https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)67629-5.pdf

Advances in leishmaniasis.

Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

In this paper we describe a number of immunological parameters for dogs with a chronic Leishmania infantum infection which exhibit patterns of progressive disease or apparent resistance. The outcome of infection was assessed by isolation of parasites, serum antibody titers to Leishmania antigen, and development of clinical signs of leishmaniasis. Our studies show that 3 years after experimental infection, asymptomatic or resistant dogs responded to L. infantum antigen both in lymphocyte proliferation assays in vitro and in delayed-type hypersensitivity reaction, whereas no serum antibodies to parasite antigen were shown. In contrast, symptomatic or susceptible animals failed to respond to parasite antigen in cell-mediated assays both in vitro and in vivo and showed considerably higher serum antibodies to leishmanial antigens. In addition, significantly higher level of interleukin 2 (IL-2) and tumor necrosis factor were found in supernatants from stimulated peripheral mononuclear cells from asymptomatic dogs compared with those from symptomatic and control uninfected dogs. IL-6 production did not vary significantly among the groups studied. Finally, we observed similar results with a group of mixed-breed dogs with natural Leishmania infections also grouped as asymptomatic or symptomatic on the basis of clinical signs of canine visceral leishmaniasis. These results demonstrate that serum antibody titers, antigen-specific proliferative responses, delayed-type hypersensitivity skin reactions, and IL-2 and tumor necrosis factor production by peripheral mononuclear cells can be used as markers of disease progression.

https://iai.asm.org/content/iai/62/1/229.full.pdf

Cellular and humoral immune responses in dogs experimentally and naturally infected with Leishmania infantum.

Visceral leishmaniaisis (kala-azar) is a disseminated protozoal infection transmitted by sandfly bite in which macrophages of the liver spleen and bone marrow are preferentially parasitized and support intracellular replication. Most human infections caused by visceralizing strains of Leishmania are probably subclinical attesting to innate resistance or more likely to T (Th1)-cell-dependent immune responses which induce acquired resistance. While treatment is not given for subclinical infection remote recrudescence still remains a possibility especially if the host becomes T-cell deficient. In contrast if the initial Th1-cell-associated immune response fails to develop or its effector mechanisms are disabled or not properly maintained recently acquired (or reactivated) kala-azar evolves to full expression as a subacute or chronic illness for which treatment is required. (excerpt)

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

In experimental Leishmania donovani infection in BALB/c mice, initial susceptibility gives way to T-cell-dependent acquired resistance and eventual control over visceral infection. Since various cytokines appear to underlie the host response to Leishmania infection, we examined infected liver tissue for gene expression of cytokines associated with Th1 (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) and Th2 cells (IL-4 and IL-10). By Northern (RNA) blot analysis, only IFN-gamma mRNA expression was detected in livers of infected euthymic mice. To determine whether activation of Th1 cells develops selectively in this model, qualitative PCR analysis was used. These results indicated that mRNAs for IFN-gamma, IL-2, IL-4, and IL-10 were all induced by L. donovani infection. The potentially negative Th2 cell-associated response did not appear to play a functional role, however, since resistance was acquired, anti-IL-4 monoclonal antibody treatment did not accelerate control over visceral infection, and serum immunoglobulin E levels remained low. As judged by PCR analysis, IL-4 and IL-10 mRNAs were also expressed under three other conditions without apparent effect: in naive euthymic mice treated with IL-2, which induces leishmanicidal activity; in rechallenged immune mice, which resist reinfection; and in nude mice, which fail to control L. donovani. These results suggest that, like other Leishmania species, L. donovani infection may trigger a potentially suppressive Th2 cell-associated cytokine response. However, in T-cell-intact mice able to control L. donovani, this response either is insufficient to influence outcome or more likely is overshadowed by the Th1 cell response.

https://iai.asm.org/content/iai/62/3/1058.full.pdf

Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis.

Summary The Marseilles region is an endemic area for visceral mediterranean leishmaniasis, but although the number of dog cases, the parasite's main host, is very high, only a few people develop the disease. We looked for sensitized healthy subjects among 25 healthy individuals living in this area by studying their in vitro lymphoproliferative response to Leishmania infantum antigens and gamma interferon synthesis. We found that 65% of tested subjects were sensitized against L. infantum. We compared their cell mediated immunity to that of 13 active Kala-Azar patients and 13 controls from non-endemic areas. In patients, results showed a specific cellular immuno-deficiency in the lymphocyte response to L. infantum antigens and a global deficiency of gamma interferon production. Interestingly, the healthy individuals from the endemic area who responded to L. infantum antigens were found to produce high γ interferon levels after L. infantum antigen stimulation. After healing, the cell mediated-immunity of the 3 patients we followed up was similar to that of the sensitized tested healthy subjects, but the former were still producing antibodies at the time of study.

Evidence of subjects sensitized to Leishmania infantum on the French Mediterranean coast: differences in gamma interferon production between this population and visceral leishmaniasis patients

Persistance de la leishmaniose viscérale dans le sud-est de la France et fréquence marquée de l'affection a l'age adulte. A propos d'observations récentes.

The authors report on 9 cases of mediterranean visceral leishmaniasis (Kala-Azar) collected in the south-eastern part of France in 1978. They emphasize the more frequent occurrence of this disease in adults than children. Out of the 40 cases detected in this region between January 1975 and December 1978, 22 affected adults (55 percent) moreover, Kala-Azar appears to occur particularly in adults with decreased general resistance and diagnosis may be difficult because classical clinical features are no complete.

Persistence of visceral leishmaniasis in the southeast of France and recorded frequency of the disease in adults. Apropos of recent cases

La tres lourde pression therapeutique qui s'exerce actuellement sur le reservoir de virus connu pourrait favoriser l'emergence de souche de Leishmania infanteum resistantes aux antimoines

[Infantile Mediterranean kala-azar in the southeast of France. Current considerations].

Resume Vingt trois serums humains riches en auto-anticorps ont ete etudies en immunofluorescence indirecte face a dix antigenes parasitaires. Dans un cas sur deux des fausses positivites ont ete relevees. C'est dans le domaine des helminthiases que ces fausses positivites apparaissent le plus souvent. Il convient dans les cas de desaccord entre les resultats serologiques et les donnees cliniques ou epidemiologiques d'evoquer la possibilite de fluorescence non specifique due a ces auto-anticorps.

J. Franck

Papers

Evidence of subjects sensitized to Leishmania infantum on the French Mediterranean coast: differences in gamma interferon production between this population and visceral leishmaniasis patients

Persistance de la leishmaniose viscérale dans le sud-est de la France et fréquence marquée de l'affection a l'age adulte. A propos d'observations récentes.

Persistence of visceral leishmaniasis in the southeast of France and recorded frequency of the disease in adults. Apropos of recent cases

[Infantile Mediterranean kala-azar in the southeast of France. Current considerations].

Les auto anticorps source de fausses positivités dans les réactions d'immunofluorescence en parasitologie