Epigenetic and transcriptional control of interferon-ß.

The three classes of interferons (IFNs) share the ability to inhibit viral replication, activating cell transcriptional programs that regulate both innate and adaptive responses to viral and intracellular bacterial challenge. Due to their unique potency in regulating viral replication, and their association with numerous autoimmune diseases, the tightly orchestrated transcriptional regulation of IFNs has long been a subject of intense investigation. The protective role of early robust IFN responses in the context of infection with SARS-CoV-2 has further underscored the relevance of these pathways. In this viewpoint, rather than focusing on the downstream effects of IFN signaling (which have been extensively reviewed elsewhere), we will summarize the historical and current understanding of the stepwise assembly and function of factors that regulate IFNß enhancer activity (the "enhanceosome") and highlight opportunities for deeper understanding of the transcriptional control of the ifnb gene.

RNA-dependent assembly of chimeric antigen nanoparticles as an efficient H5N1 pre-pandemic vaccine platform.

Highly pathogenic avian influenza viruses (HPAIVs) pose a significant threat to human health, with high mortality rates, and require effective vaccines. We showed that, harnessed with novel RNA-mediated chaperone function, hemagglutinin (HA) of H5N1 HPAIV could be displayed as an immunologically relevant conformation on self-assembled chimeric nanoparticles (cNP). A tri-partite monomeric antigen was designed including: i) an RNA-interaction domain (RID) as a docking tag for RNA to enable chaperna function (chaperna: chaperone + RNA), ii) globular head domain (gd) of HA as a target antigen, and iii) ferritin as a scaffold for 24 mer-assembly. The immunization of mice with the nanoparticles (~46 nm) induced a 25-30 fold higher neutralizing capacity of the antibody and provided cross-protection from homologous and heterologous lethal challenges. This study suggests that cNP assembly is conducive to eliciting antibodies against the conserved region in HA, providing potent and broad protective efficacy.

Intra-species sialic acid polymorphism in humans: a common niche for influenza and coronavirus pandemics?

The ongoing COVID-19 pandemic has led to more than 159 million confirmed cases with over 3.3 million deaths worldwide, but it remains mystery why most infected individuals (∼98%) were asymptomatic or only experienced mild illness. The same mystery applies to the deadly 1918 H1N1 influenza pandemic, which has puzzled the field for a century. Here we discuss dual potential properties of the 1918 H1N1 pandemic viruses that led to the high fatality rate in the small portion of severe cases, while about 98% infected persons in the United States were self-limited with mild symptoms, or even asymptomatic. These variations now have been postulated to be impacted by polymorphisms of the sialic acid receptors in the general population. Since coronaviruses (CoVs) also recognize sialic acid receptors and cause severe acute respiratory syndrome epidemics and pandemics, similar principles of influenza virus evolution and pandemicity may also apply to CoVs. A potential common principle of pathogen/host co-evolution of influenza and CoVs under selection of host sialic acids in parallel with different epidemic and pandemic influenza and coronaviruses is discussed.

Possible ramifications of climate variability on HPAI-H5N1 outbreak occurrence: Case study from the Menoufia, Egypt.

Long endemicity of the Highly Pathogenic Avian Influenza (HPAI) H5N1 subtype in Egypt poses a lot of threats to public health. Contrary to what is previously known, outbreaks have been circulated continuously in the poultry sectors all year round without seasonality. These changes call the need for epidemiological studies to prove or deny the influence of climate variability on outbreak occurrence, which is the aim of this study. This work proposes a modern approach to examine the degree to which the HPAI-H5N1disease event is being influenced by climate variability as a potential risk factor using generalized estimating equations (GEEs). GEE model revealed that the effect of climate variability differs according to the timing of the outbreak occurrence. Temperature and relative humidity could have both positive and negative effects on disease events. During the cold seasons especially in the first quarter, higher minimum temperatures, consistently show higher risks of disease occurrence, because this condition stimulates viral activity, while lower minimum temperatures support virus survival in the other quarters of the year with the highest negative effect in the third quarter. On the other hand, relative humidity negatively affects the outbreak in the first quarter of the year as the humid weather does not support viral circulation, while the highest positive effect was found in the second quarter during which low humidity favors the disease event.

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.