Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.

Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term 'programmable antivirals', with implications for antiviral prophylaxis and post-exposure therapy.

Impact of Low-level Ionizing Radiation on Cell Death During Zebrafish Embryonic Development.

Ionizing radiation (IR) has been linked to multiple types of cellular responses, but its effects on developing organisms are still poorly understood. The authors investigated whether zebrafish embryos exhibit differential responses relative to IR dose and developmental age at time of exposure. Early-stage zebrafish embryos were exposed to different levels of gamma radiation and then, at varying points after irradiation, assayed for morphological defects and levels of cell death. To quantify in vivo cellular responses to low-dose IR exposure and explore how tissue-specific cell functions affect radiation response, apoptotic cells were counted in three regions: the tail, urogenital papilla, and left eye. The authors found that increased gamma radiation doses correlated with increased levels of apoptosis in the developing tail and eye, whereas cells of the urogenital papilla appeared to undergo apoptosis independently of radiation dose. This suggests that the linear-no-threshold model may not be appropriate in all contexts. Grouping embryos by age at IR exposure revealed that gamma radiation exposure resulted in higher levels of apoptosis in embryos irradiated at 2 d post fertilization (dpf), suggesting a radiosensitive stage of development. Moreover, levels of apoptosis were statistically influenced by days grown after irradiation, with embryos fixed at later stages showing more dramatic apoptotic responses to radiation exposure. This latency to effect suggests potential competition between DNA repair and apoptosis pathways, which may lead to the accumulation of apoptotic cells only after an initial lag period.

Potential mechanisms of Zika-linked microcephaly.

A recent outbreak of Zika virus (ZIKV) in Brazil is associated with microcephaly in infants born of infected mothers. As this pandemic spreads, rapid scientific investigation is shedding new light on how prenatal infection with ZIKV causes microcephaly. In this analysis we provide an overview of both microcephaly and ZIKV, explore the connection between prenatal ZIKV infection and microcephaly, and highlight recent insights into how prenatal ZIKV infection depletes the pool of neural progenitors in the developing brain. WIREs Dev Biol 2017, 6:e273. doi: 10.1002/wdev.273 For further resources related to this article, please visit the WIREs website.

PerC Manipulates Metabolism and Surface Antigens in Enteropathogenic Escherichia coli.

Enteropathogenic Escherichia coli is an important cause of profuse, watery diarrhea in infants living in developing regions of the world. Typical strains of EPEC (tEPEC) possess a virulence plasmid, while related clinical isolates that lack the pEAF plasmid are termed atypical EPEC (aEPEC). tEPEC and aEPEC tend to cause acute vs. more chronic type infections, respectively. The pEAF plasmid encodes an attachment factor as well as a regulatory operon, perABC. PerC, a poorly understood regulator, was previously shown to regulate expression of the type III secretion system through Ler. Here we elucidate the regulon of PerC using RNA sequencing analysis to better our understanding of the role of the pEAF in tEPEC infection. We demonstrate that PerC controls anaerobic metabolism by increasing expression of genes necessary for nitrate reduction. A tEPEC strain overexpressing PerC exhibited a growth advantage compared to a strain lacking this regulator, when grown anaerobically in the presence of nitrate, conditions mimicking the human intestine. We show that PerC strongly down-regulates type I fimbriae expression by manipulating fim phase variation. The quantities of a number of non-coding RNA molecules were altered by PerC. In sum, this protein controls niche adaptation, and could help to explain the function of the PerC homologs (Pch), many of which are encoded within prophages in related, Gram-negative pathogens.