How to master the host immune system?<i>Leishmania</i>parasites have the solutions!

Rossi, Matteo A. C.; Fasel, Nicolás

doi:10.1093/intimm/dxx075

Cited by 185 publications

(165 citation statements)

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“…Strain comparisons within and between countries are, however, complicated by the large number of methods and sequences used, and there is a clear need for unification and standardization of molecular markers for a better understanding of Leishmania epidemiology (Akhoundi et al, 2017;van der Auwera & Dujardin, 2015;Schönian, Kuhls, & Mauricio, 2010). There is little evidence so far for a strong association between L. infantum infection in humans with specific variants and certain clinical forms, partly because the tropism of this species for the skin or for multiple internal organs (i.e., cutaneous/visceral forms) is mostly influenced by the host immune response (Alvar, 1994;Gradoni & Gramiccia, 1994;Rossi & Fasel, 2018 I II I II III IV I II III I II III IV V I II III New pattern discovered in this study for RsaI enzyme, named III, as this name for RsaI enzyme has not been previously used.…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity and phylogenetic relationships between Leishmania infantum from dogs, humans and wildlife in south‐east Spain

Ortuño

Latrofa

Iborra

et al. 2019

Zoonoses and Public Health

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Leishmania infantum causes human and canine leishmaniosis. The parasite, transmitted by phlebotomine sand flies, infects species other than dogs and people, including wildlife, although their role as reservoirs of infection remains unknown for most species. Molecular typing of parasites to investigate genetic variability and evolutionary proximity can help understand transmission cycles and designing control strategies. We investigated Leishmania DNA variability in kinetoplast (kDNA) and internal transcribed spacer 2 (ITS2) sequences in asymptomatically infected wildlife (n = 58) and symptomatically and asymptomatically infected humans (n = 38) and dogs (n = 15) from south‐east Spain, using single nucleotide polymorphisms (SNPs) and in silico restriction fragment length polymorphism (RFLP) analyses. All ITS2 sequences (n = 76) displayed a 99%–100% nucleotide identity with a L. infantum reference sequence, except one with a 98% identity to a reference Leishmania panamensis sequence, from an Ecuadorian patient. No heterogeneity was recorded in the 73 L. infantum ITS2 sequences except for one SNP in a human parasite sequence. In contrast, kDNA analysis of 44 L. infantum sequences revealed 11 SNP genotypes (nucleotide variability up to 4.3%) and four RFLP genotypes including B, F and newly described S and T genotypes. Genotype frequency was significantly greater in symptomatic compared to asymptomatic individuals. Both methods similarly grouped parasites as predominantly or exclusively found in humans, in dogs, in wildlife or in all three of them. Accordingly, the phylogenetic analysis of kDNA sequences revealed three main clusters, two as a paraphyletic human parasites clade and a third including dogs, people and wildlife parasites. Results suggest that Leishmania infantum genetics is complex even in small geographical areas and that, probably, several independent transmission cycles take place simultaneously including some connecting animals and humans. Investigating these transmission networks may be useful in understanding the transmission dynamics, infection risk and therefore in planning L. infantum control strategies.

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Section: Discussionmentioning

confidence: 99%

Genetic diversity and phylogenetic relationships between Leishmania infantum from dogs, humans and wildlife in south‐east Spain

Ortuño

Latrofa

Iborra

et al. 2019

Zoonoses and Public Health

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“…Macrophages produce IL-12 to promote a Th1 response during leishmanial infection, which protects the host and controls parasite replication [30,31]. Meanwhile, TNF-α and IFN-γ, implicated to be involved in the activation of macrophages, were also observed to play a role in preventing parasite replication [32]. Previous studies also verified that drugs which have inhibitory effects on L. donovani, could decrease IL-10 and IL-4 in VL mice [4,33,34].…”

Section: Discussionmentioning

confidence: 97%

Evaluation of in vitro antileishmanial efficacy of cyclosporin A and its non-immunosuppressive derivative, dihydrocyclosporin A

Zheng

Chen

et al. 2020

Parasites Vectors

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Background: New therapeutic drugs are urgently needed against visceral leishmaniasis because current drugs, such as pentavalent antimonials and miltefosine, produce severe side effects and development of resistance. Whether cyclosporine A (CsA) and its derivatives can be used as therapeutic drugs for visceral leishmaniasis has been controversial for many years. Methods:In this study, we evaluated the efficacy of CsA and its derivative, dihydrocyclosporin A (DHCsA-d), against promastigotes and intracellular amastigotes of Leishmania donovani. Sodium stibogluconate (SSG) was used as a positive control. Results:Our results showed that DHCsA-d was able to inhibit the proliferation of L. donovani promastigotes (IC 50 : 21.24 μM and 12.14 μM at 24 h and 48 h, respectively) and intracellular amastigotes (IC 50 : 5.23 μM and 4.84 μM at 24 and 48 h, respectively) in vitro, but CsA treatment increased the number of amastigotes in host cells. Both DHCsA-d and CsA caused several alterations in the morphology and ultrastructure of L. donovani, especially in the mitochondria. However, DHCsA-d showed high cytotoxicity towards cells of the mouse macrophage cell line RAW264.7, with CC50 values of 7.98 μM (24 h) and 6.65 μM (48 h). Moreover, DHCsA-d could increase IL-12, TNF-α and IFN-γ production and decrease the levels of IL-10, IL-4, NO and H 2 O 2 in infected macrophages. On the contrary, CsA decreased IL-12, TNF-α, and IFN-γ production and increased the levels of IL-10, IL-4, NO and H 2 O 2 in infected macrophages. The expression of L. donovani cyclophilin A (LdCyPA) in promastigotes and intracellular amastigotes and the expression of cyclophilin A (CyPA) in RAW 264.7 cells were found to be significantly downregulated in the CsA-treated group compared to those in the untreated group. However, no significant changes in LdCyPA and CyPA levels were found after DHCsA-d or SSG treatment. Conclusions:Our findings initially resolved the dispute regarding the efficacy of CsA and DHCsA-d for visceral leishmaniasis treatment. CsA showed no significant inhibitory effect on intracellular amastigotes. DHCsA-d significantly inhibited promastigotes and intracellular amastigotes, but it was highly cytotoxic. Therefore, CsA and DHCsA-d are not recommended as antileishmanial drugs.

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“…A first set of assays showed that Asaia WSP indeed activates an antibacterial response in macrophages, on both Asaia itself and on S. epidermidis . The study was then focused on Leishmania , an intracellular parasite that targets monocytes and macrophages (Antoniou et al, 2013;Rossi & Fasel, 2018). The experiments were realized using a macrophage cell line derived from a Leishmania -susceptible mice strain.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, a M2 response is associated with anti-inflammatory cytokine production, such as IL-4/IL-13, IL-10, TGFβ, M-CSF, expression of arginase I (with reduced NO production), inhibition of inflammation, parasite survival, and thus disease progression. In summary, while M1 activation is crucial for a successful elimination of Leishmania parasites, the M2 polarization, besides being unprotective, is in general associated with disease severity, also in relation with immune-complex pathology (Rossi & Fasel 2018). Therefore, one of the major aims in leishmaniasis research is the identification of molecules with immunotherapeutic properties, i.e.…”

Section: Introductionmentioning

confidence: 99%

Boosting innate immunity:Asaiabacteria expressing a protein fromWolbachiadetermine macrophage activation and killing ofLeishmania

Varotto-Boccazzi

Epis

Arnoldi

et al. 2020

Preprint

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AbstractLeishmaniases are severe vector-borne diseases affecting humans and animals, caused by Leishmania protozoans. Immune polarization plays a major role in determining the outcome of Leishmania infections: hosts displaying M1-polarized macrophages are protected, while those biased on the M2 side acquire a chronic infection, that could develop into an overt and potentially deadly disease. The identification of the factors involved in M1 polarization is essential for the design of therapeutic and prophylactic interventions, including vaccines. Infection by the filarial nematode Dirofilaria immitis could be one of the factors that interfere with leishmaniasis in dogs. Indeed, filarial nematodes induce a partial skew of the immune response towards M1, likely caused by their bacterial endosymbionts, Wolbachia. Here we have examined the potential of AsaiaWSP, a bacterium engineered for the expression of the Wolbachia surface protein (WSP), as an inductor of M1 macrophage activation and Leishmania killing. Macrophages stimulated with AsaiaWSP displayed a strong leishmanicidal activity, comparable to that determined by the choice-drug amphotericin B. Additionally, AsaiaWSP determined the expression of markers of classical macrophage activation, including M1 cytokines, ROS and NO, and an increase in phagocytosis activity. Asaia not expressing WSP also induced macrophage activation, although at a lower extent compared to AsaiaWSP. In summary, our study, while providing a strong evidence for the immune-stimulating properties of Wolbachia, highlights the translational potential of AsaiaWSP in the areas of the immune-prophylaxis and therapy of leishmaniases, as well as of other diseases that could be subverted by M1 macrophage activation.

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How to master the host immune system?Leishmaniaparasites have the solutions!

Abstract: Host immune response to Leishmania parasites

Cited by 185 publications

References 100 publications

Genetic diversity and phylogenetic relationships between Leishmania infantum from dogs, humans and wildlife in south‐east Spain

Genetic diversity and phylogenetic relationships between Leishmania infantum from dogs, humans and wildlife in south‐east Spain

Evaluation of in vitro antileishmanial efficacy of cyclosporin A and its non-immunosuppressive derivative, dihydrocyclosporin A

Boosting innate immunity:Asaiabacteria expressing a protein fromWolbachiadetermine macrophage activation and killing ofLeishmania

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