Arthritogenic Alphaviruses: A Worldwide Emerging Threat?

Levi, Laura; Vignuzzi, Marco

doi:10.3390/microorganisms7050133

Cited by 65 publications

(67 citation statements)

References 247 publications

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“…While the general features of structure and lifecycle are shared, alphaviruses can differ in properties such as receptor usage, tissue tropism, and pathogenesis. Within the Semliki Forest virus (SFV) complex, CHIKV and RRV cause severe polyarthritis and have emerged to produce epidemics that affect millions of people globally [3][4][5] . To date, there are no specific antiviral treatments or licensed vaccines for any alphavirus.…”

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confidence: 99%

Multiple capsid protein binding sites mediate selective packaging of the alphavirus genomic RNA

et al. 2020

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The alphavirus capsid protein (Cp) selectively packages genomic RNA (gRNA) into the viral nucleocapsid to produce infectious virus. Using photoactivatable ribonucleoside crosslinking and an innovative biotinylated Cp retrieval method, here we comprehensively define binding sites for Semliki Forest virus (SFV) Cp on the gRNA. While data in infected cells demonstrate Cp binding to the proposed genome packaging signal (PS), mutagenesis experiments show that PS is not required for production of infectious SFV or Chikungunya virus. Instead, we identify multiple Cp binding sites that are enriched on gRNA-specific regions and promote infectious SFV production and gRNA packaging. Comparisons of binding sites in cytoplasmic vs. viral nucleocapsids demonstrate that budding causes discrete changes in Cp-gRNA interactions. Notably, Cp’s top binding site is maintained throughout virus assembly, and specifically binds and assembles with Cp into core-like particles in vitro. Together our data suggest a model for selective alphavirus genome recognition and assembly.

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confidence: 99%

Multiple capsid protein binding sites mediate selective packaging of the alphavirus genomic RNA

et al. 2020

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“…SINV belongs to the alphavirus genus which includes viruses already emerged or with the potential to emerge as important human pathogens (8). Interestingly, as the alphavirus genome mimics the host messenger RNA and its replication takes place in the cytoplasm, the incoming viral RNA has the potential to directly interact with cellular miRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…CHIKV has also been reported to affect the human nervous system causing encephalopathy in newborns, infants and adults (6). Due to its ability to quickly spread into new regions, CHIKV is classified as an emergent virus (7,8), for which preventive or curative antiviral strategies are needed.…”

Section: Introductionmentioning

confidence: 99%

High-throughput fluorescence-based screen identifies the neuronal microRNA miR-124 as a positive regulator of alphavirus infection

Lopez

Girardi

Mounce

et al. 2019

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Micro (mi)RNAs are small regulatory RNAs, which act as guide for the RISC complex to modulate the expression of target genes. In addition to their role in maintaining essential physiological functions in the cell, miRNAs can also regulate viral infections. They can do so directly by targeting RNAs of viral origin or indirectly by targeting RNAs from the host and this can result in a positive or negative outcome for the virus. Here, we performed a miRNA genome-wide screen in order to identify cellular miRNAs involved in the regulation of arbovirus infection in human cells. We identified sixteen miRNAs showing a positive effect on the virus, among which a number of neuron-specific ones such as miR-124. We confirmed that overexpression of miR-124 increases Sindbis virus (SINV) viral production and that this effect is mediated by its seed sequence. We further demonstrated that the SINV genome possesses a binding site for miR-124-3p. Both inhibition of miR-124-3p or silent mutations to disrupt this binding site in the viral RNA abolished the positive regulation. We also proved that miR-124 inhibition reduces SINV infection in human differentiated neuronal cells. Finally, we showed that the proviral effect of miR-124 is conserved for other medically relevant alphaviruses. Indeed, inhibition of miR-124 expression reduces chikungunya virus (CHIKV) viral production in human cells. Altogether, our work expands the panel of positive regulation of the viral cycle by direct binding of host miRNAs to the viral RNA and provides new insights into the role of cellular miRNAs as regulators of alphavirus infection. SIGNIFICANCE STATEMENTArthropod-borne (arbo) viruses are part of a class of pathogens that are transmitted to their final hosts by insects. Because of climate change, the habitat of some of these insects, such as mosquitoes, is shifting, thereby facilitating the emergence of viral epidemics. Among the pathologies associated with arboviruses infection, neurological diseases like meningitis or encephalitis represent a significant health burden. Using a genome-wide miRNA screen, we identified the neuronal miR-124 as a positive regulator of the Sindbis and chikungunya alphaviruses. We also showed that this effect was in part direct, thereby opening novel avenues to treat alphaviruses infection.

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“…Vector-borne infections are also affected by climate change. Large-scale outbreaks were first described for Monkeypox virus in central Africa in the 1970s [117], while outbreaks of mosquitoborne Chikungunya virus [85] and Dengue virus infections in the Indian Ocean islands were seen mostly in the twentyfirst century [124]. The historic Ebola outbreak in West Africa in 2013-2014, followed by a more recent one in the Republic of Congo with 1891 fatalities [37], has attracted extensive media attention.…”

Section: Public Health Relevancementioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

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The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Arthritogenic Alphaviruses: A Worldwide Emerging Threat?

Cited by 65 publications

References 247 publications

Multiple capsid protein binding sites mediate selective packaging of the alphavirus genomic RNA

Multiple capsid protein binding sites mediate selective packaging of the alphavirus genomic RNA

High-throughput fluorescence-based screen identifies the neuronal microRNA miR-124 as a positive regulator of alphavirus infection

Antivirals in medical biodefense

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