Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies

Influenza A viruses cause seasonal epidemics and global pandemics, representing a considerable burden to healthcare systems. Central to the replication cycle of influenza viruses is the viral RNA-dependent RNA polymerase which transcribes and replicates the viral RNA genome. The polymerase undergoes conformational rearrangements and interacts with viral and host proteins to perform these functions. Here we determine the structure of the 1918 influenza virus polymerase in transcriptase and replicase conformations using cryo-electron microscopy (cryo-EM). We then structurally and functionally characterise the binding of single-domain nanobodies to the polymerase of the 1918 pandemic influenza virus. Combining these functional and structural data we identify five sites on the polymerase which are sensitive to inhibition by nanobodies. We propose that the binding of nanobodies at these sites either prevents the polymerase from assuming particular functional conformations or interactions with viral or host factors. The polymerase is highly conserved across the influenza A subtypes, suggesting these sites as effective targets for potential influenza antiviral development.

Retrospective analysis of cerebral neurological complications against background of seasonal respiratory viral infections and new coronavirus infection Covid‑19

Based on the example of seasonal epidemics of respiratory viral infections, it is partially possible to model the outcomes of neurological complications from Covid‑19, taking into account the pathogenetic features of the virus effect on the vascular wall and nerve cells. The accumulated experience of doctors of various specialties makes it possible to prevent such life-threatening complications as ACVA, PATE, intoxication, and sepsis. From the first days of the disease, it is necessary to conduct dynamic monitoring of blood rheology, the level of systemic oxygenation, use anticoagulants in preventive doses in patients at the early stages of the disease, conduct therapy aimed at reducing the risk of cytokine storm development.

How immunity from and interaction with seasonal coronaviruses can shape SARS-CoV-2 epidemiology

We hypothesized that cross-protection from seasonal epidemics of human coronaviruses (HCoVs) could have affected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, including generating reduced susceptibility in children. To determine what the prepandemic distribution of immunity to HCoVs was, we fitted a mathematical model to 6 y of seasonal coronavirus surveillance data from England and Wales. We estimated a duration of immunity to seasonal HCoVs of 7.8 y (95% CI 6.3 to 8.1) and show that, while cross-protection between HCoV and SARS-CoV-2 may contribute to the age distribution, it is insufficient to explain the age pattern of SARS-CoV-2 infections in the first wave of the pandemic in England and Wales. Projections from our model illustrate how different strengths of cross-protection between circulating coronaviruses could determine the frequency and magnitude of SARS-CoV-2 epidemics over the coming decade, as well as the potential impact of cross-protection on future seasonal coronavirus transmission.

Antiviral Treatments for Influenza

Influenza is an acute respiratory illness caused by the influenza A, B, and C viruses. It can occur in local outbreaks or seasonal epidemics, with possibility to spread worldwide in a pandemic when a novel strain with significant antigenic differences emerges. During the past years, several new drugs have become available, with different accessibility related to specific countries' approval. We have conducted a review of literature, analyzing the most recent data on efficacy and safety of drugs currently available to treat influenza, with a particular attention toward special populations. Efficacy and safety profile of neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, peramivir) and recently approved cap-dependent endonuclease inhibitor baloxavir marboxil are reported in literature, but still little information is available about special populations such as critically ill patients and patients with a history of chronic respiratory disease. Moreover, the emergence of strains with reduced or no susceptibility to current drugs is a matter of concern, suggesting the need of constant monitoring of viral variants.

FluSense

Influenza is a highly contagious respiratory infection that leads to regular seasonal epidemics. It is a major contributor to morbidity and mortality, and in the United States, since 2010, it has infected between 9.2 million and 60.8 million people and has caused between 12,000 and 56,000 deaths. [2]. Moreover, the economic impact [1] of influenza is estimated to be 47 billion to 150 billion dollars per year in the USA alone.

An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad “universal” IAV protection, and identifies a promising candidate for influenza vaccine clinical development.One-Sentence SummaryAn inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a “universal” influenza virus vaccine.

Incidencia, características y medidas aplicadas en pacientes con gripe A (H1N1) en el contexto hospitalario durante el periodo 2016-2018

Introducción: El virus de la gripe ocasiona anualmente epidemias estacionales con amplia extensión mundial y se estima que entre el 5 y el 20% de la población padece gripe cada año. En abril de 2009 se confirmaron los primeros casos de infección humana causados por un nuevo virus de la gripe A (H1N1). Objetivo y Método: En el período de epidemia (semana 40-20) del 2016-2018 se realizó un estudio observacional descriptivo prospectivo multicéntrico en dos hospitales públicos del área metropolitana sur de Barcelona con el objetivo de determinar la incidencia de pacientes positivos en gripe A (H1N1), así como las características demográficas y clínico-evolutivas de estos pacientes, la temporalidad en la detección del virus y medidas aplicadas por control de la infección.Resultados: Los resultados del presente trabajo indican que la incidencia acumulada de Gripe A durante el periodo de estudio fue de 233,68 casos por cada 100.000 habitantes. Casi el 90% de los pacientes padecía antecedentes patológicos siendo los más prevalentes la patología cardíaca y respiratoria. Además, el 40% de los pacientes hospitalizados presentó complicaciones, principalmente la neumonía. El tratamiento y días de aislamiento fueron según los estándares recomendados. Conclusión: Estos hallazgos muestran la elevada incidencia de gripe A, así como los beneficios de que los equipos de control de la infección realicen el seguimiento del cumplimiento del tratamiento y medidas para evitar la transmisión. Introduction:The influenza virus causes seasonal epidemics worldwide and it is estimated that between 5 and 20% of the population suffers from influenza each year. The first cases of human infection caused by a new influenza A virus (H1N1) were confirmed in April 2009.Objective and Method: In the epidemic period (week 40-20) of 2016-2018, a multicenter prospective descriptive observational study was carried out in two public hospitals in the southern metropolitan area of Barcelona in order to determine the incidence of positive patients in influenza A (H1N1), as well as the demographic and clinical-evolutionary characteristics of these patients, the timing of virus detection and measures applied for infection control.Results: The results of the present work indicate that the cumulative incidence of Influenza A during the study period was 233,68 per 100,000 inhabitants. Almost 90% of the patients had an underlying chronic condition, mostly heart disease and respiratory pathology. Furthermore, 40% of the patients presented complications, mainly pneumonia. Treatment and days of isolation were according to standard recommendations. Conclusion: These findings show the high incidence of influenza A virus (N1H1) as well as the benefits that apports the infection control teams surveillance, monitoring the compliance with treatment and days of measures to avoid the transmission.

The Nature of Immune Responses to Influenza Vaccination in High-Risk Populations

The current pandemic has brought a renewed appreciation for the critical importance of vaccines for the promotion of both individual and public health. Influenza vaccines have been our primary tool for infection control to prevent seasonal epidemics and pandemics such as the 2009 H1N1 influenza A virus pandemic. Certain high-risk populations, including the elderly, people with obesity, and individuals with comorbidities such as type 2 diabetes mellitus, are more susceptible to increased disease severity and decreased vaccine efficacy. High-risk populations have unique microenvironments and immune responses that contribute to increased vulnerability for influenza infections. This review focuses on these differences as we investigate the variations in immune responses to influenza vaccination. In order to develop better influenza vaccines, it is critical to understand how to improve responses in our ever-growing high-risk populations.

Identification and Structural Aspects of G-Quadruplex-Forming Sequences from the Influenza A Virus Genome

Influenza A virus (IAV) causes seasonal epidemics and sporadic pandemics, therefore is an important research subject for scientists around the world. Despite the high variability of its genome, the structure of viral RNA (vRNA) possesses features that remain constant between strains and are biologically important for virus replication. Therefore, conserved structural motifs of vRNA can represent a novel therapeutic target. Here, we focused on the presence of G-rich sequences within the influenza A/California/07/2009(H1N1) genome and their ability to form RNA G-quadruplex structures (G4s). We identified 12 potential quadruplex-forming sequences (PQS) and determined their conservation among the IAV strains using bioinformatics tools. Then we examined the propensity of PQS to fold into G4s by various biophysical methods. Our results revealed that six PQS oligomers could form RNA G-quadruplexes. However, three of them were confirmed to adopt G4 structures by all utilized methods. Moreover, we showed that these PQS motifs are present within segments encoding polymerase complex proteins indicating their possible role in the virus biology.

How immunity from and interaction with seasonal coronaviruses can shape SARS-CoV-2 epidemiology

We hypothesised that cross-protection from seasonal epidemics of human coronaviruses (HCoVs) could have affected SARS-CoV-2 transmission, including generating reduced susceptibility in children. To determine what the pre-pandemic distribution of immunity to HCoVs was, we fitted a mathematical model to 6 years of seasonal coronavirus surveillance data from England and Wales. We estimated a duration of immunity to seasonal HCoVs of 7.3 years (95%CI 6.8 - 7.9) and show that, while cross-protection between HCoV and SARS-CoV-2 may contribute to the age distribution, it is insufficient to explain the age pattern of SARS-CoV-2 infections in the first wave of the pandemic in England and Wales. Projections from our model illustrate how different strengths of cross-protection between circulating coronaviruses could determine the frequency and magnitude of SARS-CoV-2 epidemics over the coming decade, as well as the potential impact of cross-protection on future seasonal coronavirus transmission.