leishmaniases

Leishmaniasis is a chronic inflammatory disease of the skin, mucous membranes, or viscera caused by obligate intracellular, kinetoplastid protozoan parasites transmitted through the bite of infected sandflies.

Leishmaniasis is endemic throughout the Middle East, South Asia, Africa, and Latin America. Numerous U.S. soldiers were infected with Leishmania in the Persian Gulf during Operation Desert Storm.

Leishmaniasis may also be epidemic, as is tragically the case in Sudan, India, Bangladesh, and Brazil, where tens of thousands of people have died of visceral leishmaniasis.

Finally, leishmanial infection, like other intracellular organisms (mycobacteria, Histoplasma, Toxoplasma, and trypanosomes), is exacerbated by AIDS.

Pathogenesis

The life cycle of Leishmania involves two forms: the promastigote, which develops and lives extracellularly in the sandfly vector, and the amastigote, which multiplies intracellularly in host macrophages. Mammals, including rodents, dogs, and foxes, are reservoirs of Leishmania. When sandflies bite infected humans or animals, macrophages harboring amastigotes are ingested. The amastigotes differentiate into promastigotes and multiply within the digestive tract of the sandfly and migrate to the pharynx, where they are poised for transmission by a sandfly bite. When the infected sandfly bites a person, the infectious slender, flagellated promastigotes are released into the host dermis along with the sandfly saliva, which potentiates parasite infectivity.

The promastigotes are phagocytosed by macrophages, and the acidity within the phagolysosome induces them to transform into round amastigotes that lack flagella but contain a single DNA-containing specialized mitochondrion called the kinetoplast.

Amastigotes proliferate within macrophages, and dying macrophages release progeny amastigotes which can infect additional macrophages.

How far the amastigotes spread throughout the body depends on the Leishmania species. Cutaneous disease is caused primarily by Leishmania major and Leishmania aethiopica in the Old World and Leishmania mexicana and Leishmania braziliensis in the New World; mucocutaneous disease (also called espundia) is caused by L. braziliensis; and visceral disease involving the liver and spleen is caused by Leishmania donovani in the Old World and Leishmania chagasi in the New World.

Tropism of Leishmania species appears to be linked to the optimal temperature for their growth. Parasites that cause visceral disease grow at 37°C in vitro, whereas parasites that cause mucocutaneous disease grow only at lower temperatures.

Leishmania manipulate innate host defenses to facilitate their entry and survival in host macrophages.148 Promastigotes produce two abundant surface glycoconjugates, which appear to be important for their virulence.

The first, lipophosphoglycan, forms a dense glycocalyx that both activates complement (leading to C3b deposition on the parasite surface) and inhibits complement action (by preventing membrane attack complex insertion into the parasite membrane). Thus, the parasite becomes coated with C3 but avoids destruction by the membrane attack complex.

The C3b on the surface of the parasite binds to Mac-1 and CR1 on macrophages, targeting the promastigote for phagocytosis by the macrophage. Once inside the cell, lipophosphoglycan protects the parasites within the phagolysosomes by scavenging oxygen radicals and by inhibiting lysosomal enzymes. The second surface glycoprotein, gp63, is a zinc-dependent proteinase that cleaves complement and some lysosomal antimicrobial enzymes. Gp63 also binds to fibronectin receptors on macrophages and promotes promastigote adhesion to macrophages. Leishmania amastigotes also produce molecules that facilitate their survival and replication within macrophages. Amastigotes reproduce in macrophage phagolysosomes, which have a pH of 4.5. However, the amastigotes are protected from this hostile environment by a proton-transporting ATPase, which maintains the intracellular parasite pH at 6.5.

Much of our knowledge of mechanisms of resistance and susceptibility to Leishmania comes from experimental mouse models.150 Parasite-specific CD4+ helper T lymphocytes of the TH1 subset are needed to control Leishmania in mice and humans. Leishmania evade host immunity by altering macrophage gene expression and impairing the development of the TH1 response.

In animal models, mice that are resistant to Leishmania infection produce high levels of TH1-derived IFN-γ, which activates macrophages to kill the parasites through toxic metabolites of oxygen and nitric oxide. In contrast, in mouse strains that are susceptible to leishmaniasis, there is a dominant TH2 response, and TH2 cytokines such as IL-4, IL-13, and IL-10 prevent effective killing of Leishmania by inhibiting activation of macrophages.

Morphology

Leishmania species produce four different lesions in humans: visceral, cutaneous, mucocutaneous, and diffuse cutaneous.

Visceral leishmaniasis

In visceral leishmaniasis, L. donovani or L. chagasi parasites invade macrophages throughout the mononuclear phagocyte system and cause severe systemic disease marked by hepatosplenomegaly, lymphadenopathy, pancytopenia, fever, and weight loss.

The spleen may weigh as much as 3 kg, and the lymph nodes may measure 5 cm in diameter. Phagocytic cells are enlarged and filled with Leishmania, many plasma cells are present, and the normal architecture of the spleen is obscured.

In the late stages, the liver becomes increasingly fibrotic. Phagocytic cells crowd the bone marrow and also may be found in the lungs, gastrointestinal tract, kidneys, pancreas, and testes.

Often there is hyperpigmentation of the skin in the extremities, which is why the disease is called kala-azar or "black fever" in Hindi. In the kidneys, there may be an immune complex-mediated mesangioproliferative glomerulonephritis, and in advanced cases, there may be amyloid deposition.

The overloading of phagocytic cells with parasites predisposes the patients to bacterial infections, the usual cause of death. Hemorrhages related to thrombocytopenia may also be fatal.

Cutaneous leishmaniasis

Cutaneous leishmaniasis, caused by L. major, L. mexicana, and L. braziliensis, is a relatively mild, localized disease consisting of a single ulcer on exposed skin.

The lesion (often called tropical sore) begins as an itching papule surrounded by induration, changes into a shallow and slowly expanding ulcer with irregular borders, and usually heals by involution within 6 months without treatment. On microscopic examination, the lesion is granulomatous, usually with many giant cells and few parasites.

Mucocutaneous leishmaniasis

Mucocutaneous leishmaniasis, caused by L. braziliensis, is found only in the New World. Moist, ulcerating or nonulcerating lesions, which may be disfiguring, develop in the larynx and at the mucocutaneous junctions of the nasal septum, anus, or vulva.

On microscopic examination, there is a mixed inflammatory infiltrate with parasite-containing histiocytes in association with lymphocytes and plasma cells. Later, the tissue reaction becomes granulomatous, and the number of parasites declines. Eventually, the lesions remit and scar, although reactivation may occur after long intervals by mechanisms that are not currently understood.

Diffuse cutaneous leishmaniasis

Diffuse cutaneous leishmaniasis is a rare form of dermal infection, thus far found in Ethiopia and adjacent East Africa and in Central and South America. Diffuse cutaneous leishmaniasis begins as a single skin nodule, which continues spreading until the entire body is covered by bizarre nodular lesions.

These lesions, which resemble keloids or large verrucae, are frequently confused with the nodules of lepromatous leprosy. The lesions do not ulcerate but contain vast aggregates of foamy macrophages stuffed with leishmania. Patients are usually immunologically unresponsive not only to leishmanin but also to other skin antigens, and the lesions often respond poorly to treatment.