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Concept: Influenzavirus A

293

Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women’s health.

Concepts: Reproduction, Lung, Pneumonia, Epidermal growth factor, Epithelium, Skin, Cervix, Influenzavirus A

167

Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand-binding interactions for a high-avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza, but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, while control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.

Concepts: Microbiology, Sialic acid, Therapy, Influenza, Human respiratory syncytial virus, Orthomyxoviridae, Influenza A virus, Influenzavirus A

29

The influenza A virus M2 channel (AM2) is crucial in the viral life cycle. Despite many previous experimental and computational studies, the mechanism of the activating process in which proton permeation acidifies the virion to release the viral RNA and core proteins is not well understood. Herein the AM2 proton permeation process has been systematically characterized using multiscale computer simulations, including quantum, classical, and reactive molecular dynamics methods. We report, to our knowledge, the first complete free-energy profiles for proton transport through the entire AM2 transmembrane domain at various pH values, including explicit treatment of excess proton charge delocalization and shuttling through the His37 tetrad. The free-energy profiles reveal that the excess proton must overcome a large free-energy barrier to diffuse to the His37 tetrad, where it is stabilized in a deep minimum reflecting the delocalization of the excess charge among the histidines and the cost of shuttling the proton past them. At lower pH values the His37 tetrad has a larger total charge that increases the channel width, hydration, and solvent dynamics, in agreement with recent 2D-IR spectroscopic studies. The proton transport barrier becomes smaller, despite the increased charge repulsion, due to backbone expansion and the more dynamic pore water molecules. The calculated conductances are in quantitative agreement with recent experimental measurements. In addition, the free-energy profiles and conductances for proton transport in several mutants provide insights for explaining our findings and those of previous experimental mutagenesis studies.

Concepts: Protein, Electron, Virus, Chemistry, PH, Computer simulation, Influenzavirus A, M2 protein

27

Catastrophic antiphospholipid syndrome (CAPS) has been associated with several bacterial and viral infections. We presented a case report of a woman who presented to the emergency room, with influenza A virus subtype H1N1 which progressed to CAPS in the course of 17 days. We believe this is the first case that links CAPS with H1N1.

Concepts: Bacteria, Microbiology, Virus, Infection, Influenza, Influenza vaccine, Antiphospholipid syndrome, Influenzavirus A

27

The purpose of this study was to develop a new class of influenza A virus haemagglutinin (HA) blockers by tethering thiosialoside molecules to metal nanoparticles and producing glycoclusters that enhance the affinity of HA binding by N-acetylneuraminic acid.

Concepts: Influenzavirus A

21

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8+T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38+HLA-DR+PD-1+CD8+T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38+HLA-DR+CD8+T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38+HLA-DR+CD8+T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38+HLA-DR+CD8+T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.

Concepts: Protein, Virus, Influenza, Influenza pandemic, Swine influenza, Influenza vaccine, Orthomyxoviridae, Influenzavirus A

16

Humidity has been associated with influenza’s seasonality, but the mechanisms underlying the relationship remain unclear. There is no consistent explanation for influenza’s transmission patterns that applies to both temperate and tropical regions. This study aimed to determine the relationship between ambient humidity and viability of the influenza A virus (IAV) during transmission between hosts and to explain the mechanisms underlying it. We measured the viability of IAV in droplets consisting of various model media, chosen to isolate effects of salts and proteins found in respiratory fluid, and in human mucus, at relative humidities (RH) ranging from 17% to 100%. In all media and mucus, viability was highest when RH was either close to 100% or below ∼50%. When RH decreased from 84% to 50%, the relationship between viability and RH depended on droplet composition: viability decreased in saline solutions, did not change significantly in solutions supplemented with proteins, and increased dramatically in mucus. Additionally, viral decay increased linearly with salt concentration in saline solutions but not when they were supplemented with proteins. There appear to be three regimes of IAV viability in droplets, defined by humidity: physiological conditions (∼100% RH) with high viability, concentrated conditions (50% to near 100% RH) with lower viability depending on the composition of media, and dry conditions (<50% RH) with high viability. This paradigm could help resolve conflicting findings in the literature on the relationship between IAV viability in aerosols and humidity, and results in human mucus could help explain influenza's seasonality in different regions.

Concepts: Influenza, Influenzavirus A

13

Persons who read information about a hypothetical influenza strain with scientific (H11N3 influenza) or exotic-sounding (Yarraman flu) name reported higher worry and vaccination intentions than did those who read about strains named after an animal reservoir (horse flu). These findings suggest that terms used for influenza in public communications can influence reactions.

Concepts: Scientific method, Infectious disease, Virus, Vaccine, Influenza, Strain, Influenza vaccine, Influenzavirus A

12

The type I interferon pathway plays a critical role in both host defense and tolerance against viral infection and thus requires refined regulatory mechanisms. RIPK3-mediated necroptosis has been shown to be involved in anti-viral immunity. However, the exact role of RIPK3 in immunity to Influenza A Virus (IAV) is poorly understood. In line with others, we, herein, show that Ripk3-/- mice are highly susceptible to IAV infection, exhibiting elevated pulmonary viral load and heightened morbidity and mortality. Unexpectedly, this susceptibility was linked to an inability of RIKP3-deficient macrophages (Mφ) to produce type I IFN in the lungs of infected mice. In Mφ infected with IAV in vitro, we found that RIPK3 regulates type I IFN both transcriptionally, by interacting with MAVS and limiting RIPK1 interaction with MAVS, and post-transcriptionally, by activating protein kinase R (PKR)-a critical regulator of IFN-β mRNA stability. Collectively, our findings indicate a novel role for RIPK3 in regulating Mφ-mediated type I IFN anti-viral immunity, independent of its conventional role in necroptosis.

Concepts: Immune system, Virus, RNA, Infection, Interferon, Influenza, Regulation, Influenzavirus A

8

Clinical influenza A virus isolates are frequently not sequenced directly. Instead, a majority of these isolates (~70% in 2015) are first subjected to passaging for amplification, most commonly in non-human cell culture. Here, we find that this passaging leaves distinct signals of adaptation, which can confound evolutionary analyses of the viral sequences. We find distinct patterns of adaptation to Madin-Darby (MDCK) and monkey cell culture absent from unpassaged hemagglutinin sequences. These patterns also dominate pooled datasets not separated by passaging type, and they increase in proportion to the number of passages performed. By contrast, MDCK-SIAT1 passaged sequences seem mostly (but not entirely) free of passaging adaptations. Contrary to previous studies, we find that using only internal branches of influenza virus phylogenetic trees is insufficient to correct for passaging artifacts. These artifacts can only be safely avoided by excluding passaged sequences entirely from subsequent analysis. We conclude that future influenza virus evolutionary analyses should appropriately control for potentially confounding effects of passaging adaptations.

Concepts: Genetics, Natural selection, Evolution, Influenza, Sequence, Orthomyxoviridae, Influenza A virus, Influenzavirus A