Evolutionary Conservation of the PA-X Open Reading Frame in Segment 3 of Influenza A Virus

PA-X is a fusion protein of influenza A virus encoded in part from a +1 frameshifted X open reading frame (X-ORF) in segment 3. We show that the X-ORFs of diverse influenza A viruses can be divided into two groups that differ in selection pressure and likely function, reflected in the presence of an internal stop codon and a change in synonymous diversity. Notably, truncated forms of PA-X evolved convergently in swine and dogs, suggesting a strong species-specific effect

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding

AbstractPandemic influenza viral infections have been associated with viral pneumonia. Chimeric influenza viruses with the hemagglutinin segment of the 1918, 1957, 1968, or 2009 pandemic influenza viruses in the context of a seasonal H1N1 influenza genome were constructed to analyze the role of hemagglutinin (HA) in pathogenesis and cell tropism in a mouse model. We also explored whether there was an association between the ability of lung surfactant protein D (SP-D) to bind to the HA and the ability of the corresponding chimeric virus to infect bronchiolar and alveolar epithelial cells of the lower respiratory tract. Viruses expressing the hemagglutinin of pandemic viruses were associated with significant pathology in the lower respiratory tract, including acute inflammation, and showed low binding activity for SP-D. In contrast, the virus expressing the HA of a seasonal influenza strain induced only mild disease with little lung pathology in infected mice and exhibited strong in vitro binding to SP-D

Ocean warming favours a northern Argyrosomus species over its southern congener, whereas preliminary metabolic evidence suggests that hybridization may promote their adaptation

DATA AVAILABILITY : The data underlying this article are available in the article and in its online supplementary material.Anthropogenic-induced climate change is having profound impacts on aquatic ecosystems, and the resilience of fish populations will be determined by their response to these impacts. The northern Namibian coast is an ocean warming hotspot, with temperatures rising faster than the global average. The rapid warming in Namibia has had considerable impacts on marine fauna, such as the southern extension of the distribution of Argyrosomus coronus from southern Angola into northern Namibian waters, where it now overlaps and hybridizes with the closely related Namibian species, A. inodorus. Understanding how these species (and their hybrids) perform at current and future temperatures is vital to optimize adaptive management for Argyrosomus species. Intermittent flow-through respirometry was used to quantify standard and maximum metabolic rates for Argyrosomus individuals across a range of temperatures. The modelled aerobic scope (AS) of A. inodorus was notably higher at cooler temperatures (12, 15, 18 and 21°C) compared with that of A. coronus, whereas the AS was similar at 24°C. Although only five hybrids were detected and three modelled, their AS was in the upper bounds of the models at 15, 18 and 24°C. These findings suggest that the warming conditions in northern Namibia may increasingly favour A. coronus and promote the poleward movement of the leading edge of their southern distribution. In contrast, the poor aerobic performance of both species at cold temperatures (12°C) suggests that the cold water associated with the permanent Lüderitz Upwelling Cell in the south may constrain both species to central Namibia. This is most concerning for A. inodorus because it may be subjected to a considerable coastal squeeze.The National Research Foundation—National Commission on Research Science and Technology, South Africa—Namibia Agreement on Cooperation in Science and Technology.https://academic.oup.com/conphysam2024BiochemistryGeneticsMicrobiology and Plant PathologySDG-14:Life below wate

Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity.

UNLABELLED: Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts. To test this, a number of clade A and B avian virus-derived NS segments were introduced into human H1N1 and H3N2 viruses. In no case was the peak virus titer substantially reduced following infection of various mammalian cell types. Exemplar reassortant viruses also replicated to similar titers in mice, although mice infected with viruses with the avian virus-derived segment 8s had reduced weight loss compared to that achieved in mice infected with the A/Puerto Rico/8/1934 (H1N1) parent. In vitro, the viruses coped similarly with type I interferons. Temporal proteomics analysis of cellular responses to infection showed that the avian virus-derived NS segments provoked lower levels of expression of interferon-stimulated genes in cells than wild type-derived NS segments. Thus, neither the A nor the B allele of avian virus-derived NS segments necessarily attenuates virus replication in a mammalian host, although the alleles can attenuate disease. Phylogenetic analyses identified 32 independent incursions of an avian virus-derived A allele into mammals, whereas 6 introductions of a B allele were identified. However, A-allele isolates from birds outnumbered B-allele isolates, and the relative rates of Aves-to-Mammalia transmission were not significantly different. We conclude that while the introduction of an avian virus segment 8 into mammals is a relatively rare event, the dogma of the B allele being especially restricted is misleading, with implications in the assessment of the pandemic potential of avian influenza viruses. IMPORTANCE: Influenza A virus (IAV) can adapt to poultry and mammalian species, inflicting a great socioeconomic burden on farming and health care sectors. Host adaptation likely involves multiple viral factors. Here, we investigated the role of IAV segment 8. Segment 8 has evolved into two distinct clades: the A and B alleles. The B-allele genes have previously been suggested to be restricted to avian virus species. We introduced a selection of avian virus A- and B-allele segment 8s into human H1N1 and H3N2 virus backgrounds and found that these reassortant viruses were fully competent in mammalian host systems. We also analyzed the currently available public data on the segment 8 gene distribution and found surprisingly little evidence for specific avian host restriction of the B-clade segment. We conclude that B-allele segment 8 genes are, in fact, capable of supporting infection in mammals and that they should be considered during the assessment of the pandemic risk of zoonotic influenza A viruses.Wellcome Trust (Grant ID: 108070/Z/15/Z), Medical Research Council (Grant ID: MR/K000276/1), Biotechnology and Biological Sciences Research Council (Grant IDs: BB/J004324/1, BB/J01446X/1), Division of Intramural Research National Institute of Allergy and Infectious Diseases, University Of Edinburgh (Chancellor’s Fellowship)This is the final version of the article. It first appeared from the American Society for Microbiology via http://dx.doi.org/10.1128/JVI.01205-1

Identification of a novel splice variant form of the influenza a virus m2 ion channel with an antigenically distinct ectodomain

Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42) with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle

Animal Models of Zika Virus Infection during Pregnancy

Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics

Encephalitis with coinfection by Jamestown canyon virus (JCV) and varicella zoster virus (VZV)

We present the case of a 59-year-old Midwestern farmer who presented with altered mental status, dysarthria, urinary incontinence, and a right-sided L5 dermatomal rash; he had recently received a course of oral corticosteroids for treatment of radicular low back pain. Lumbar puncture revealed the presence of varicella zoster virus (VZV) and IgM antibodies against a California-group encephalitis virus, later confirmed as Jamestown Canyon virus (JCV). Unfortunately, the patient’s health declined despite aggressive treatment, developing progressive subarachnoid hemorrhage. He died after withdrawal of supportive care following 3 weeks in the intensive care unit. To our knowledge, this is the first documented case of encephalitis associated with coinfection by VZV and JCV. While the relative contributions of these viral pathogens to the patient’s illness are difficult to ascertain, the clinical features of this case are consistent with co-pathogenesis, possibly driven by antecedent corticosteroid use. This case highlights the emerging role of viral coinfections in the etiology of viral illnesses