MicroRNA-based control of tick-borne flavivirus neuropathogenesis: Challenges and perspectives

Teterina, Natalya L.; Maximova, Olga A.; Kenney, Heather; Liu, Guangping; Pletnev, Alexander G.

doi:10.1016/j.antiviral.2016.01.003

Cited by 13 publications

(24 citation statements)

References 43 publications

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“…To address this, first we modified 2×511(T) to increase miRNA target stability and prevent formation of escape mutants under miRNA-mediated selective pressure (S3 Fig). Previously, we showed that insertion of multiple copies of miRNA targets into distant regions of flavivirus genome minimizes the probability of formation of escape mutants, which may be capable of infecting cells expressing these miRNAs [47][48][49]. Correspondingly, we introduced duplicated capsid gene region (dCGR) into genome of 2×511(T) virus and inserted two additional target sequences for mir-511-3p between two copies of capsid protein gene, generating C/3'NCR-511(T) virus (Fig 6A and S6 Fig).…”

Section: Targeting Multiple Regions Of Zikv Genome For Mir-511-3p Inhmentioning

confidence: 99%

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

et al. 2020

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Sexual transmission and persistence of Zika virus (ZIKV) in the testes pose new challenges for controlling virus outbreaks and developing live-attenuated vaccines. It has been shown that testicular infection of ZIKV is initiated in the testicular interstitium, followed by spread of the virus in the seminiferous tubules. This leads to testicular damage and/or viral dissemination into the epididymis and eventually into semen. However, it remains unknown which cell types are targeted by ZIKV in the testicular interstitium, and what is the specific order of infectious events leading to ZIKV invasion of the seminiferous tubules. Here, we demonstrate that interstitial leukocytes expressing mir-511-3p microRNA are the initial targets of ZIKV in the testes, and infection of mir-511-3p-expressing cells in the testicular interstitium is necessary for downstream infection of the seminiferous tubules. Mir-511-3p is expressed concurrently with CD206, a marker of lineage 2 (M2) macrophages and monocyte derived dendritic cells (moDCs). Selective restriction of ZIKV infection of CD206-expressing M2 macrophages/moDCs results in the attenuation of macrophage-associated inflammatory responses in vivo and prevents the disruption of the Sertoli cell barrier in vitro. Finally, we show that targeting of viral genome for mir-511-3p significantly attenuates early ZIKV replication not only in the testes, but also in many peripheral organs, including spleen, epididymis, and pancreas. This incriminates M2 macrophages/moDCs as important targets for visceral ZIKV replication following hematogenous dissemination of the virus from the site of infection.

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Section: Targeting Multiple Regions Of Zikv Genome For Mir-511-3p Inhmentioning

confidence: 99%

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

et al. 2020

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“…The available data on abundant host microRNAs (116,117) enable the design of target sites along with various virus genomes specific for host microRNAs (118,119). One major disadvantage of virus attenuation by this strategy is the instability of the target miRNA sequence in the modified genome, which can result in a reversion of the virus to the virulent phenotype, although several results on counterstrategies were reported (120)(121)(122). Other approaches offer replication-defective, chimeric vaccines, in which parts of the TBFV genome are replaced by homologous genomic regions derived from a heterologous (e.g., mosquito-borne) flavivirus.…”

Section: Prevention Control and Treatmentmentioning

confidence: 99%

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

2018

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SUMMARYThe tick-borne pathogen Powassan virus is a rare cause of encephalitis in North America and the Russian Far East. The number of documented cases described since the discovery of Powassan virus in 1958 may be <150, although detection of cases has increased over the past decade. In the United States, the incidence of Powassan virus infections expanded from the estimated 1 case per year prior to 2005 to 10 cases per year during the subsequent decade. The increased detection rate may be associated with several factors, including enhanced surveillance, the availability of improved laboratory diagnostic methods, the expansion of the vector population, and, perhaps, altered human activities that lead to more exposure. Nonetheless, it remains unclear whether Powassan virus is indeed an emerging threat or if enzootic cycles in nature remain more-or-less stable with periodic fluctuations of host and vector population sizes. Despite the low disease incidence, the approximately 10% to 15% case fatality rate of neuroinvasive Powassan virus infection and the temporary or prolonged sequelae in >50% of survivors make Powassan virus a medical concern requiring the attention of public health authorities and clinicians. The medical importance of Powassan virus justifies more research on developing specific and effective treatments and prevention and control measures.

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“…Isolated in 1950s from ixodid ticks in Malaysia 16 , this virus did not appear to be associated with human diseases and, unlike most members of TBEV complex, requires only biosafety level 2 biocontainment. Moreover, LGTV is being considered as a genetic platform for development of live attenuated vaccines against neurotropic tick-borne flaviviruses 17 18 19 , underscoring relevance of the virus for vaccine research.…”

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confidence: 99%

Concurrent micro-RNA mediated silencing of tick-borne flavivirus replication in tick vector and in the brain of vertebrate host

Tsetsarkin

Liu

Kenney

et al. 2016

Sci Rep

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Tick-borne viruses include medically important zoonotic pathogens that can cause life-threatening diseases. Unlike mosquito-borne viruses, whose impact can be restrained via mosquito population control programs, for tick-borne viruses only vaccination remains the reliable means of disease prevention. For live vaccine viruses a concern exists, that spillovers from viremic vaccinees could result in introduction of genetically modified viruses into sustainable tick-vertebrate host transmission cycle in nature. To restrict tick-borne flavivirus (Langat virus, LGTV) vector tropism, we inserted target sequences for tick-specific microRNAs (mir-1, mir-275 and mir-279) individually or in combination into several distant regions of LGTV genome. This caused selective attenuation of viral replication in tick-derived cells. LGTV expressing combinations of target sequences for tick- and vertebrate CNS-specific miRNAs were developed. The resulting viruses replicated efficiently and remained stable in simian Vero cells, which do not express these miRNAs, however were severely restricted to replicate in tick-derived cells. In addition, simultaneous dual miRNA targeting led to silencing of virus replication in live Ixodes ricinus ticks and abolished virus neurotropism in highly permissive newborn mice. The concurrent restriction of adverse replication events in vertebrate and invertebrate hosts will, therefore, ensure the environmental safety of live tick-borne virus vaccine candidates.

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MicroRNA-based control of tick-borne flavivirus neuropathogenesis: Challenges and perspectives

Cited by 13 publications

References 43 publications

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

Concurrent micro-RNA mediated silencing of tick-borne flavivirus replication in tick vector and in the brain of vertebrate host

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