Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones

Phillips, Angela M; Ponomarenko, Anna I.; Chen, Kenny; Ashenberg, Orr; Miao, J.; McHugh, Sean M.; Butty, Vincent; Whittaker, Charles A.; Moore, Christopher; Bloom, Jesse D.; Lin, Yu‐Shan; Shoulders, Matthew D.

doi:10.1371/journal.pbio.3000008

Cited by 30 publications

(56 citation statements)

References 63 publications

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“…It is possible that these variants can confer antigenic escape, since recently, it has been registered that a reinfection case containing A222V and D614G mutations has occurred (85). Nucleocapsid variation has also been documented in the nucleoprotein of the influenza virus (86) (87) and nucleocapsid of the hepatitis virus (88). Both RNA viruses escape cellular immunity by these mechanisms and could also be the case for SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Large-scale population analysis of SARS-CoV-2 whole genome sequences reveals host-mediated viral evolution with emergence of mutations in the viral Spike protein associated with elevated mortality rates

Farkas

Mella

Haigh

2020

Preprint

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Background We aimed to further characterize and analyze in depth intra-host variation and founder variants of SARS-CoV-2 worldwide up until August 2020, by examining in excess of 94,000 SARS-CoV-2 viral sequences in order to understand SARS-CoV-2 variant evolution, how these variants arose and identify any increased mortality associated with these variants. Methods and Findings We combined worldwide sequencing data from GISAID and Sequence Read Archive (SRA) repositories and discovered SARS-CoV-2 hypermutation occurring in less than 2% of COVID19 patients, likely caused by host mechanisms involved APOBEC3G complexes and intra-host microdiversity. Most of this intra-host variation occurring in SARS-CoV-2 are predicted to change viral proteins with defined variant signatures, demonstrating that SARS-CoV-2 can be actively shaped by the host immune system to varying degrees. At the global population level, several SARS-CoV-2 proteins such as Nsp2, 3C-like proteinase, ORF3a and ORF8 are under active evolution, as evidenced by their increased πN/πS ratios per geographical region. Importantly, two emergent variants: V1176F in co-occurrence with D614G mutation in the viral Spike protein, and S477N, located in the Receptor Binding Domain (RBD) of the Spike protein, are associated with high fatality rates and are increasingly spreading throughout the world. The S477N variant arose quickly in Australia and experimental data support that this variant increases Spike protein fitness and its binding to ACE2. Conclusions SARS-CoV-2 is evolving non-randomly, and human hosts shape emergent variants with positive fitness that can easily spread into the population. We propose that V1776F and S477N variants occurring in the Spike protein are two novel mutations occurring in SARS-CoV-2 and may pose significant public health concerns in the future.

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Section: Discussionmentioning

confidence: 99%

Large-scale population analysis of SARS-CoV-2 whole genome sequences reveals host-mediated viral evolution with emergence of mutations in the viral Spike protein associated with elevated mortality rates

Farkas

Mella

Haigh

2020

Preprint

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“…The R328V substitution in SiAr126 NP did not affect the growth capacity of the recombinant virus, both in cell culture and in vivo . This was unexpected because, in the case of IAV, MxA escape-associated substitutions in NP usually result in virus attenuation, possibly due to misfolding of NP [ 59 ] and/or defective nuclear vRNP import [ 60 ]. Obviously, position 328 is not critical for viral growth but hypercritical for MxA sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

et al. 2020

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Infections with emerging and re-emerging arboviruses are of increasing concern for global health. Tick-transmitted RNA viruses of the genus Thogotovirus in the Orthomyxoviridae family have considerable zoonotic potential, as indicated by the recent emergence of Bourbon virus in the USA. To successfully infect humans, arboviruses have to escape the restrictive power of the interferon defense system. This is exemplified by the high sensitivity of thogotoviruses to the antiviral action of the interferon-induced myxovirus resistance protein A (MxA) that inhibits the polymerase activity of incoming viral ribonucleoprotein complexes. Acquiring resistance to human MxA would be expected to enhance the zoonotic potential of these pathogens. Therefore, we screened a panel of 10 different thogotovirus isolates obtained from various parts of the world for their sensitivity to MxA. A single isolate from Nigeria, Jos virus, showed resistance to the antiviral action of MxA in cell culture and in MxA-transgenic mice, whereas the prototypic Sicilian isolate SiAr126 was fully MxA-sensitive. Further analysis identified two amino acid substitutions (G327R and R328V) in the viral nucleoprotein as determinants for MxA resistance. Importantly, when introduced into SiAr126, the R328V mutation resulted in complete MxA escape of the recombinant virus, without causing any viral fitness loss. The escape mutation abolished viral nucleoprotein recognition by MxA and allowed unhindered viral growth in MxA-expressing cells and in MxA-transgenic mice. These findings demonstrate that thogotoviruses can overcome the species barrier by escaping MxA restriction and reveal that these tick-transmitted viruses may have a greater zoonotic potential than previously suspected.

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“…The MX1 gene has been systematically studied in human and mice anti influenza virus infections. The MX1 gene is a dynamin-like guanosine triphosphatase that blocks the importation of influenza ribonucleoprotein, a process known to be sufficient to confer resistance to influenza viruses [40,41]. In humans, the MX1 gene product MxA inhibits a step of the influenza virus replication cycle following primary transcription [42].…”

Section: Discussionmentioning

confidence: 99%

A Homeostasis Hypothesis of Avian Influenza Resistance in Chickens

An¹,

Wang

et al. 2019

Genes

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Avian influenza has caused significant damage to the poultry industry globally. Consequently, efforts have been made to elucidate the disease mechanisms as well as the mechanisms of disease resistance. Here, by investigating two chicken breeds with distinct responses to avian influenza virus (AIV), Leghorn GB2 and Fayoumi M43, we compared their genome, methylation, and transcriptome differences. MX1, HSP90AB1, and HSP90B1 exhibited high degrees of genetic differentiation (FST) between the two species. Except for the MX1-involved direct anti-virus mechanism, we found that at the methylation and transcriptome levels, the more AIV-resistant breed, Fayoumi, exhibited less variation compared with Leghorn after AIV inoculation, which included change trends in differentially expressed regions, top-fold change genes with FDR-corrected p < 0.05, immune response related genes, and housekeeping genes. Fayoumi also showed better consistency regarding changes in methylation and changes at the transcriptome level. Our results suggest a homeostasis hypothesis for avian influenza resistance, with Fayoumi maintaining superior homeostasis at both the epigenetic and gene expression levels. Three candidate genes—MX1, HSP90AB1, and HSP90B1—showed genetic differentiation and altered gene expression, methylation, and protein expression, which merit attention in further functional studies.

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Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones

Cited by 30 publications

References 63 publications

Large-scale population analysis of SARS-CoV-2 whole genome sequences reveals host-mediated viral evolution with emergence of mutations in the viral Spike protein associated with elevated mortality rates

Large-scale population analysis of SARS-CoV-2 whole genome sequences reveals host-mediated viral evolution with emergence of mutations in the viral Spike protein associated with elevated mortality rates

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

A Homeostasis Hypothesis of Avian Influenza Resistance in Chickens

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