response to Leishmania antigens and anti-IL-12 inhibits proliferation and IFN-γ secretion by some cured PBMC. Other cytokines also appear to be important in immunity to Leishmania but their roles are not as well characterized. Leishmania antigen stimulation of PBMC from cured patients show
2576-442: Is quite short. They circulate in bloodstream for about 6 to 10 hours after leaving bone marrow , whereupon they undergo spontaneous apoptosis . Microbial pathogens have been reported to influence cellular apoptosis by different strategies. Obviously because of the inhibition of caspase 3-activation, L. major can induce the delay of neutrophils apoptosis and extend their lifespan for at least 2–3 days. The fact of extended lifespan
2668-407: Is similar to that of other kinetoplastids . They share the same main morphological features: a single flagellum which has an invagination - the flagellar pocket - at its base; a kinetoplast , which is found in the single mitochondrion ; and a subpelicular array of microtubules, which make up the main part of the cytoskeleton . Leishmania possesses a lipophosphoglycan coat over the outside of
2760-401: Is sorely lacking and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Possibly due to the lack of financial return, new drugs are slow to emerge and much of the basic research into potential drug targets takes place in universities, funded by charitable organizations. Product Development Partnership, Drugs for Neglected Diseases initiative works on
2852-670: Is that of the Bodonidae , followed by Trypanosoma brucei , the latter being confined to the African continent. Trypanosoma cruzi groups with trypanosomes from bats, South American mammals, and kangaroos suggest an origin in the Southern Hemisphere. These clades are only distantly related. The remaining clades in this tree are Blastocrithidia , Herpetomonas , and Phytomonas . The four genera Leptomonas , Crithidia , Leishmania , and Endotrypanum form
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2944-517: Is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA. Although it was suggested that Leishmania might have evolved in the Neotropics , this is probably true for species belonging to the subgenera Viannia and Endotrypanum . However, there is evidence that the primary evolution of the subgenera Leishmania and Sauroleishmania is the Old World. While
3036-456: Is the inhibition of the adaptive immune system . This occurs especially during the intercellular phases, when amastigotes search for new macrophages to infect and are more susceptible to immune responses. Nearly all types of phagocytes are targeted. For example, mincle has been shown to be targeted by L. major . Interaction between mincle and a protein released by the parasite results in a weakened immune response in dendritic cells . To save
3128-509: Is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania . The parasite migrates to the internal organs such as the liver , spleen (hence " visceral "), and bone marrow , and, if left untreated, will almost always result in the death of the host. Signs and symptoms include fever , weight loss , fatigue , anemia , and substantial swelling of
3220-533: Is these opportunistic infections that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks. Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment—generally
3312-512: Is to protect from sand fly bites. To decrease the risk of being bitten, these precautionary measures are suggested: 1. Avoid outdoor activities, especially from dusk to dawn, when sand flies generally are the most active. 2. When outdoors (or in unprotected quarters), minimize the amount of exposed (uncovered) skin to the extent that is tolerable in the climate. Wear long-sleeved shirts, long pants, and socks; and tuck your shirt into your pants. 3. Apply insect repellent to exposed skin and under
3404-633: Is to suppress CMI enough to prevent tissue damage. However, an excessive regulatory response can prevent clearance of Leishmania and could explain the anergy of VL, poor response to drug treatment, development of PKDL, and relapses. A role for regulatory cells in VL has long been suspected. A variety of regulatory T and B cells have been implicated in VL, including Type 1 T helper cells that secrete IL-10 in addition to IFN-γ, natural T reg, Tr1, CD8+ T reg, and B reg. All of these lymphocytes act, at least in part, by secreting IL-10 and other suppressive cytokines. CD4+ T regs are present at increased frequency in
3496-469: Is very beneficial for the development of infection because the final host cells for these parasites are macrophages, which normally migrate to the sites of infection within two or three days. The pathogens are not dronish; instead they take over the command at the primary site of infection. They induce the production by PMNs of the chemokines MIP-1α and MIP-1β ( macrophage inflammatory protein ) to recruit macrophages. An important factor in prolonging infection
3588-426: Is visualization of the amastigotes in splenic aspirate or bone marrow aspirate . However, the technique is associated with discomfort, high risk of tissue damage, while being expensive and difficult. The detection is also unreliable as it gives high false negative results, while the true positives are often having very low infection. Serological testing is much more frequently used in areas where leishmaniasis
3680-693: The Mundinia species appear to be more universal in their evolution. One theory is that different lineages became isolated geographically during different periods and it is this that gave rise to this evolutionary mosaicism. But there is no doubt that the Leishmaniinae are a monophyletic group. A large data set analysis suggests that Leishmania evolved 90 to 100 million years ago in Gondwana . The reptile infecting species originated in mammalian clades. Sauroleishmania species were originally defined on
3772-643: The Paraleishmania . There are four Mundinia species - L. (Mundinia) enriettii , L. (Mundinia) martiniquensis , L. (Mundinia) macropodum , and L. (Mundinia) orientalis, which is found in Thailand. L. archibaldi' s specific status is unsettled but it is closely related to L. donovani . L. herreri belongs to the genus Endotypanum rather than to Leishmania . L. donovani and L. infantum are closely related. The selenoenzyme Seltryp appears to be unique to this order. It has been removed from
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3864-605: The South Sudanese Civil War , kala-azar has spread rapidly among the population. The Indian medical practitioner Upendranath Brahmachari was nominated for the Nobel Prize in Physiology or Medicine in 1929 for his discovery of ureastibamine (an antimonial compound for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis. Brahmachari's cure for visceral leishmaniasis
3956-706: The Upper Nile region, are almost totally cut off from the rest of the country, and most people tend to remain at their place of birth although there have been huge population movements due to the civil war, leading to severe epidemics. Kala-azar first came to the attention of Western doctors in 1824 in Jessore , British Raj (now Bangladesh ), where it was initially thought to be a form of malaria . Assam gave kala-azar one of its common names, Assam fever . Another common name, kala-azar ( Hindustani : काला आज़ार ( Devanagari ) کالا آزار ( Nastaleeq ) kālā āzār ),
4048-561: The immune system and thrive, the Leishmania 'hides' inside its host's cells. This location enables it to avoid the action of the humoral immune response (because the pathogen is safely inside a cell and outside the open bloodstream), and furthermore it may prevent the immune system from destroying its host through nondanger surface signals which discourage apoptosis . The primary cell types Leishmania infiltrates are phagocytotic cells such as neutrophils and macrophages . Usually,
4140-562: The phylogenetic designation, Leishmania donovani . Several species have since been classified and grouped under two major subgenera i.e. Leishmania Viannia (generally located in the Neotropics ) or Leishmania Leishmania (generally located in the Paleotropics , with the major exception of the L. mexicana subgroup). Leishmania currently affects 6 million people in 98 countries. About 0.9–1.6 million new cases occur each year, and 21 species are known to cause disease in humans: it
4232-403: The sandfly , the protozoan parasites of L. major may switch the strategy of the first immune defense from eating/inflammation/killing to eating/no inflammation/no killing of their host phagocyte and corrupt it for their own benefit. They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMNs) rigorously as a tricky hideout, where they proliferate unrecognized from
4324-1131: The 1980s. A treatment with paromomycin costs about US$ 15. The drug had originally been identified in the 1960s. The Indian government approved paromomycin for sale and use in August 2006. Immunity to Leishmania is determined by the interplay of white blood cells , cytokines , immune complexes , and genetic and environmental factors. Protective immunity develops either after successful treatment of VL (cured) or after asymptomatic infections that resolve without development of VL (asymptomatic). Both types of immunity are characterized by cell-mediated immunity (CMI), including skin test positivity , proliferation , and interleukin 2 (IL-2), interferon gamma (IFN-γ), and interleukin 12 (IL-12) secretion by peripheral blood mononuclear cells (PBMC) in response to Leishmania antigens . T cells isolated from both cured and asymptomatic PBMC activate autologous macrophages to kill intracellular amastigotes. IFN-γ activates macrophages to kill intracellular parasites so its role in VL has been studied extensively and IFN-γ production
4416-570: The School of Tropical Medicine at Calcutta to discover that kala-azar was transmitted by sandflies. On 31 October 2023, Bangladesh has been declared to be the first country to totally eradicate the disease. Combination drug therapies are currently under investigation, particularly by the Drugs for Neglected Diseases initiative (DNDi). Combination therapies allow for the use of existing drugs in combination, each in lower doses, which helps to decrease
4508-426: The alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. As the fly bites, the promastigotes are released from the proboscis and introduced locally at the bite site. Once inside the human host, promastigotes invade macrophages . Inside the cells they transform back into the smaller amastigote form. The amastigotes replicate in
4600-547: The basis that they infected reptiles ( lizards ) rather than mammals . Based on molecular evidences, they have been moved to subgenus status within Leishmania . This subgenus probably evolved from a group that originally infected mammals. 53 species are recognised in this genus. The status of several of these is disputed, so the final number may differ. At least 20 species infect humans. To make things more complex, hybrids might be involved, as it has been reported in Brazil with
4692-465: The bloodstream to find new hosts. In this way the infection is progressive, spreading to the host's mononuclear phagocyte system , particularly the spleen and liver. The free amastigotes in peripheral tissues are then ingested by sandfly to enter another cycle. The cell-mediated immunity (CMI) that kills Leishmania also produces inflammation. If the inflammation is excessive, it can cause tissue damage. The role of regulatory T and regulatory B cells
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#17327795419654784-520: The bone marrow of VL patients, are one source of IL-10, and proliferate in response to Leishmania antigen. Levels of FoxP3 mRNA were also up-regulated in lesional tissue from PKDL patients. However, T regs are not elevated in spleen cells from VL patients nor does depletion of T regs increase Leishmania antigen specific IFN-γ secretion The highest levels of IL-10 mRNA in spleen cells is in CD8+ and other non-FoxP3+ T cells. White blood cell CD8+ T cells from VL patients have elevated IL-10 levels. There
4876-435: The cell. Lipophosphoglycan is a trigger for toll-like receptor 2 , a signalling receptor involved in triggering an innate immune response in mammals. The precise structure of lipophosphoglycan varies depending on the species and lifecycle stage of the parasite. The glycan component is particularly variable and different lipophosphoglycan variants can be used as a molecular marker for different lifecycle stages. Lectins ,
4968-543: The center of the epidemic, Duar , was left with four survivors out of a population of a thousand, and from the late 1980s to the mid-1990s a total of 100,000 died from the sickness in that region alone. In the words of Jill Seaman , the doctor who led relief efforts in the Upper Nile for the French organization Médecins Sans Frontières , "Where else in the world could 50% of a population die without anyone knowing?" Due to
5060-483: The development of new treatments (combination treatments and new chemical entities) for visceral leishmaniasis. The traditional treatment is with pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate . Resistance is now common in India, and rates of resistance have been shown to be as high as 60% in parts of Bihar, India. The treatment of choice for visceral leishmaniasis acquired in India
5152-509: The disease and it gave correct, negative results in 93% of the people without the disease. Other types of tests have not been studied thoroughly enough to ascertain their efficacy. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT anti-leishmania antigen test, standard within MSF ,
5244-404: The disease progresses. In addition to skin test negativity, VL patient PBMC do not proliferate or secrete IL-2 or IFN-γ in response to Leishmania antigens. Memory T cells may be depleted in VL patient PBMC. Since IL-10 is known to suppress innate and acquired immunity and prevent IFN-γ from activating macrophages, its role in VL has been studied extensively and elevated IL-10 production
5336-505: The disease was also first isolated in India by Scottish doctor William Leishman (who observed the parasite in spleen smears of a soldier who died of the disease in Dumdum, Calcutta, India - hence the name dumdum fever ) and Irish physician Charles Donovan , working independently of each other. As they published their discovery almost simultaneously, the species was named by Sir Ronald Ross for both of them— Leishmania donovani . Today,
5428-476: The disease with them, and when it arrived it hit the Upper Nile with a force comparable to smallpox hitting the American Indians . The isolated people of the Upper Nile had no access to medicine or education about the new disease among them. Worse, their immune systems were defenseless against this new pathogen, foreign to them though it came only from another part of their own country. One village at
5520-476: The disease's geographical range is broad, it is not continuous. The disease clusters around areas of drought, famine, and high population density. In Africa, this has meant a knot of infection centers mostly in South Sudan, Sudan , Ethiopia, Kenya , and Somalia . Living conditions here have changed very little in the past century, and the people are not normally very mobile. Parts of South Sudan, in particular
5612-434: The disease, and the other symptoms are very easy to mistake for those of malaria . Misdiagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in people with kala-azar, however. Pneumonia , tuberculosis , and dysentery are omnipresent in the immuno-depressed regions where leishmaniasis thrives, and, as with AIDS , it
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#17327795419655704-614: The early Cretaceous period. The first written reference to the conspicuous symptoms of cutaneous leishmaniasis surfaced in the Paleotropics within oriental texts dating back to the 7th century BC (allegedly transcribed from sources several hundred years older, between 1500 and 2000 BC). Due to its broad and persistent prevalence throughout antiquity as a mysterious disease of diverse symptomatic outcomes, leishmaniasis has been dubbed with various names ranging from "white leprosy" to " black fever ". Some of these names suggest links to negative cultural beliefs or mythology, which still feed into
5796-465: The ends of sleeves and pant legs. Follow the instructions on the label of the repellent. The most effective repellents generally are those that contain the chemical DEET (N,N-diethylmetatoluamide). 1. Stay in well-screened or air-conditioned areas. 2. Keep in mind that sand flies are much smaller than mosquitoes and therefore can get through smaller holes. 3. Spray living/sleeping areas with an insecticide to kill insects. 4. If you are not sleeping in
5888-531: The eyes. (This disease is not the same as cutaneous leishmaniasis , a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions.) Two species of Leishmania are known to give rise to the visceral form of the disease. The species commonly found in East Africa and the Indian subcontinent is L. donovani and the species found in Europe, North Africa, and Latin America
5980-408: The first or second day of treatment (a course of treatment is 28 days) which does not affect the efficacy. Because it is available as an oral formulation, the expense and inconvenience of hospitalization is avoided, and outpatient distribution of the drug becomes an option, making miltefosine a drug of choice. However, there are some important disadvantages: 1) there is evidence of reduced efficacy after
6072-424: The following advantages for the parasite: However, studies have shown this is unlikely, as the pathogens are seen to leave apoptopic cells and no evidence is known of macrophage uptake by this method. An important aspect of the Leishmania protozoan is its glycoconjugate layer of lipophosphoglycan (LPG). This is held together with a phosphoinositide membrane anchor, and has a tripartite structure consisting of
6164-466: The global burden of visceral leishmaniasis (VL) was contributed by seven countries in 2015: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan. In India, more than 70% of VL cases are reported from the state of Bihar. North Bihar , India (including Araria , Purnea , and Kishanganj ) is the endemic zone of this disease. The disease is endemic in more than 70 countries. In Iran this includes Ardabil, Fars, and North Khorasan. However, while
6256-432: The host. This is vital, as the Leishmania parasites live within macrophages and need to prevent the macrophages from killing them. Lipophosphoglycan has a role in resisting the complement system , inhibiting the oxidative burst response, inducing an inflammation response and preventing natural killer T cells recognising that the macrophage is infected with the Leishmania parasite. In order to avoid destruction by
6348-561: The immune system and enter the long-lived macrophages to establish a "hidden" infection . Upon microbial infection, PMNs move out from the bloodstream through the vessels' endothelial layer, to the site of the infected tissue (dermal tissue after fly bite). They immediately initiate the first immune response and phagocytize the invader by recognition of foreign and activating surfaces on the parasite. Activated PMN secrete chemokines , IL-8 particularly, to attract further granulocytes and stimulate phagocytosis. Further, L. major increases
6440-490: The incidence of severe side effects and drug toxicity, as well as the risk for development of resistance against the drugs; they have been shown to be cost-effective strategies. Comparative homology modelling of the enzyme Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) in L. donovani suggest that among all of the computationally screened compounds, pentamidine , 1,3-dinitro adamantane , acyclovir and analogs of acyclovir had higher binding affinities than
6532-538: The integrity of the surrounding tissue from the toxic cell components and proteolytic enzymes contained in neutrophils, the apoptotic PMNs are silently cleared by macrophages. Dying PMNs expose the "eat me"-signal phosphatidylserine which is transferred to the outer leaflet of the plasma membrane during apoptosis. By reason of delayed apoptosis, the parasites that persist in PMNs are taken up into macrophages, employing an absolutely physiological and nonphlogistic process. The strategy of this "silent phagocytosis" has
6624-481: The liver and spleen . Of particular concern, according to the World Health Organization (WHO), is the emerging problem of HIV /VL co-infection. VL is the second-largest parasitic killer in the world (after malaria ), responsible for an estimated 20,000 to 30,000 deaths each year worldwide. Upendranath Brahmachari synthesised urea stibamine (carbostibamide) in 1922 and determined that it
6716-426: The most hostile part of the macrophage cell, inside the phagolysosome , whose normal defensive response they are able to prevent. After repeated multiplication, they break down their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis response of the macrophage. The daughter cells protozoans then migrate to fresh cells or through
6808-514: The name kala-azar is used interchangeably with the scientific name visceral leishmaniasis for the most acute form of the disease caused by L. donovani . The disease is endemic in West Bengal , where it was first discovered, but is seen at its most deadly in north and east Africa. It can also be found throughout the Arab world and southern Europe (where the causative organism is L. infantum ), and
6900-504: The organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse. Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests. Other tests being developed include detects erythrosalicylic acid . As of 2018, there are no vaccines or preventive drugs for visceral leishmaniasis, but vaccines are in development. The most effective method to prevent infection
6992-508: The people responded to this new treatment. Miltefosine has received approval by the Indian regulatory authorities in 2002, in Germany in 2004 and in U.S.A. in 2014. It is now registered in other countries such as Nepal, Argentina, Bangladesh, Bolivia, Colombia, Ecuador, Guatemala, Honduras, Mexico, Pakistan, Paraguay, Peru, and Israel. The drug is generally better tolerated than other drugs. Main side effects are gastrointestinal disturbance in
7084-477: The percentage of regulatory B cells increased three-fold during VL. Depletion of B cells increased CD4+ T cell proliferation and IFN-γ secretion but decreased IL-10 secretion. Blocking IL-10 or programmed cell death receptors on B cells increased Leishmania antigen specific T cell proliferation and IFN-γ secretion. Co-culture of T cells with B cells decreased the percentage of CD4+ T cell proliferation and IFN-γ secretion four-fold. The gold standard for diagnosis
7176-424: The presence of Type 2 or regulatory T cells. Some clones secreted soluble factors that caused the death of CD8+ regulatory T cells but not CD4+ T cells from VL patients, which might explain the strong protective immunity of asymptomatic patients. VL patients are unable to clear their infections because they lack CMI. This anergy may be limited to Leishmania antigens or extend to mitogens and other antigens as
7268-411: The presence of not only the primary causative protozoan parasite, i.e. Leishmania donovani (LD) but also co-infection with another protozoan member called Leptomonas seymouri (LS). The latter parasite (LS) further contained a RNA virus known as Leptomonas seymouri narna-like virus 1 ( Lepsey NLV1 ). So, it appears that a great majority of kala-azar patients in the Indian subcontinent are exposed to
7360-440: The production of interferon gamma (IFNγ)-inducible protein 10 (IP10) by PMNs is blocked in attendance of Leishmania , what involves the shut down of inflammatory and protective immune response by NK and Th1 cell recruitment. The pathogens stay viable during phagocytosis since their primary hosts, the PMNs, expose apoptotic cell-associated molecular pattern (ACAMP) signaling "no pathogen". The lifespan of neutrophil granulocytes
7452-489: The real substrate (guanosine monophosphate). DNDi has a number of compounds in preclinical and phase 1 development, but no novel drugs are expected in the next 5 years. In the meantime, new combination therapies, and well as improvements to existing drugs targets, are under development. Single-dosage administrations of liposomal amphotericin B have been shown to be effective, and oral formulations are currently under development to increase access and facilitate distribution of
7544-448: The secretion of IL-8 by PMNs. This mechanism is observed during infection with other obligate intracellular parasites , as well. For microbes like these, multiple intracellular survival mechanisms exist. Surprisingly, the coinjection of apoptotic and viable pathogens causes by far a more fulminate course of disease than injection of only viable parasites. When the anti-inflammatory signal phosphatidylserine usually found on apoptotic cells,
7636-457: The social stigmatization of leishmaniasis today. In India, both cutaneous and visceral leishmaniasis are caused by Leishmania donovani . The first records of cutaneous leishmaniasis in India were from British medical officers in the early 19th century. The disease was by then known as "oriental sore" or "Delhi boil"; while the visceral form was variously called "Burdwan [after the city Burdwan ] fever", " kala azar" (black fever), or "Dumdum [
7728-499: The subgenera Leishmania , Sauroleishmania , Mundinia and Viannia . The proposed Paraleishmania included species of Endotypanum, Leishmamnia - L. colomubensis , L. herreri , L. hertigi and L. deanei and L. equatorensis . In a recent revision these species were given different generic status. Four subgenera of Leishmania are now recognised - Leishmania , Sauroleishmania , Viannia and Mundinia (the L. enriettii complex). The genus Endotrypanum and Porcisia belong to
7820-406: The subgenus Viannia . L. deanei and L. hertigi , both of which infect porcupines have been moved to the genus Porcisia. Subgenus Leishmania Ross, 1903 sensu Saf'janova, 1982 Subgenus Mundinia Shaw,Camargo and Teixeira 2016 Subgenus Sauroleishmania Ranque, 1973 sensu Saf'janova, 1982 ↑ Species described as Sauroleishmania . Their development is not like other members of
7912-721: The subgenus and so their taxonomic position is doubtful. Subgenus Viannia Lainson & Shaw 1987 The relationships between Leishmania and other genera such as Endotrypanum , Novymonas , Porcisia , and Zelonia is presently unclear as they are closely related. Endotrypanum colombiensis , ofter known as Leishmania colombiensis, has been associated with both cutaneous and visceral leishmaniasis in Venezuela. Genus Endotrypanum Genus Novymonas Kostygov and Yurchenko 2016 Genus Porcisia Shaw, Camargo and Teixeira, 2016 Genus Zelonia Shaw, Camargo and Teixeira, 2016 The biochemistry and cell biology of Leishmania
8004-534: The terminal branches, suggesting a relatively recent origin. Several of these genera may be polyphyletic and may need further division. The origins of genus Leishmania itself are unclear. One theory proposes an African origin, with migration to the Americas. Another proposes migration from the Americas to the Old World via the Bering Strait land bridge around 15 million years ago. A third theory proposes
8096-474: The type species for this subgenus. This division has been confirmed by all subsequent studies. Shaw, Camargo and Teixeira created the subgenus Mundinia while revising Leishmaniinae in 2016. Endotrypanum is closely related to Leishmania . Some Endotypanum species are unique in that they infect the erythrocytes of their hosts (sloths). All species are confined to Central and South America. E. colombiensis infections have been found in man. Sauroleishmania
8188-425: The violence has been concentrated in the more populated south, and kala-azar was concentrated there too. But the wars have driven a steady stream of refugees out of the region, and these traveled either across the southern border or into the remoter western part of the country called the Upper Nile, where both war and the disease that went with it had not yet penetrated. These refugees, moving at foot-speed, carried
8280-421: Was an effective substitute for the other antimony-containing compounds in the treatment of VL caused by Leishmania donovani . When people develop visceral leishmaniasis, the most typical symptoms are fever and the enlargement of the spleen , with enlargement of the liver sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of
8372-423: Was originally described by Ranquein 1973 as a separate genus, but molecular studies suggest this is actually a subgenus rather than a separate genus. The proposed division of the Leishmania into Euleishmania and Paraleishmania groups in 2000 emphasized the deep phylogenic distance between parasites, some of which had been named as Leishmania species. The Euleishmania included species currently placed in
8464-560: Was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine. During the nineteenth century, kala-azar was discovered near moving bodies of water in southeast Asia. Dr. Jean Dow and Dr. William McClure, are credited with finding the cure for the disease in China. Largely uncredited for her contribution, Dow was one of the first to isolate the microorganism in China and conduct clinical studies on its origin. This work continued under Ernest Struthers and Lionel Napier at
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