Leishmania virulence and genetic heterogeneity

Chang, Kwang-Poo; Akman, Leyla; Nielsen, Jared S.

doi:10.1016/s0738-081x(99)00055-3

Cited by 11 publications

(6 citation statements)

References 10 publications

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“…Taxonomic studies of field Leishmania isolates indicate a tremendous diversity within this genus [34], and genetic diversity may have a direct impact on relevant properties of the organisms, including distinct clinical manifestations and drug susceptibility [35]. So, it is not surprising that the effect of HIV PIs on Leishmania species responsible for visceral or mucocutaneous leishmaniasis seems to be very distinct.…”

Section: Discussionmentioning

confidence: 99%

HIV Aspartyl Peptidase Inhibitors Interfere with Cellular Proliferation, Ultrastructure and Macrophage Infection of Leishmania amazonensis

et al. 2009

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Background Leishmania is the etiologic agent of leishmanisais, a protozoan disease whose pathogenic events are not well understood. Current therapy is suboptimal due to toxicity of the available therapeutic agents and the emergence of drug resistance. Compounding these problems is the increase in the number of cases of Leishmania-HIV coinfection, due to the overlap between the AIDS epidemic and leishmaniasis.Methodology/Principal FindingsIn the present report, we have investigated the effect of HIV aspartyl peptidase inhibitors (PIs) on the Leishmania amazonensis proliferation, ultrastructure, interaction with macrophage cells and expression of classical peptidases which are directly involved in the Leishmania pathogenesis. All the HIV PIs impaired parasite growth in a dose-dependent fashion, especially nelfinavir and lopinavir. HIV PIs treatment caused profound changes in the leishmania ultrastructure as shown by transmission electron microscopy, including cytoplasm shrinking, increase in the number of lipid inclusions and some cells presenting the nucleus closely wrapped by endoplasmic reticulum resembling an autophagic process, as well as chromatin condensation which is suggestive of apoptotic death. The hydrolysis of HIV peptidase substrate by L. amazonensis extract was inhibited by pepstatin and HIV PIs, suggesting that an aspartyl peptidase may be the intracellular target of the inhibitors. The treatment with HIV PIs of either the promastigote forms preceding the interaction with macrophage cells or the amastigote forms inside macrophages drastically reduced the association indexes. Despite all these beneficial effects, the HIV PIs induced an increase in the expression of cysteine peptidase b (cpb) and the metallopeptidase gp63, two well-known virulence factors expressed by Leishmania spp.Conclusions/SignificanceIn the face of leishmaniasis/HIV overlap, it is critical to further comprehend the sophisticated interplays among Leishmania, HIV and macrophages. In addition, there are many unresolved questions related to the management of Leishmania-HIV-coinfected patients. For instance, the efficacy of therapy aimed at controlling each pathogen in coinfected individuals remains largely undefined. The results presented herein add new in vitro insight into the wide spectrum efficacy of HIV PIs and suggest that additional studies about the synergistic effects of classical antileishmanial compounds and HIV PIs in macrophages coinfected with Leishmania and HIV-1 should be performed.

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Section: Discussionmentioning

confidence: 99%

HIV Aspartyl Peptidase Inhibitors Interfere with Cellular Proliferation, Ultrastructure and Macrophage Infection of Leishmania amazonensis

et al. 2009

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“…The application of new biomedical technologies to the study of leishmanial parasites will certainly have a substantial impact on our understanding of the molecular mechanisms of parasitism (with particular reference to the impact of genetic diversity on those relevant properties of organisms which may be associated with distinct clinical manifestations) as well [25].…”

Section: Determination Of Population Structure and Genetic Variation mentioning

confidence: 99%

Recent advances in the taxonomy of the New World leishmanial parasites

Cupolillo

Alves

Brahim

et al. 2001

Med Microbiol Immunol

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“…Extensive molecular phylogenic studies in the last 20 years have extended the number of species included in the genus Leishmania from several to dozens (Chang et al 1999). This diversity is concomitant with differences in factors responsible for interaction of parasites with the vector and the vertebrate host, leading to the extensive vector and host specificities observed among different species (Molyneux and Ashford 1983;WHO 1990b).…”

Section: Discussionmentioning

confidence: 99%

“…Infection is only a prerequisite for virulence or disease (Chang et al 1999). Therefore, it can be assumed that infecting but nonpathogenic species, such as L. tarentolae, have maintained the evasive/invasive determinants, but have deficiencies in pathoantigens.…”

Section: Discussionmentioning

confidence: 99%

Effect of A2 gene on infectivity of the nonpathogenic parasite Leishmania tarentolae

et al. 2011

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Several species of protozoan parasites of the genus Leishmania are pathogenic to mammals and cause a wide spectrum of pathologies in human. However, the genus includes some species which infect reptiles. Leishmania tarentolae is a lizard pathogen absolutely nonpathogenic to mammals. Recent studies have shown that among some major virulence factors, A2 is absent in this species. First identified as an amastigote-specific gene in Leishmania donovani, A2 has been proved to play a major role in parasite virulence and visceralization capability. In this study, we have transfected A2 episomally into L. tarentolae and evaluated its effect on infectivity and survival of the parasites, in vitro and in vivo. During infection of in vitro-cultured intraperitoneal macrophages of BALB/c mice, A2-expressing L. tarentolae parasites demonstrated significantly higher level of infectivity in days 3 and 4 post-infection in comparison with the wild-type strain as control. Furthermore, in vivo infection showed that A2 has significantly increased the ability of L. tarentolae to survive in the liver of BALB/c mice. Altogether, our results show that A2 is functional in L. tarentolae, although through an unknown mechanism, and loss of A2 has been one of the factors partly contributing to the loss of virulence of L. tarentolae.

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Leishmania virulence and genetic heterogeneity

Cited by 11 publications

References 10 publications

HIV Aspartyl Peptidase Inhibitors Interfere with Cellular Proliferation, Ultrastructure and Macrophage Infection of Leishmania amazonensis

HIV Aspartyl Peptidase Inhibitors Interfere with Cellular Proliferation, Ultrastructure and Macrophage Infection of Leishmania amazonensis

Recent advances in the taxonomy of the New World leishmanial parasites

Effect of A2 gene on infectivity of the nonpathogenic parasite Leishmania tarentolae

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