Parasitology. Alan Gunn

Leishmania Establishes Within Mammalian Phagocytes

      After an infected sandfly feeds, mononuclear phagocytes quickly detect and ingest the promastigotes that enter the blood circulation. Initial attachment of a parasite to a phagocyte begins at the tip of the parasite’s flagellum via a ligand‐receptor process. The principal ligands are phosphoglycans and the zinc metalloprotease enzyme GP63 (glycoprotein 63) on the surface of the promastigote whilst on the phagocyte, a variety of complement receptors are involved in the attachment process. After phagocytosing the Leishmania parasite, a phagocyte holds it within a membrane‐bound vesicle called a phagosome. Lysomes then fuse with the phagosome and discharge hydrolytic enzymes and microbicidal peptides into it. They also acidify the contents. The structure then becomes to known as a parasitophorous vacuole or phagolysosome. Different species of Leishmania cause the formation of different types of phagolysosomes: those produced by L. mexicana tend to be large and contain many parasites whilst those formed by L. donovani tend to be much smaller.

      The combination of a rise in temperature associated with moving to a mammalian host and the drop in pH caused by enclosure within a phagolysosome induce the promastigote to change into the amastigote form. This transformation takes about 1–4 hours following ingestion and is essential if the parasite is to survive the acidic pH and hydrolytic enzymes within the phagolysosome. Transformation includes changes the composition of the cell surface phosphoglycans. Some of these, the glycoinositol phospholipids (GIPLs) directly inhibit the production of nitric oxide (NO) by the phagocyte. The expression of GP63 is downregulated in the amastigote but they continue to express it, and it is important for both the survival of the parasite and as a virulence factor (Olivier et al. 2012). The membrane changes associated with transformation to the amastigote stage means amastigotes invade phagocytes using a different set of ligands and receptors to the promastigote stage. Despite these changes, phagocytes remain capable of destroying amastigotes. Therefore, the reasons why some people develop serious or even fatal infections, whilst in others the infection is resolved, possibly without displaying any symptoms is uncertain.

      4.2.1.2 Visceral Leishmaniasis

      Classical visceral leishmaniasis is commonly known as kala‐azar and causes fevers like those of malaria. Both malaria and kala‐azar occur in the same areas, so it is important for doctors to distinguish between them. The name kala‐azar (black head) derives from the symptomatic darkening of the forehead and mouth of patients suffering from visceral leishmaniasis. In India, great plagues of visceral leishmaniasis occurred in Assam in the late nineteenth and early twentieth centuries that depopulated whole villages. Serious outbreaks still occur today, and visceral leishmaniasis remains an important cause of morbidity and mortality in over 70 countries around the world. Most cases of visceral leishmaniasis occur in South Asia (~67%), but it is also a big problem in parts of East Africa (e.g., Sudan in the region bordering with Ethiopia). There is also a focus of infection in South America, especially in Brazil.

The clinical picture of visceral leishmaniasis differs geographically. There is, nonetheless, a basic pattern to the course of the disease. The first stage begins when a papule develops at the site of the sandfly bite, but this eventually regresses. Low‐grade recurrent fevers then develop anything from 10 days to 2 years or more afterwards, and these persist throughout the course of the disease. Within the spleen, immune‐related responses destroy red blood cells, and this causes anaemia. In addition, the liver becomes enlarged (hepatomegaly) as does the spleen (splenomegaly). Enlargement of the spleen results from a combination of hyperplasia induced by the need to produce new mononuclear phagocytes and from infected mononuclear phagocytes filling with parasites. The patient often suffers from diarrhoea and this, together with the fever, leads to anorexia, malnutrition, and dehydration. If the disease is not treated, 90% of those suffering visceral leishmaniasis will die. Recovery can be rapid and complete with or without treatment. However, in many cases the parasite persists and may appear on the skin in raised macules causing the disfiguring condition post kala‐azar dermal leishmaniasis.

      4.2.1.3 Post Kala‐Azar Dermal Leishmaniasis

      Post kala‐azar dermal leishmaniasis (PKDL) is a condition that is usually associated with L. donovani and develops as sequel to visceral leishmaniasis in 2.5–20% of cases (hence ‘post‐kala‐azar’). It may manifest itself anything from immediately afterwards to several years following the condition. It is characterised by the development of nodules and/or macules that can be extensive and cover any area of the body and may be mistaken for leprosy. The nodules are irregular raised masses on the skin surface whilst macules (Latin macula = blemish or small spot) are flat discoloured areas on the skin surface. These regions contain numerous amastigotes, and if they occur on exposed parts of the body, they are a ready source of infection for sandflies. The identification and treatment of patients suffering from PKDL is therefore an important part of any control programme. There are marked differences the occurrence and development of PKDL between countries, which suggests that host, and/or parasite factors may be important in whether it develops. For example, most cases of PKDL (~50%) occur in the Sudan and the condition tends to develop more rapidly there than in India.

      Some workers consider that the development of PKDL is associated with the incomplete or inefficient treatment of visceral leishmaniasis following treatment with the drugs sodium stibogluconate and pentamidine. However, PKDL may also occur after treatment with miltefosine. In India, Das et al. (2009) found about 20% of PKDL cases occurred in people for whom there was no record of either visceral leishmaniasis or the prescription of the drugs used to treat it. However, these people tested positive for L. donovani and therefore carried an asymptomatic infection.

      4.2.1.4 Cutaneous Leishmaniasis

Cutaneous leishmaniasis manifests itself in a variety of different forms depending upon the species of Leishmania. Clinically, cutaneous leishmaniasis divides into three basic types depending upon how the disease presents. Localized Cutaneous Leishmaniasis (LCL) generally takes the form of a dry ulcer. It develops at the bite site of the sandfly vector and usually heals by itself although this may take some time and leave permanent scarring. This form of disease is common in India, Central Asia, the Middle East, and parts of southern Europe; L. major and L. tropica are responsible for most infections in these regions. LCL is also common in South America where species such as L. venezuelensis and L. mexicana are responsible. Diffuse (disseminated) cutaneous Leishmaniasis (DCL) is a rarer and much more serious condition than LCL. It manifests as numerous raised (but not ulcerating) papules and nodules that spread to cover large areas of the body. The condition is often associated with immune suppression, and there are several reports of HIV co‐infection (e.g., Corrêa Soares et al. 2020). Unlike LCL, patients with DCL seldom recover without treatment. In the ‘Old World’, Leishmania aethiopica is the most common cause of DCL whilst in South America L. mexicana and L. amazonensis are implicated. As mentioned earlier, any one species of Leishmania may cause different types of leishmaniasis.

      Mucocutaneous leishmaniasis (MCL) arises from the formation of an ulcerative lesion that afflicts the mouth, palate, and nose. As a rule, MCL develops and spreads slowly over a period of years and eventually destroys the affected region. It is most common in South America, particularly Brazil and the Amazon regions of Peru, Ecuador, Colombia, and Argentina where the condition is known as ‘espundia’. The discovery of pre‐Inca pottery illustrating disfigured faces suggests that the disease pre‐dates the European invasion of South America. However, some workers claim that the conquistadors and early Spanish settlers introduced MCL into South America. Espundia has a low mortality (~5%) provided the patient receives medical care. However, in the absence of treatment, mortality but would be undoubtedly higher. Death from MCL commonly results from complications such as aspiration pneumonia although some sufferers suffocate owing to laryngeal closure. Leishmania braziliensis is responsible for most cases of MCL although L. guyensis is also important. Leishmania major and some other species of Leishmania can also cause MCL, but these cases are rare. Leishmania guyanensis and L. braziliensis are naturally infected with Leishmania RNA virus