Antigenic evolution of human influenza H3N2 neuraminidase is constrained by charge balancing

As one of the main influenza antigens, neuraminidase (NA) in H3N2 virus has evolved extensively for more than 50 years due to continuous immune pressure. While NA has emerged as an effective vaccine target recently, biophysical constraints on the antigenic evolution of NA remain largely elusive. Here, we apply deep mutational scanning to characterize the local fitness landscape in an antigenic region of NA in six different human H3N2 strains that were isolated around 10 years apart. The local fitness landscape correlates well among strains and the pairwise epistasis is highly conserved. Our analysis further demonstrates that local net charge governs the pairwise epistasis in this antigenic region. In addition, we show that residue coevolution in this antigenic region can be predicted by charge states and pairwise epistasis. Overall, this study demonstrates the importance of quantifying epistasis and the underlying biophysical constraint for building a predictive model of influenza evolution.

Betacoronavirus-specific alternate splicing

Viruses can subvert a number of cellular processes in order to block innate antiviral responses, and many viruses interact with cellular splicing machinery. SARS-CoV-2 infection was shown to suppress global mRNA splicing, and at least 10 SARS-CoV-2 proteins bind specifically to one or more human RNAs. Here, we investigate 17 published experimental and clinical datasets related to SARS-CoV-2 infection as well as datasets from the betacoronaviruses SARS-CoV and MERS as well as Streptococcus pneumonia, HCV, Zika virus, Dengue virus, influenza H3N2, and RSV. We show that genes showing differential alternative splicing in SARS-CoV-2 have a similar functional profile to those of SARS-CoV and MERS and affect a diverse set of genes and biological functions, including many closely related to virus biology. Additionally, the differentially spliced transcripts of cells infected by coronaviruses were more likely to undergo intron-retention, contain a pseudouridine modification and a smaller number of exons than differentially spliced transcripts in the control groups. Viral load in clinical COVID-19 samples was correlated with isoform distribution of differentially spliced genes. A significantly higher number of ribosomal genes are affected by DAS and DGE in betacoronavirus samples, and the betacoronavirus differentially spliced genes are depleted for binding sites of RNA-binding proteins. Our results demonstrate characteristic patterns of differential splicing in cells infected by SARS-CoV-2, SARS-CoV, and MERS, potentially modifying a broad range of cellular functions and affecting a diverse set of genes and biological functions.

A Mutation Network Method for Transmission Analysis of Human Influenza H3N2

Characterizing the spatial transmission pattern is critical for better surveillance and control of human influenza. Here, we propose a mutation network framework that utilizes network theory to study the transmission of human influenza H3N2. On the basis of the mutation network, the transmission analysis captured the circulation pattern from a global simulation of human influenza H3N2. Furthermore, this method was applied to explore, in detail, the transmission patterns within Europe, the United States, and China, revealing the regional spread of human influenza H3N2. The mutation network framework proposed here could facilitate the understanding, surveillance, and control of other infectious diseases.

Whole genomic analysis of two influenza H3N2 virus strains isolated from Qinghai, China

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Whole genomic analysis of two influenza H3N2 virus strains isolated from Qinghai, China

Background Influenza H3N2 virus has a faster evolution rate than other types of influenza viruses. This study was performed to better understand the molecular evolution of influenza H3N2 in Qinghai Province, China in 2017.Methods Complete sequences of eight gene segments of two influenza H3N2 isolates in 2017 in Qinghai Province were sequenced and analyzed by MEGA 6.06 software.Results Phylogenetic analysis showed that two Qinghai H3N2 isolates were relatively close to the 2016–2017 vaccine strain, 3C.2a-A/Hong Kong/4801/2014. In HA protein, compared with the 2015-2016 WHO recommended vaccine strain A/Switzerland/971 5293/2013, six amino acid substitutions were observed in epitopes A and B in Qinghai isolates in 2017, however, only two amino acid substitutions were observed in epitopes A and B in Qinghai isolates compared with the A/Hong Kong/4801/2014, which indicated 2016-2017 vaccine strain might have a better protection against the strains circulating in Qinghai Province in 2017 . Besides, amino acid substitution of K160T at the glycosylation site of HA and H75P in PB1-F2 in the two Qinghai isolates might affect the antibodies binding ability and the virulence of influenza virus. And there was no key amino acid substitution in the key sites of segment NA, M, NP, NS, PA and PB2.Conclusions The presence of several antigenic site mutations in Qinghai H3N2 isolates confirms the evolution of circulating H3N2 strains. Enhancing the surveillance of influenza epidemic by whole genome sequencing is important to monitor whether the selected vaccine strains are protective against the circulating strains in Qinghai Province.