Correlation between presence of Leishmania RNA virus 1 and clinical characteristics of nasal mucosal leishmaniosis

Ito, Marcos Massayuki; Catanhêde, Lilian Motta; Katsuragawa, Tony Hiroshi; Silva, Cipriano Ferreira da; Camargo, Luís Marcelo Aranha; Mattos, Ricardo de Godoi; Vilallobos-Salcedo, Juan Miguel

doi:10.1016/j.bjorl.2015.07.014

Cited by 41 publications

(58 citation statements)

References 29 publications

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“…Our studies extend the generality of LRV1-dependent virulence to Lbr because LRV1 + Lbr likewise induces strong TLR3-dependent cytokine responses. These findings are especially important in light of published work on the association of LRV1 with MCL, with mixed results depending on the geographic region and methods used (6,(16)(17)(18)(19). Our data show that, in in vitro infections, LRV1 contributes strongly to the proinflammatory phenotype associated with elevated pathogenicity, as seen in Lgy, which suggests that, in human infections, it may be informative to seek for correlations between LRV1 and the severity of CL in Lbr infections.…”

Section: Discussionmentioning

confidence: 61%

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Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

Brettmann

Shaik

Zangger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Many Leishmania (Viannia) parasites harbor the double-stranded RNA virus Leishmania RNA virus 1 (LRV1), which has been associated with increased disease severity in animal models and humans and with drug treatment failures in humans. Remarkably, LRV1 survives in the presence of an active RNAi pathway, which in many organisms controls RNA viruses. We found significant levels (0.4 to 2.5%) of small RNAs derived from LRV1 in both Leishmania braziliensis and Leishmania guyanensis, mapping across both strands and with properties consistent with Dicer-mediated cleavage of the dsRNA genome. LRV1 lacks cis-or trans-acting RNAi inhibitory activities, suggesting that virus retention must be maintained by a balance between RNAi activity and LRV1 replication. To tilt this balance toward elimination, we targeted LRV1 using long-hairpin/stem-loop constructs similar to those effective against chromosomal genes. LRV1 was completely eliminated, at high efficiency, accompanied by a massive overproduction of LRV1-specific siRNAs, representing as much as 87% of the total. For both L. braziliensis and L. guyanensis, RNAi-derived LRV1-negative lines were no longer able to induce a Tolllike receptor 3-dependent hyperinflammatory cytokine response in infected macrophages. We demonstrate in vitro a role for LRV1 in virulence of L. braziliensis, the Leishmania species responsible for the vast majority of mucocutaneous leishmaniasis cases. These findings establish a targeted method for elimination of LRV1, and potentially of other Leishmania viruses, which will facilitate mechanistic dissection of the role of LRV1-mediated virulence. Moreover, our data establish a third paradigm for RNAi-viral relationships in evolution: one of balance rather than elimination.dsRNA virus | protozoan parasite | endosymbiont | trypanosomatid protozoa | microbial pathogenesis

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Section: Discussionmentioning

confidence: 61%

“…Although in some studies LRV1 was not correlated with MCL (16,17), in others there was a strong association (6,18,19). Recent studies show that LRV1 in Lbr and Lgy clinical isolates correlates with drug treatment failure (16,20).…”

Section: Significancementioning

confidence: 99%

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

Brettmann

Shaik

Zangger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…There are now ample data suggesting that LRV1 contributes to the severity in human leishmaniasis (6,13,17,19,20,55), suggesting that anti-LRV1 inhibitors could be clinically useful, alone or in conjunction with existing antileishmanials. Unfortunately, pharmacokinetic studies of the two compounds studied here in mammals suggest that neither of these are good candidates for testing of this hypothesis just yet, as the concentration needed for LRV1 elimination (10 μM) is above the maximum achievable serum concentration in various mammalian models, typically less than 1 μM (38,49,56).…”

Section: Antiviral Cures and The Generation Of Isogenic Lrv1mentioning

confidence: 99%

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNALeishmaniaRNA virus 1 (LRV1) pathogenicity factor

Kuhlmann

Robinson

Bluemling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2′-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1 + and LRV1 − lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-ofprinciple in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1-mediated virulence.trypanosomatid protozoan parasite | endobiont virus | viral segregation | chemotherapy | virulence

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“…A related species LRV2 is found in smaller fraction of isolates of L. aethiopica and L. major [11–12]. A significant percentage of L. braziliensis and L. guyanensis bear LRV1 45% up to 74.4 % [13–15]. Phylogenetic studies suggest that Leishmania /virus association is likely to be very ancient, since the phylogeny of LRVs closely parallels that of their host Leishmania [7,16].…”

mentioning

confidence: 99%

Low frequency of LRV1 in Leishmania braziliensis strains isolated from typical and atypical lesions in the State of Minas Gerais, Brazil

Macedo

Menezes-Neto

Rugani

et al. 2016

Molecular and Biochemical Parasitology

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The double stranded RNA (dsRNA) virus Leishmaniavirus (Totiviridae) was first described in Leishmania guyanensis and L. braziliensis (LRV1), and more recently from L. major and L. aethiopica (LRV2). Parasites bearing LRV1 elicit a higher pro-inflammatory profile, arising through activation of Toll like receptor 3 (TLR3) interacting with the viral dsRNA. LRV1 is most common in Leishmania from the Amazon region; however data for other regions of Brazil are more limited. Here we applied PCR tests with validated ‘universal’ LRV1 primers to search for LRV1 in 40 strains of cultured L. braziliensis from several locales within Minas Gerais State, including patients presenting with atypical lesion pathology. All strains were negative however. These data are in agreement with results from other areas of Southeastern Brazil that LRV1 is relatively uncommon.

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Correlation between presence of Leishmania RNA virus 1 and clinical characteristics of nasal mucosal leishmaniosis

Abstract: Correlation between clinical phenotype and presence of LRV1 was not observed, although the frequency of the virus is two-fold higher in mucosal lesions than that found in the literature on skin lesions in the same geographical area.

Cited by 41 publications

References 29 publications

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNALeishmaniaRNA virus 1 (LRV1) pathogenicity factor

Low frequency of LRV1 in Leishmania braziliensis strains isolated from typical and atypical lesions in the State of Minas Gerais, Brazil

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