Endobiont Viruses Sensed by the Human Host – Beyond Conventional Antiparasitic Therapy

Fichorova, Raina N.; Lee, Yujin; Yamamoto, Hidemi S.; Takagi, Yuko; Hayes, Gary R.; Goodman, Rachel; Chepa-Lotrea, Xenia; Buck, Olivia R.; Murray, R J; Kula, Tomasz; Beach, David; Singh, Bibhuti N.; Nibert, Max L.

doi:10.1371/journal.pone.0048418

Cited by 115 publications

(148 citation statements)

References 64 publications

(110 reference statements)

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“…Thus, although other parasite or host factors may play a significant role in the development of MCL (21,22), current data support a role for LRV1 in exacerbating the pathogenesis of human leishmaniasis caused by Lbr and Lgy. A similar role in pathogenicity has been proposed for the Trichomonas vaginalis totiviruses (23). In contrast, endobiont viruses in other systems more often impair the host or have no known effect on disease.…”

Section: Significancesupporting

confidence: 55%

Tilting the balance between RNA interference and replication eradicates Leishmania RNA 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: Significancesupporting

confidence: 55%

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

Brettmann

Shaik

Zangger

et al. 2016

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

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“…Some constitute important agricultural pathogens and rotaviruses (Reoviridae) cause serious human disease. For protozoan viruses, their role in the exacerbation of human disease is only now beginning to be appreciated (6,29). Because viral elements are critical factors acting to exacerbate the disease where studied, candidate anti-LRV1 agents should be viewed as "antipathogenicity" treatments rather than sterilizing cures (30), which could be used alone or more likely in combination with existing antileishmanial agents in the treatment of ongoing infection.…”

Section: Significancementioning

confidence: 99%

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA 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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“…Furthermore, some T. vaginalis strains are infected by a dsRNA virus from the genus Trichomonasvirus, named TVV [32]. The presence of TVV and M. hominis may affect the pathogenicity of the parasite [33,34].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Trichomonas vaginalis in women of reproductive age at a family health clinic

Glehn

Sá

Silva

et al. 2017

J Infect Dev Ctries

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Introduction: Trichomonas vaginalis is considered the most prevalent curable sexually transmitted infection, and its occurrence exceeds that of gonococcal and chlamydia infections. This parasite has been identified as responsible for the increased risk of transmission of HIV and has also been associated with prostate and cervical cancer. Many carriers of T. vaginalis are asymptomatic and, when experiencing a health problem, they most often have nonspecific symptoms. The aim of this research was to estimate the presence of T. vaginalis and the associated factors in women of childbearing age at a primary health care clinic in the Federal District of Brazil. Methodology: A cross-sectional study was conducted with consecutive sampling of an outpatient population of women of childbearing age (excluding minors and pregnant women). The women answered a questionnaire and were examined. After vaginal pH measurement and whiff testing, a vaginal secretion sample was obtained for inoculation in TYM, a specific T. vaginalis culture medium. Results: The presence of T. vaginalis was identified in 16% of the sample. Fewer lifetime sexual partners and consistent condom use were identified as factors of protection against the infection. Complaints of dyspareunia were proportionally higher among women with positive cultures for T. vaginalis. Conclusions: The prevalence of T. vaginalis infection was high in the sample studied. The infection was positively associated with the number of lifetime sexual partners, and consistent condom use was a protective factor. Vaginal complaints were more common among women with T. vaginalis, but only dyspareunia had significant association.

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Endobiont Viruses Sensed by the Human Host – Beyond Conventional Antiparasitic Therapy

Cited by 115 publications

References 64 publications

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

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

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor

Prevalence of Trichomonas vaginalis in women of reproductive age at a family health clinic

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