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17 pages, 2412 KiB

Open AccessEditor’s ChoiceArticle

Persistent Cutaneous Leishmania major Infection Promotes Infection-Adapted Myelopoiesis

by Fabio Luiz Bandeira Ferreira, Olivier Séguin, Albert Descoteaux and Krista M. Heinonen

Microorganisms 2022, 10(3), 535; https://doi.org/10.3390/microorganisms10030535 - 28 Feb 2022

Cited by 6 | Viewed by 3681

Abstract

Hematopoietic stem/progenitor cells (HSPC) are responsible for the generation of most immune cells throughout the lifespan of the organism. Inflammation can activate bone marrow HSPCs, leading to enhanced myelopoiesis to replace cells, such as neutrophils, which are attracted to inflamed tissues. We have [...] Read more.

Hematopoietic stem/progenitor cells (HSPC) are responsible for the generation of most immune cells throughout the lifespan of the organism. Inflammation can activate bone marrow HSPCs, leading to enhanced myelopoiesis to replace cells, such as neutrophils, which are attracted to inflamed tissues. We have previously shown that HSPC activation promotes parasite persistence and expansion in experimental visceral leishmaniasis through the increased production of permissive monocytes. However, it is not clear if the presence of the parasite in the bone marrow was required for infection-adapted myelopoiesis. We therefore hypothesized that persistent forms of Leishmania major (cutaneous leishmaniasis) could also activate HSPCs and myeloid precursors in the C57Bl/6 mouse model of intradermal infection in the ear. The accrued influx of myeloid cells to the lesion site corresponded to an increase in myeloid-biased HSPCs in the bone marrow and spleen in mice infected with a persistent strain of L. major, together with an increase in monocytes and monocyte-derived myeloid cells in the spleen. Analysis of the bone marrow cytokine and chemokine environment revealed an attenuated type I and type II interferon response in the mice infected with the persistent strain compared to the self-healing strain, while both strains induced a rapid upregulation of myelopoietic cytokines, such as IL-1β and GM-CSF. These results demonstrate that an active infection in the bone marrow is not necessary for the induction of infection-adapted myelopoiesis, and underline the importance of considering alterations to the bone marrow output when analyzing in vivo host-pathogen interactions. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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10 pages, 511 KiB

Open AccessArticle

Comparative Study of Real-Time PCR (TaqMan Probe and Sybr Green), Serological Techniques (ELISA, IFA and DAT) and Clinical Signs Evaluation, for the Diagnosis of Canine Leishmaniasis in Experimentally Infected Dogs

by María Paz Peris, Adriana Esteban-Gil, Paula Ortega-Hernández, Mariano Morales, Nabil Halaihel and Juan Antonio Castillo

Microorganisms 2021, 9(12), 2627; https://doi.org/10.3390/microorganisms9122627 - 20 Dec 2021

Cited by 10 | Viewed by 4179

Abstract

Canine leishmaniasis (CanL) diagnosis is not fully resolved. Currently, two specific methodologies are in continuous development, the detection of the parasite DNA or RNA in target organs and the detection of specific antibodies against Leishmania sp. For a correct diagnosis, it has been [...] Read more.

Canine leishmaniasis (CanL) diagnosis is not fully resolved. Currently, two specific methodologies are in continuous development, the detection of the parasite DNA or RNA in target organs and the detection of specific antibodies against Leishmania sp. For a correct diagnosis, it has been shown that the joint use of this type of test is necessary. In this work, a Sybr Green and a TaqMan Probe based on real time PCRs (qPCR) was performed for the detection of Leishmania sp. in order to correlate the results with clinicopathological and serological evaluations (IFA, ELISA and DAT) to propose an optimal biological sample to be used to detect the parasite in both early and late stages of the infection. A total of four samples were processed: conjunctival swabs, popliteal lymph node aspirates, bone marrow aspirates, and peripheral blood from experimentally infected dogs belonging to a larger study. Our results indicated that a single non-invasive sample (conjunctival swab) and the application of both types of qPCR would be reliable for determining Leishmania infection as well as the disease stage in dogs, thus avoiding bone marrow, lymph node aspirate or blood samples collection. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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11 pages, 2277 KiB

Open AccessArticle

Hematological Changes in Dogs with Visceral Leishmaniasis Are Associated with Increased IFN-γ and TNF Gene Expression Levels in the Bone Marrow

by Valter Almeida, Isadora Lima, Deborah Fraga, Eugenia Carrillo, Javier Moreno and Washington L. C. dos-Santos

Microorganisms 2021, 9(8), 1618; https://doi.org/10.3390/microorganisms9081618 - 29 Jul 2021

Cited by 7 | Viewed by 2775

Abstract

Visceral leishmaniasis is associated with a variety of hematological abnormalities. In this study, we correlated the hematological changes in the peripheral blood of dogs naturally infected with Leishmania infantum (L. infantum) with the distribution of cell lineages and cytokine gene expression patterns in [...] Read more.

Visceral leishmaniasis is associated with a variety of hematological abnormalities. In this study, we correlated the hematological changes in the peripheral blood of dogs naturally infected with Leishmania infantum (L. infantum) with the distribution of cell lineages and cytokine gene expression patterns in the bone marrow. Samples from 63 naturally semidomiciled dogs living in an endemic area of visceral leishmaniasis were analyzed. L. infantum infection was detected in 50 dogs (79.3%). Among those, 18 (32%) had positive splenic cultures and showed more clinical signs. They also had lower red blood cell counts and leukocytosis with an increased number of neutrophils and monocytes in peripheral blood compared to dogs negative to this test. L. infantum DNA was detected in the bone marrow of 8/14 dogs with positive splenic culture. Dogs with L. infantum infection in the bone marrow presented with histiocytosis (p = 0.0046), fewer erythroid cell clusters (p = 0.0127) and increased gene expression levels of IFN-γ (p = 0.0015) and TNF (p = 0.0091). The data shown herein suggest that inflammatory and cytokine gene expression changes in bone marrow may contribute to the peripheral blood hematological changes observed in visceral leishmaniasis. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1910 KiB

Open AccessArticle

Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series

by Magali Van den Kerkhof, Philippe Leprohon, Dorien Mabille, Sarah Hendrickx, Lindsay B. Tulloch, Richard J. Wall, Susan Wyllie, Eric Chatelain, Charles E. Mowbray, Stéphanie Braillard, Marc Ouellette, Louis Maes and Guy Caljon

Microorganisms 2021, 9(7), 1408; https://doi.org/10.3390/microorganisms9071408 - 29 Jun 2021

Cited by 10 | Viewed by 2939

Abstract

Current treatment options for visceral leishmaniasis have several drawbacks, and clinicians are confronted with an increasing number of treatment failures. To overcome this, the Drugs for Neglected Diseases initiative (DNDi) has invested in the development of novel antileishmanial leads, including a [...] Read more.

Current treatment options for visceral leishmaniasis have several drawbacks, and clinicians are confronted with an increasing number of treatment failures. To overcome this, the Drugs for Neglected Diseases initiative (DNDi) has invested in the development of novel antileishmanial leads, including a very promising class of oxaboroles. The mode of action/resistance of this series to Leishmania is still unknown and may be important for its further development and implementation. Repeated in vivo drug exposure and an in vitro selection procedure on both extracellular promastigote and intracellular amastigote stages were both unable to select for resistance. The use of specific inhibitors for ABC-transporters could not demonstrate the putative involvement of efflux pumps. Selection experiments and inhibitor studies, therefore, suggest that resistance to oxaboroles may not emerge readily in the field. The selection of a genome-wide cosmid library coupled to next-generation sequencing (Cos-seq) was used to identify resistance determinants and putative targets. This resulted in the identification of a highly enriched cosmid, harboring genes of chromosome 2 that confer a subtly increased resistance to the oxaboroles tested. Moderately enriched cosmids encompassing a region of chromosome 34 contained the cleavage and polyadenylation specificity factor (cpsf) gene, encoding the molecular target of several related benzoxaboroles in other organisms. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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11 pages, 12202 KiB

Open AccessArticle

Development and Clinical Evaluation of Serum and Urine-Based Lateral Flow Tests for Diagnosis of Human Visceral Leishmaniasis

by Sarfaraz Ahmad Ejazi, Somsubhra Thakur Choudhury, Anirban Bhattacharyya, Mohd Kamran, Krishna Pandey, Vidya Nand Ravi Das, Pradeep Das, Fernando Oliveira da Silva, Dorcas Lamounier Costa, Carlos Henrique Nery Costa, Mehebubar Rahaman, Rama Prosad Goswami and Nahid Ali

Microorganisms 2021, 9(7), 1369; https://doi.org/10.3390/microorganisms9071369 - 23 Jun 2021

Cited by 8 | Viewed by 3914

Abstract

Visceral leishmaniasis (VL), a fatal parasitic infection, is categorized as being neglected among tropical diseases. The use of conventional tissue aspiration for diagnosis is not possible in every setting. The immunochromatography-based lateral flow assay (LFA) has attracted attention for a long time due [...] Read more.

Visceral leishmaniasis (VL), a fatal parasitic infection, is categorized as being neglected among tropical diseases. The use of conventional tissue aspiration for diagnosis is not possible in every setting. The immunochromatography-based lateral flow assay (LFA) has attracted attention for a long time due to its ability to give results within a few minutes, mainly in resource-poor settings. In the present study, we optimized and developed the LFA to detect anti-Leishmania antibodies for VL diagnosis. The performance of the developed test was evaluated with serum and urine samples of Indian VL patients and Brazilian sera. The new test exploits well-studied and highly-sensitive purified antigens, LAg isolated from Leishmania donovani promastigotes and protein G conjugated colloidal-gold as a signal reporter. The intensity of the bands depicting the antigen–antibody complex was optimized under different experimental conditions and quantitatively analyzed by the ImageJ software. For the diagnosis of human VL in India, LFA was found to be 96.49% sensitive and 95% specific with serum, and 95.12% sensitive and 96.36% specific with urine samples, respectively. The sensitivity and specificity of LFA were 88.57% and 94.73%, respectively, for the diagnosis of Brazilian VL using patients’ sera infected with Leishmania infantum. LFA is rapid and simple to apply, suitable for field usage where results can be interpreted visually and particularly sensitive and specific in the diagnosis of human VL. Serum and urine LFA may improve diagnostic outcomes and could be an alternative for VL diagnosis in settings where tissue aspiration is difficult to perform. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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14 pages, 3004 KiB

Open AccessArticle

MPLA and AddaVax^® Adjuvants Fail to Promote Intramuscular LaAg Vaccine Protectiveness against Experimental Cutaneous Leishmaniasis

by Diogo Oliveira-Maciel, Júlio Souza dos-Santos, Gabriel Oliveira-Silva, Mirian França de Mello, Alessandra Marcia da Fonseca-Martins, Monique Pacheco Duarte Carneiro, Tadeu Diniz Ramos, Luan Firmino-Cruz, Daniel Claudio Oliveira Gomes, Bartira Rossi-Bergmann and Herbert Leonel de Matos Guedes

Microorganisms 2021, 9(6), 1272; https://doi.org/10.3390/microorganisms9061272 - 11 Jun 2021

Cited by 2 | Viewed by 3868

Abstract

There is so far no vaccine approved for human leishmaniasis, mainly because of the lack of appropriate adjuvants. This study aimed to evaluate in mice the capacity of a mixture of monophosphoryl lipid A (MPLA) and AddaVax^® adjuvants in enhancing the efficacy [...] Read more.

There is so far no vaccine approved for human leishmaniasis, mainly because of the lack of appropriate adjuvants. This study aimed to evaluate in mice the capacity of a mixture of monophosphoryl lipid A (MPLA) and AddaVax^® adjuvants in enhancing the efficacy of a Leishvacin^®-like vaccine comprised of Leishmania amazonensis whole antigens (LaAg). For that, mice were immunized with LaAg plus MPLA/AddaVax^® by the intramuscular route (i.m.) prior to challenge with 2 × 10⁵ and 2 × 10⁶ living parasites. Immunization with LaAg alone reduced the lesion growth of the 2 × 10⁵-challenged mice only in the peak of infection, but that was not accompanied by reduced parasite load, and thus not considered protective. Mice given a 2 × 10⁶ -challenge were not protected by LaAg. The association of LaAg with MPLA/AddaVax^® was able to enhance the cutaneous hypersensitivity response compared with LaAg alone. Despite this, there was no difference in proliferative cell response to antigen ex vivo. Moreover, regardless of the parasite challenge, association of LaAg with MPL/AddaVax^® did not significantly enhance protection in comparison with LaAg alone. This work demonstrated that MPL/AddaVax^® is not effective in improving the efficacy of i.m. LaAg vaccine against cutaneous leishmaniasis. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1685 KiB

Open AccessArticle

Lutzomyia longipalpis Antimicrobial Peptides: Differential Expression during Development and Potential Involvement in Vector Interaction with Microbiota and Leishmania

by Erich Loza Telleria, Bruno Tinoco-Nunes, Tereza Leštinová, Lívia Monteiro de Avellar, Antonio Jorge Tempone, André Nóbrega Pitaluga, Petr Volf and Yara Maria Traub-Csekö

Microorganisms 2021, 9(6), 1271; https://doi.org/10.3390/microorganisms9061271 - 11 Jun 2021

Cited by 13 | Viewed by 3298

Abstract

Antimicrobial peptides (AMPs) are produced to control bacteria, fungi, protozoa, and other infectious agents. Sand fly larvae develop and feed on a microbe-rich substrate, and the hematophagous females are exposed to additional pathogens. We focused on understanding the role of the AMPs attacin [...] Read more.

Antimicrobial peptides (AMPs) are produced to control bacteria, fungi, protozoa, and other infectious agents. Sand fly larvae develop and feed on a microbe-rich substrate, and the hematophagous females are exposed to additional pathogens. We focused on understanding the role of the AMPs attacin (Att), cecropin (Cec), and four defensins (Def1, Def2, Def3, and Def4) in Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. Larvae and adults were collected under different feeding regimens, in addition to females artificially infected by Leishmania infantum. AMPs’ gene expression was assessed by qPCR, and gene function of Att and Def2 was investigated by gene silencing. The gene knockdown effect on bacteria and parasite abundance was evaluated by qPCR, and parasite development was verified by light microscopy. We demonstrate that L. longipalpis larvae and adults trigger AMPs expression during feeding, which corresponds to an abundant presence of bacteria. Att and Def2 expression were significantly increased in Leishmania-infected females, while Att suppression favored bacteria growth. In conclusion, L. longipalpis AMPs’ expression is tuned in response to bacteria and parasites but does not seem to interfere with the Leishmania cycle. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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19 pages, 4240 KiB

Open AccessArticle

Malnutrition Aggravates Alterations Observed in the Gut Structure and Immune Response of Mice Infected with Leishmania infantum

by Felipe Gaitán-Albarracín, Monica Losada-Barragán, Nathalia Pinho, Renata Azevedo, Jonathan Durães, Juan Sebastián Arcila-Barrera, Rodrigo C. Menezes, Fernanda N. Morgado, Vinicius de Frias Carvalho, Adriana Umaña-Pérez and Patricia Cuervo

Microorganisms 2021, 9(6), 1270; https://doi.org/10.3390/microorganisms9061270 - 11 Jun 2021

Cited by 3 | Viewed by 3303

Abstract

Malnutrition is a risk factor for developing visceral leishmaniasis and its severe forms. Our group demonstrated that malnourished animals infected with Leishmania infantum had severe atrophies in lymphoid organs and T cell subpopulations as well as altered levels of thymic and splenic chemotactic [...] Read more.

Malnutrition is a risk factor for developing visceral leishmaniasis and its severe forms. Our group demonstrated that malnourished animals infected with Leishmania infantum had severe atrophies in lymphoid organs and T cell subpopulations as well as altered levels of thymic and splenic chemotactic factors, all of which resulted in dysfunctional lymphoid microenvironments that promoted parasite proliferation. Here, we hypothesize that malnutrition preceding parasite infection leads to structural and immunological changes in the gut mucosae, resulting in a failure in the immune response sensed in the intestine. To evaluate this, we analyzed the immunopathological events resulting from protein malnutrition in the guts of BALB/c mice infected with L. infantum. We observed lymphocytic/lymphoplasmacytic inflammatory infiltrates and lymphoid hyperplasia in the duodenum of well-nourished-infected mice; such alterations were worsened when malnutrition preceded infection. Parasite infection induced a significant increase of duodenal immunoglobulin A (IgA) of well-nourished animals, but those levels were significantly decreased in malnourished-infected mice. In addition, increased levels of Th17-related cytokines in duodenums of malnourished animals supported local inflammation. Together, our results suggest that the gut plays a potential role in responses to L. infantum infection—and that such responses are impaired in malnourished individuals. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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19 pages, 10895 KiB

Open AccessArticle

Leishmania-Induced Dendritic Cell Migration and Its Potential Contribution to Parasite Dissemination

by Amanda Rebouças, Thaílla S. Silva, Lilian S. Medina, Bruno D. Paredes, Luciana S. Aragão, Bruno S. F. Souza, Valéria M. Borges, Albert Schriefer, Patricia S. T. Veras, Claudia I. Brodskyn and Juliana P. B. de Menezes

Microorganisms 2021, 9(6), 1268; https://doi.org/10.3390/microorganisms9061268 - 11 Jun 2021

Cited by 6 | Viewed by 3115

Abstract

Leishmania, an intracellular parasite species, causes lesions on the skin and in the mucosa and internal organs. The dissemination of infected host cells containing Leishmania is crucial to parasite survival and the establishment of infection. Migratory phenomena and the mechanisms underlying the [...] Read more.

Leishmania, an intracellular parasite species, causes lesions on the skin and in the mucosa and internal organs. The dissemination of infected host cells containing Leishmania is crucial to parasite survival and the establishment of infection. Migratory phenomena and the mechanisms underlying the dissemination of Leishmania-infected human dendritic cells (hDCs) remain poorly understood. The present study aimed to investigate differences among factors involved in hDC migration by comparing infection with visceral leishmaniasis (VL) induced by Leishmaniainfantum with diverse clinical forms of tegumentary leishmaniasis (TL) induced by Leishmaniabraziliensis or Leishmania amazonensis. Following the infection of hDCs by isolates obtained from patients with different clinical forms of Leishmania, the formation of adhesion complexes, actin polymerization, and CCR7 expression were evaluated. We observed increased hDC migration following infection with isolates of L. infantum (VL), as well as disseminated (DL) and diffuse (DCL) forms of cutaneous leishmaniasis (CL) caused by L. braziliensis and L. amazonensis, respectively. Increased expression of proteins involved in adhesion complex formation and actin polymerization, as well as higher CCR7 expression, were seen in hDCs infected with L. infantum, DL and DCL isolates. Together, our results suggest that hDCs play an important role in the dissemination of Leishmania parasites in the vertebrate host. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1741 KiB

Open AccessArticle

In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil

by Caroline Ricce Espada, Erica V. de Castro Levatti, Mariana Côrtes Boité, Dorcas Lamounier, Jorge Alvar, Elisa Cupolillo, Carlos Henrique Nery Costa, Joelle Rode and Silvia R. B. Uliana

Microorganisms 2021, 9(6), 1228; https://doi.org/10.3390/microorganisms9061228 - 5 Jun 2021

Cited by 9 | Viewed by 3753

Abstract

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower [...] Read more.

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC₅₀ for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 μM. The EC₅₀ of the 73 strains determined in promastigotes varied between 5.89 and 23.7 μM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 2141 KiB

Open AccessArticle

Gut Microbiota Dynamics in Natural Populations of Pintomyia evansi under Experimental Infection with Leishmania infantum

by Rafael José Vivero, Victor Alfonso Castañeda-Monsalve, Luis Roberto Romero, Gregory D. Hurst, Gloria Cadavid-Restrepo and Claudia Ximena Moreno-Herrera

Microorganisms 2021, 9(6), 1214; https://doi.org/10.3390/microorganisms9061214 - 4 Jun 2021

Cited by 8 | Viewed by 3674

Abstract

Pintomyia evansi is recognized by its vectorial competence in the transmission of parasites that cause fatal visceral leishmaniasis in rural and urban environments of the Caribbean coast of Colombia. The effect on and the variation of the gut microbiota in female P. evansi [...] Read more.

Pintomyia evansi is recognized by its vectorial competence in the transmission of parasites that cause fatal visceral leishmaniasis in rural and urban environments of the Caribbean coast of Colombia. The effect on and the variation of the gut microbiota in female P. evansi infected with Leishmania infantum were evaluated under experimental conditions using 16S rRNA Illumina MiSeq sequencing. In the coinfection assay with L. infantum, 96.8% of the midgut microbial population was composed mainly of Proteobacteria (71.0%), followed by Cyanobacteria (20.4%), Actinobacteria (2.7%), and Firmicutes (2.7%). In insect controls (uninfected with L. infantum) that were treated or not with antibiotics, Ralstonia was reported to have high relative abundance (55.1–64.8%), in contrast to guts with a high load of infection from L. infantum (23.4–35.9%). ASVs that moderately increased in guts infected with Leishmania were Bacillus and Aeromonas. Kruskal–Wallis nonparametric variance statistical inference showed statistically significant intergroup differences in the guts of P. evansi infected and uninfected with L. infantum (p < 0.05), suggesting that some individuals of the microbiota could induce or restrict Leishmania infection. This assay also showed a negative effect of the antibiotic treatment and L. infantum infection on the gut microbiota diversity. Endosymbionts, such as Microsporidia infections (<2%), were more often associated with guts without Leishmania infection, whereas Arsenophonus was only found in guts with a high load of Leishmania infection and treated with antibiotics. Finally, this is the first report that showed the potential role of intestinal microbiota in natural populations of P. evansi in susceptibility to L. infantum infection. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 3582 KiB

Open AccessArticle

17-AAG-Induced Activation of the Autophagic Pathway in Leishmania Is Associated with Parasite Death

by Antonio Luis de O. A. Petersen, Benjamin Cull, Beatriz R. S. Dias, Luana C. Palma, Yasmin da S. Luz, Juliana P. B. de Menezes, Jeremy C. Mottram and Patrícia S. T. Veras

Microorganisms 2021, 9(5), 1089; https://doi.org/10.3390/microorganisms9051089 - 19 May 2021

Cited by 8 | Viewed by 2990

Abstract

The heat shock protein 90 (Hsp90) is thought to be an excellent drug target against parasitic diseases. The leishmanicidal effect of an Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), was previously demonstrated in both in vitro and in vivo models of cutaneous leishmaniasis. Parasite death was [...] Read more.

The heat shock protein 90 (Hsp90) is thought to be an excellent drug target against parasitic diseases. The leishmanicidal effect of an Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), was previously demonstrated in both in vitro and in vivo models of cutaneous leishmaniasis. Parasite death was shown to occur in association with severe ultrastructural alterations in Leishmania, suggestive of autophagic activation. We hypothesized that 17-AAG treatment results in the abnormal activation of the autophagic pathway, leading to parasite death. To elucidate this process, experiments were performed using transgenic parasites with GFP-ATG8-labelled autophagosomes. Mutant parasites treated with 17-AAG exhibited autophagosomes that did not entrap cargo, such as glycosomes, or fuse with lysosomes. ATG5-knockout (Δatg5) parasites, which are incapable of forming autophagosomes, demonstrated lower sensitivity to 17-AAG-induced cell death when compared to wild-type (WT) Leishmania, further supporting the role of autophagy in 17-AAG-induced cell death. In addition, Hsp90 inhibition resulted in greater accumulation of ubiquitylated proteins in both WT- and Δatg5-treated parasites compared to controls, in the absence of proteasome overload. In conjunction with previously described ultrastructural alterations, herein we present evidence that treatment with 17-AAG causes abnormal activation of the autophagic pathway, resulting in the formation of immature autophagosomes and, consequently, incidental parasite death. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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16 pages, 2785 KiB

Open AccessArticle

The Modulation of NADPH Oxidase Activity in Human Neutrophils by Moroccan Strains of Leishmania major and Leishmania tropica Is Not Associated with p47^phox Phosphorylation

by Hasnaa Maksouri, Dounia Darif, Jerome Estaquier, Myriam Riyad, Christophe Desterke, Meryem Lemrani, Pham My-Chan Dang and Khadija Akarid

Microorganisms 2021, 9(5), 1025; https://doi.org/10.3390/microorganisms9051025 - 10 May 2021

Cited by 1 | Viewed by 2676

Abstract

Polymorphonuclear neutrophils (PMNs) are the first phagocyte recruited and infected by Leishmania. They synthetize superoxide anions (O₂⁻) under the control of the NADPH oxidase complex. In Morocco, Leishmania major and L. tropica are the main species responsible for cutaneous [...] Read more.

Polymorphonuclear neutrophils (PMNs) are the first phagocyte recruited and infected by Leishmania. They synthetize superoxide anions (O₂⁻) under the control of the NADPH oxidase complex. In Morocco, Leishmania major and L. tropica are the main species responsible for cutaneous leishmaniasis (CL). The impact of these parasites on human PMN functions is still unclear. We evaluated the in vitro capacity of primary Moroccan strains of L. major and L. tropica to modulate PMN O₂⁻ production and p47^phox phosphorylation status of the NADPH oxidase complex. PMNs were isolated from healthy blood donors, and their infection rate was measured by microscopy. O₂⁻ production was measured by superoxide dismutase–inhibitable reduction of cytochrome C. P47^phox phosphorylation was analyzed by Western blot using specific antibodies against Ser328 and Ser345 sites. Whereas we did not observe any difference in PMN infectivity rate, our results indicated that only L. tropica promastigotes inhibited both fMLF- and PMA-mediated O₂⁻ production independently of p47^phox phosphorylation. Leishmania soluble antigens (SLAs) from both species significantly inhibited O₂⁻ induced by fMLF or PMA. However, they only decreased PMA-induced p47phox phosphorylation. L. major and L. tropica modulated differently O₂⁻ production by human PMNs independently of p47^phox phosphorylation. The inhibition of ROS production by L. tropica could be a mechanism of its survival within PMNs that might explain the reported chronic pathogenicity of L. tropica CL. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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7 pages, 430 KiB

Open AccessCommunication

Loop-Mediated Isothermal Amplification Allows Rapid, Simple and Accurate Molecular Diagnosis of Human Cutaneous and Visceral Leishmaniasis Caused by Leishmania infantum When Compared to PCR

by Ana Victoria Ibarra-Meneses, Carmen Chicharro, Carmen Sánchez, Emilia García, Sheila Ortega, Joseph Mathu Ndung’u, Javier Moreno, Israel Cruz and Eugenia Carrillo

Microorganisms 2021, 9(3), 610; https://doi.org/10.3390/microorganisms9030610 - 16 Mar 2021

Cited by 5 | Viewed by 2395

Abstract

Loop-mediated isothermal amplification allows the rapid, sensitive and specific amplification of DNA without complex and expensive equipment. We compared the diagnostic performance of Loopamp™ Leishmania Detection Kit (Eiken Chemical Co., Ltd., Tokyo, Japan) with conventional and real-time polymerase chain reaction (PCR) for human [...] Read more.

Loop-mediated isothermal amplification allows the rapid, sensitive and specific amplification of DNA without complex and expensive equipment. We compared the diagnostic performance of Loopamp™ Leishmania Detection Kit (Eiken Chemical Co., Ltd., Tokyo, Japan) with conventional and real-time polymerase chain reaction (PCR) for human cutaneous and visceral leishmaniasis caused by L. infantum. A total of 230 DNA samples from cutaneous (CL) and visceral (VL) leishmaniasis cases and controls from Spain, characterized by Leishmania nested PCR (LnPCR) were tested by: (i) the Loopamp™ Leishmania Detection Kit (Loopamp), run on Genie III real-time fluorimeter (OptiGene, UK); and (ii) real-time quantitative PCR (qPCR). The Loopamp test returned 98.8% (95% confidence interval—CI: 96.0–100.00) sensitivity and specificity of 97.7% (95% CI: 92.2–100) on VL samples, and 100% (95% CI: 99.1–100) sensitivity and 100.0% (95% CI: 98.8–100.0) specificity on CL samples. The Loopamp time-to-positivity (Tp) obtained by real-time fluorimetry showed excellent concordance (C = 97.91%) and strong correlation (r = 0.799) with qPCR’s cycle threshold (Ct). The performance of Loopamp is comparable to that of LnPCR and qPCR in the diagnosis of cutaneous and visceral leishmaniasis due to L. infantum. The excellent correlation between the Tp and Ct should be further investigated to determine the accuracy of Loopamp to quantify parasite load in tissues. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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14 pages, 2719 KiB

Open AccessArticle

A Multi-Country, Single-Blinded, Phase 2 Study to Evaluate a Point-of-Need System for Rapid Detection of Leishmaniasis and Its Implementation in Endemic Settings

by Prakash Ghosh, Abhijit Sharma, Narayan Raj Bhattarai, Kumar Abhishek, Thilini Nisansala, Amresh Kumar, Susanne Böhlken-Fascher, Rajashree Chowdhury, Md Anik Ashfaq Khan, Khaledul Faisal, Faria Hossain, Md. Rasel Uddin, Md. Utba Rashid, Shomik Maruf, Keshav Rai, Monica Sooriyaarachchi, Withanage Lakma Kumari Abhayarathna, Prahlad Karki, Shiril Kumar, Shalindra Ranasinghe, Basudha Khanal, Satyabrata Routray, Pradeep Das, Dinesh Mondal and Ahmed Abd El Wahed Show full author list Hide full author list

Microorganisms 2021, 9(3), 588; https://doi.org/10.3390/microorganisms9030588 - 12 Mar 2021

Cited by 11 | Viewed by 3736

Abstract

With the advancement of isothermal nucleic acid amplification techniques, detection of the pathogenic DNA in clinical samples at point-of-need is no longer a dream. The newly developed recombinase polymerase amplification (RPA) assay incorporated in a suitcase laboratory has shown promising diagnostic efficacy over [...] Read more.

With the advancement of isothermal nucleic acid amplification techniques, detection of the pathogenic DNA in clinical samples at point-of-need is no longer a dream. The newly developed recombinase polymerase amplification (RPA) assay incorporated in a suitcase laboratory has shown promising diagnostic efficacy over real-time PCR in detection of leishmania DNA from clinical samples. For broader application of this point-of-need system, we undertook a current multi-country diagnostic evaluation study towards establishing this technique in different endemic settings which would be beneficial for the ongoing elimination programs for leishmaniasis. For this study purpose, clinical samples from confirmed visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) patients were subjected to both real-time PCR and RPA assay in Bangladesh, India, and Nepal. Further skin samples from confirmed cutaneous leishmaniasis (CL) patients were also included from Sri Lanka. A total of 450 clinical samples from VL patients, 429 from PKDL patients, 47 from CL patients, and 322 from endemic healthy/healthy controls were under investigation to determine the diagnostic efficacy of RPA assay in comparison to real-time PCR. A comparative sensitivity of both methods was found where real-time PCR and RPA assay showed 96.86% (95% CI: 94.45–98.42) and 88.85% (95% CI: 85.08–91.96) sensitivity respectively in the diagnosis of VL cases. This new isothermal method also exhibited promising diagnostic sensitivity (93.50%) for PKDL cases, when a skin sample was used. Due to variation in the sequence of target amplicons, RPA assay showed comparatively lower sensitivity (55.32%) than that of real-time PCR in Sri Lanka for the diagnosis of CL cases. Except for India, the assay presented absolute specificity in the rest of the sites. Excellent concordance between the two molecular methods towards detection of leishmania DNA in clinical samples substantiates the application of RPA assay incorporated in a suitcase laboratory for point-of-need diagnosis of VL and PKDL in low resource endemic settings. However, further improvisation of the method is necessary for diagnosis of CL. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1857 KiB

Open AccessArticle

Inoculation of the Leishmania infantum HSP70-II Null Mutant Induces Long-Term Protection against L. amazonensis Infection in BALB/c Mice

by Manuel Soto, Laura Ramírez, José Carlos Solana, Emma C. L. Cook, Elena Hernández-García, José María Requena and Salvador Iborra

Microorganisms 2021, 9(2), 363; https://doi.org/10.3390/microorganisms9020363 - 12 Feb 2021

Cited by 9 | Viewed by 2701

Abstract

Leishmania amazonensis parasites are etiological agents of cutaneous leishmaniasis in the New World. BALB/c mice are highly susceptible to L. amazonensis challenge due to their inability to mount parasite-dependent IFN-γ-mediated responses. Here, we analyzed the capacity of a single administration of the LiΔHSP70-II [...] Read more.

Leishmania amazonensis parasites are etiological agents of cutaneous leishmaniasis in the New World. BALB/c mice are highly susceptible to L. amazonensis challenge due to their inability to mount parasite-dependent IFN-γ-mediated responses. Here, we analyzed the capacity of a single administration of the LiΔHSP70-II genetically-modified attenuated L. infantum line in preventing cutaneous leishmaniasis in mice challenged with L. amazonensis virulent parasites. In previous studies, this live attenuated vaccine has demonstrated to induce long-protection against murine leishmaniasis due to Old World Leishmania species. Vaccinated mice showed a reduction in the disease evolution due to L. amazonensis challenge, namely reduction in cutaneous lesions and parasite burdens. In contrast to control animals, after the challenge, protected mice showed anti-Leishmania IgG2a circulating antibodies accompanied to the induction of Leishmania-driven specific IFN-γ systemic response. An analysis performed in the lymph node draining the site of infection revealed an increase of the parasite-specific IFN-ϒ production by CD4⁺ and CD8⁺ T cells and a decrease in the secretion of IL-10 against leishmanial antigens. Since the immunity caused by the inoculation of this live vaccine generates protection against different forms of murine leishmaniasis, we postulate LiΔHSP70-II as a candidate for the development of human vaccines. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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12 pages, 1433 KiB

Open AccessArticle

Neutrophil Gelatinase-Associated Lipocalin (NGAL) Is Related with the Proteinuria Degree and the Microscopic Kidney Findings in Leishmania-Infected Dogs

by María Paz Peris, Mariano Morales, Sonia Ares-Gómez, Adriana Esteban-Gil, Pablo Gómez-Ochoa, Manuel Gascón, Bernardino Moreno and Juan Antonio Castillo

Microorganisms 2020, 8(12), 1966; https://doi.org/10.3390/microorganisms8121966 - 11 Dec 2020

Cited by 8 | Viewed by 2772

Abstract

Early diagnosis of renal damage in Leishmania infected dogs may allow appropriate treatments and prevent some deaths. This study investigates neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of kidney disease in dogs experimentally infected with Leishmania infantum. Serum, urine, and kidney samples [...] Read more.

Early diagnosis of renal damage in Leishmania infected dogs may allow appropriate treatments and prevent some deaths. This study investigates neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of kidney disease in dogs experimentally infected with Leishmania infantum. Serum, urine, and kidney samples were collected from 30 infected beagle dogs and six uninfected control dogs. Based on proteinuria and azotemia values, dogs were initially classified. NGAL was measured in urine and serum samples. Then, the urinary NGAL to creatinine ratio (uNGAL/C) was calculated. Kidney samples were taken for histopathological studies, and the dogs were classified according to the severity of glomerular and tubulointerstitial lesions. In Leishmania-infected dogs, the uNGAL/C was significantly higher in proteinuric non-azotemic dogs compared with non-proteinuric non-azotemic dogs (p = 0.038). Serum NGAL (sNGAL) concentration did not differ between groups. Microscopic studies revealed several degrees of glomerulonephritis and slight focal lymphoplasmacytic interstitial nephritis in 89% and 55% of infected dogs, respectively. Urinary protein to creatinine ratio (UPC) and uNGAL/C were significantly higher in dogs with affected glomeruli compared to infected dogs without renal lesions (p = 0.045 and p = 0.043, respectively). The results show that uNGAL/C correlates with proteinuria and the presence of moderate glomerular lesions in non-azotemic dogs experimentally infected with L. infantum. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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6 pages, 203 KiB

Open AccessCommunication

Serodiagnosis of Visceral Leishmaniasis in Northeastern Italy: Evaluation of Seven Serological Tests

by Margherita Ortalli, Daniele Lorrai, Paolo Gaibani, Giada Rossini, Caterina Vocale, Maria Carla Re and Stefania Varani

Microorganisms 2020, 8(12), 1847; https://doi.org/10.3390/microorganisms8121847 - 24 Nov 2020

Cited by 9 | Viewed by 2754

Abstract

This study compares the performance of seven assays, including two ELISA (Leishmania ELISA IgG + IgM, Vircell Microbiologists; Leishmania infantum IgG ELISA, NovaTec), three rK39-based immunochromatographic tests (rK39-ICTs) (Leishmania Dipstick Rapydtest, Apacor; On Site Leishmania IgG/IgM Combo Rapid Test, CTK Biotech; LEISHMANIA Strip [...] Read more.

This study compares the performance of seven assays, including two ELISA (Leishmania ELISA IgG + IgM, Vircell Microbiologists; Leishmania infantum IgG ELISA, NovaTec), three rK39-based immunochromatographic tests (rK39-ICTs) (Leishmania Dipstick Rapydtest, Apacor; On Site Leishmania IgG/IgM Combo Rapid Test, CTK Biotech; LEISHMANIA Strip quick Test, Cypress Diagnostic), one indirect immunofluorescent antibody test (IFAT) (Leishmania-Spot IF, BioMérieux), and one western blot (WB) (Leishmania WESTERN BLOT IgG, LDBio Diagnostics) for serodiagnosis of visceral leishmaniasis (VL). Serum samples from 27 VL patients living in northeastern Italy were analyzed, as well as the serum samples from 50 individuals in whom VL diagnosis was excluded. The WB and the IFAT had 96% sensitivity, followed by the ELISA (63% and 74%, respectively). The rK39-ICT exhibited the worst performance among the serological tests, with sensitivities ranging from 52% to 70%. By combining selected ELISA/ICT, the sensitivity of VL detection reached 89%. IFAT and WB outperformed ELISA and rK39-ICT by possessing optimal sensitivity, but their high cost and complexity of execution would not allow their employment as screening tests. In conclusion, the combination of easy-to-perform tests, such as ICT and ELISA, could improve sensitivity in the serodiagnosis of Mediterranean VL. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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20 pages, 4022 KiB

Open AccessArticle

Central Asian Rodents as Model Animals for Leishmania major and Leishmania donovani Research

by Barbora Vojtkova, Tatiana Spitzova, Jan Votypka, Tereza Lestinova, Iveta Kominkova, Michaela Hajkova, David Santos-Mateus, Michael A. Miles, Petr Volf and Jovana Sadlova

Microorganisms 2020, 8(9), 1440; https://doi.org/10.3390/microorganisms8091440 - 20 Sep 2020

Cited by 8 | Viewed by 4236

Abstract

The clinical manifestation of leishmaniases depends on parasite species, host genetic background, and immune response. Manifestations of human leishmaniases are highly variable, ranging from self-healing skin lesions to fatal visceral disease. The scope of standard model hosts is insufficient to mimic well the [...] Read more.

The clinical manifestation of leishmaniases depends on parasite species, host genetic background, and immune response. Manifestations of human leishmaniases are highly variable, ranging from self-healing skin lesions to fatal visceral disease. The scope of standard model hosts is insufficient to mimic well the wide disease spectrum, which compels the introduction of new model animals for leishmaniasis research. In this article, we study the susceptibility of three Asian rodent species (Cricetulus griseus, Lagurus lagurus, and Phodopus sungorus) to Leishmania major and L. donovani. The external manifestation of the disease, distribution, as well as load of parasites and infectiousness to natural sand fly vectors, were compared with standard models, BALB/c mice and Mesocricetus auratus. No significant differences were found in disease outcomes in animals inoculated with sand fly- or culture-derived parasites. All Asian rodent species were highly susceptible to L. major. Phodopus sungorus showed the non-healing phenotype with the progressive growth of ulcerative lesions and massive parasite loads. Lagurus lagurus and C. griseus represented the healing phenotype, the latter with high infectiousness to vectors, mimicking best the character of natural reservoir hosts. Both, L. lagurus and C. griseus were also highly susceptible to L. donovani, having wider parasite distribution and higher parasite loads and infectiousness than standard model animals. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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18 pages, 2185 KiB

Open AccessArticle

The Absence of C-5 DNA Methylation in Leishmania donovani Allows DNA Enrichment from Complex Samples

by Bart Cuypers, Franck Dumetz, Pieter Meysman, Kris Laukens, Géraldine De Muylder, Jean-Claude Dujardin and Malgorzata Anna Domagalska

Microorganisms 2020, 8(8), 1252; https://doi.org/10.3390/microorganisms8081252 - 18 Aug 2020

Cited by 8 | Viewed by 3415

Abstract

Cytosine C5 methylation is an important epigenetic control mechanism in a wide array of eukaryotic organisms and generally carried out by proteins of the C-5 DNA methyltransferase family (DNMTs). In several protozoans, the status of this mechanism remains elusive, such as in Leishmania [...] Read more.

Cytosine C5 methylation is an important epigenetic control mechanism in a wide array of eukaryotic organisms and generally carried out by proteins of the C-5 DNA methyltransferase family (DNMTs). In several protozoans, the status of this mechanism remains elusive, such as in Leishmania, the causative agent of the disease leishmaniasis in humans and a wide array of vertebrate animals. In this work, we showed that the Leishmania donovani genome contains a C-5 DNA methyltransferase (DNMT) from the DNMT6 subfamily, whose function is still unclear, and verified its expression at the RNA level. We created viable overexpressor and knock-out lines of this enzyme and characterized their genome-wide methylation patterns using whole-genome bisulfite sequencing, together with promastigote and amastigote control lines. Interestingly, despite the DNMT6 presence, we found that methylation levels were equal to or lower than 0.0003% at CpG sites, 0.0005% at CHG sites, and 0.0126% at CHH sites at the genomic scale. As none of the methylated sites were retained after manual verification, we conclude that there is no evidence for DNA methylation in this species. We demonstrated that this difference in DNA methylation between the parasite (no detectable DNA methylation) and the vertebrate host (DNA methylation) allowed enrichment of parasite vs. host DNA using methyl-CpG-binding domain columns, readily available in commercial kits. As such, we depleted methylated DNA from mixes of Leishmania promastigote and amastigote DNA with human DNA, resulting in average Leishmania:human enrichments from 62× up to 263×. These results open a promising avenue for unmethylated DNA enrichment as a pre-enrichment step before sequencing Leishmania clinical samples. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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Review

Jump to: Research

29 pages, 4733 KiB

Open AccessReview

Leishmania 360°: Guidelines for Exosomal Research

by Áurea Martins Gabriel, Adan Galué-Parra, Washington Luiz Assunção Pereira, Ketil Winther Pedersen and Edilene Oliveira da Silva

Microorganisms 2021, 9(10), 2081; https://doi.org/10.3390/microorganisms9102081 - 2 Oct 2021

Cited by 5 | Viewed by 6546

Abstract

Leishmania parasites are a group of kinetoplastid pathogens that cause a variety of clinical disorders while maintaining cell communication by secreting extracellular vesicles. Emerging technologies have been adapted for the study of Leishmania-host cell interactions, to enable the broad-scale analysis of the [...] Read more.

Leishmania parasites are a group of kinetoplastid pathogens that cause a variety of clinical disorders while maintaining cell communication by secreting extracellular vesicles. Emerging technologies have been adapted for the study of Leishmania-host cell interactions, to enable the broad-scale analysis of the extracellular vesicles of this parasite. Leishmania extracellular vesicles (LEVs) are spheroidal nanoparticles of polydispersed suspensions surrounded by a layer of lipid membrane. Although LEVs have attracted increasing attention from researchers, many aspects of their biology remain unclear, including their bioavailability and function in the complex molecular mechanisms of pathogenesis. Given the importance of LEVs in the parasite-host interaction, and in the parasite-parasite relationships that have emerged during the evolutionary history of these organisms, the present review provides an overview of the available data on Leishmania, and formulates guidelines for LEV research. We conclude by reporting direct methods for the isolation of specific LEVs from the culture supernatant of the promastigotes and amastigotes that are suitable for a range of different downstream applications, which increases the compatibility and reproducibility of the approach for the establishment of optimal and comparable isolation conditions and the complete characterization of the LEV, as well as the critical immunomodulatory events triggered by this important group of parasites. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1983 KiB

Open AccessReview

Effects of Visceralising Leishmania on the Spleen, Liver, and Bone Marrow: A Pathophysiological Perspective

by Aikaterini Poulaki, Evangelia-Theophano Piperaki and Michael Voulgarelis

Microorganisms 2021, 9(4), 759; https://doi.org/10.3390/microorganisms9040759 - 5 Apr 2021

Cited by 24 | Viewed by 5453

Abstract

The leishmaniases constitute a group of parasitic diseases caused by species of the protozoan genus Leishmania. In humans it can present different clinical manifestations and are usually classified as cutaneous, mucocutaneous, and visceral (VL). Although the full range of parasite—host interactions remains [...] Read more.

The leishmaniases constitute a group of parasitic diseases caused by species of the protozoan genus Leishmania. In humans it can present different clinical manifestations and are usually classified as cutaneous, mucocutaneous, and visceral (VL). Although the full range of parasite—host interactions remains unclear, recent advances are improving our comprehension of VL pathophysiology. In this review we explore the differences in VL immunobiology between the liver and the spleen, leading to contrasting infection outcomes in the two organs, specifically clearance of the parasite in the liver and failure of the spleen to contain the infection. Based on parasite biology and the mammalian immune response, we describe how hypoxia-inducible factor 1 (HIF1) and the PI3K/Akt pathway function as major determinants of the observed immune failure. We also summarize existing knowledge on pancytopenia in VL, as a direct effect of the parasite on bone marrow health and regenerative capacity. Finally, we speculate on the possible effect that manipulation by the parasite of the PI3K/Akt/HIF1 axis may have on the myelodysplastic (MDS) features observed in VL. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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9 pages, 552 KiB

Open AccessReview

Role of Circulating Immune Complexes in the Pathogenesis of Canine Leishmaniasis: New Players in Vaccine Development

by Cristina Cacheiro-Llaguno, Nuria Parody, Marta R. Escutia and Jerónimo Carnés

Microorganisms 2021, 9(4), 712; https://doi.org/10.3390/microorganisms9040712 - 30 Mar 2021

Cited by 14 | Viewed by 3943

Abstract

During canine visceral leishmaniasis (CanL), due to Leishmania infantum (L. infantum), uncontrolled infection leads to a strong humoral immune response. As a consequence of the production of high antibody levels and the prolonged presence of parasite antigens, circulating immune complexes (CIC) [...] Read more.

During canine visceral leishmaniasis (CanL), due to Leishmania infantum (L. infantum), uncontrolled infection leads to a strong humoral immune response. As a consequence of the production of high antibody levels and the prolonged presence of parasite antigens, circulating immune complexes (CIC) are formed, which can be deposited in certain organs and tissues, inducing vasculitis, uveitis, dermatitis and especially glomerulonephritis and renal failure. A method to detect CIC and quantify their levels in serum samples from dogs infected with L. infantum has been recently described. It allowed demonstration of a correlation between CIC levels and disease severity. Thus, CIC measurement may be useful for diagnosis, assessment of disease progression and monitoring response to treatment. This is an interesting finding, considering that there remains an urgent need for identification of novel biomarkers to achieve a correct diagnosis and for optimal disease staging of dogs suffering from Leishmania infection. The objective of the present review is to shed light on the role of CIC in CanL, as well as to highlight their potential use not only as diagnostic and prognostic biomarkers but also as a valuable tool in vaccine development and new immunotherapy strategies to prevent or control disease outcome. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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22 pages, 1364 KiB

Open AccessReview

Leishmania Protein Kinases: Important Regulators of the Parasite Life Cycle and Molecular Targets for Treating Leishmaniasis

by Antonia Efstathiou and Despina Smirlis

Microorganisms 2021, 9(4), 691; https://doi.org/10.3390/microorganisms9040691 - 27 Mar 2021

Cited by 31 | Viewed by 5860

Abstract

Leishmania is a protozoan parasite of the trypanosomatid family, causing a wide range of diseases with different clinical manifestations including cutaneous, mucocutaneous and visceral leishmaniasis. According to WHO, one billion people are at risk of Leishmania infection as they live in endemic areas [...] Read more.

Leishmania is a protozoan parasite of the trypanosomatid family, causing a wide range of diseases with different clinical manifestations including cutaneous, mucocutaneous and visceral leishmaniasis. According to WHO, one billion people are at risk of Leishmania infection as they live in endemic areas while there are 12 million infected people worldwide. Annually, 0.9–1.6 million new infections are reported and 20–50 thousand deaths occur due to Leishmania infection. As current chemotherapy for treating leishmaniasis exhibits numerous drawbacks and due to the lack of effective human vaccine, there is an urgent need to develop new antileishmanial therapy treatment. To this end, eukaryotic protein kinases can be ideal target candidates for rational drug design against leishmaniasis. Eukaryotic protein kinases mediate signal transduction through protein phosphorylation and their inhibition is anticipated to be disease modifying as they regulate all essential processes for Leishmania viability and completion of the parasitic life cycle including cell-cycle progression, differentiation and virulence. This review highlights existing knowledge concerning the exploitation of Leishmania protein kinases as molecular targets to treat leishmaniasis and the current knowledge of their role in the biology of Leishmania spp. and in the regulation of signalling events that promote parasite survival in the insect vector or the mammalian host. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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23 pages, 608 KiB

Open AccessReview

Leishmaniasis in the United States: Emerging Issues in a Region of Low Endemicity

by John M. Curtin and Naomi E. Aronson

Microorganisms 2021, 9(3), 578; https://doi.org/10.3390/microorganisms9030578 - 11 Mar 2021

Cited by 44 | Viewed by 7015

Abstract

Leishmaniasis, a chronic and persistent intracellular protozoal infection caused by many different species within the genus Leishmania, is an unfamiliar disease to most North American providers. Clinical presentations may include asymptomatic and symptomatic visceral leishmaniasis (so-called Kala-azar), as well as cutaneous or [...] Read more.

Leishmaniasis, a chronic and persistent intracellular protozoal infection caused by many different species within the genus Leishmania, is an unfamiliar disease to most North American providers. Clinical presentations may include asymptomatic and symptomatic visceral leishmaniasis (so-called Kala-azar), as well as cutaneous or mucosal disease. Although cutaneous leishmaniasis (caused by Leishmania mexicana in the United States) is endemic in some southwest states, other causes for concern include reactivation of imported visceral leishmaniasis remotely in time from the initial infection, and the possible long-term complications of chronic inflammation from asymptomatic infection. Climate change, the identification of competent vectors and reservoirs, a highly mobile populace, significant population groups with proven exposure history, HIV, and widespread use of immunosuppressive medications and organ transplant all create the potential for increased frequency of leishmaniasis in the U.S. Together, these factors could contribute to leishmaniasis emerging as a health threat in the U.S., including the possibility of sustained autochthonous spread of newly introduced visceral disease. We summarize recent data examining the epidemiology and major risk factors for acquisition of cutaneous and visceral leishmaniasis, with a special focus on implications for the United States, as well as discuss key emerging issues affecting the management of visceral leishmaniasis. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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15 pages, 1095 KiB

Open AccessReview

Urine-Based Antigen (Protein) Detection Test for the Diagnosis of Visceral Leishmaniasis

by Antonio Campos-Neto and Claudia Abeijon

Microorganisms 2020, 8(11), 1676; https://doi.org/10.3390/microorganisms8111676 - 28 Oct 2020

Cited by 6 | Viewed by 3645

Abstract

This review describes and appraises a novel protein-based antigen detection test for visceral leishmaniasis (VL). The test detects in patient’s urine six proteins from Leishmania infantum (chagasi) and Leishmania donovani, the etiological agents of VL. The gold standard test for VL is [...] Read more.

This review describes and appraises a novel protein-based antigen detection test for visceral leishmaniasis (VL). The test detects in patient’s urine six proteins from Leishmania infantum (chagasi) and Leishmania donovani, the etiological agents of VL. The gold standard test for VL is microscopic observation of the parasites in aspirates from spleen, liver, or bone marrow (and lymph node for dogs). Culture of the parasites or detection of their DNA in these aspirates are also commonly used. Serological tests are available but they cannot distinguish patients with active VL from either healthy subjects exposed to the parasites or from subjects who had a successful VL treatment. An antigen detection test based on the agglutination of anti-leishmania carbohydrates antibody coated latex beads has been described. However, the results obtained with this carbohydrate-based test have been conflicting. Using mass spectrometry, we discovered six L. infantum/L. donovani proteins excreted in the urine of VL patients and used them as markers for the development of a robust mAb-based antigen (protein) detection test. The test is assembled in a multiplexed format to simultaneously detect all six markers. Its initial clinical validation showed a sensitivity of 93% and specificity of 100% for VL diagnosis. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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21 pages, 555 KiB

Open AccessReview

Leishmania Immunity: Advancing Immunotherapy and Vaccine Development

by Nnamdi M. Ikeogu, Gloria N. Akaluka, Chidalu A. Edechi, Enitan S. Salako, Chukwunonso Onyilagha, Aida F. Barazandeh and Jude E. Uzonna

Microorganisms 2020, 8(8), 1201; https://doi.org/10.3390/microorganisms8081201 - 7 Aug 2020

Cited by 51 | Viewed by 9751

Abstract

Parasitic diseases still constitute a major global health problem affecting billions of people around the world. These diseases are capable of becoming chronic and result in high morbidity and mortality. Worldwide, millions of people die each year from parasitic diseases, with the bulk [...] Read more.

Parasitic diseases still constitute a major global health problem affecting billions of people around the world. These diseases are capable of becoming chronic and result in high morbidity and mortality. Worldwide, millions of people die each year from parasitic diseases, with the bulk of those deaths resulting from parasitic protozoan infections. Leishmaniasis, which is a disease caused by over 20 species of the protozoan parasite belonging to the genus Leishmania, is an important neglected disease. According to the World Health Organization (WHO), an estimated 12 million people are currently infected in about 98 countries and about 2 million new cases occur yearly, resulting in about 50,000 deaths each year. Current treatment methods for leishmaniasis are not very effective and often have significant side effects. In this review, we discussed host immunity to leishmaniasis, various treatment options currently being utilized, and the progress of both immunotherapy and vaccine development strategies used so far in leishmaniasis. We concluded with insights into what the future holds toward the fight against this debilitating parasitic disease. Full article

(This article belongs to the Special Issue Leishmania and Leishmaniasis)

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