SARS-CoV-2, a coronavirus that emerged in late 2019, has spread rapidly worldwide, and information about the modes of transmission of SARS-CoV-2 among humans is critical to apply appropriate ...infection control measures and to slow its spread. Here we show that SARS-CoV-2 is transmitted efficiently via direct contact and via the air (via respiratory droplets and/or aerosols) between ferrets, 1 to 3 days and 3 to 7 days after exposure respectively. The pattern of virus shedding in the direct contact and indirect recipient ferrets is similar to that of the inoculated ferrets and infectious virus is isolated from all positive animals, showing that ferrets are productively infected via either route. This study provides experimental evidence of robust transmission of SARS-CoV-2 via the air, supporting the implementation of community-level social distancing measures currently applied in many countries in the world and informing decisions on infection control measures in healthcare settings.
SARS-CoV-2 emerged in late 2019 and caused a pandemic, whereas the closely related SARS-CoV was contained rapidly in 2003. Here, an experimental set-up is used to study transmission of SARS-CoV and ...SARS-CoV-2 through the air between ferrets over more than a meter distance. Both viruses cause a robust productive respiratory tract infection resulting in transmission of SARS-CoV-2 to two of four indirect recipient ferrets and SARS-CoV to all four. A control pandemic A/H1N1 influenza virus also transmits efficiently. Serological assays confirm all virus transmission events. Although the experiments do not discriminate between transmission via small aerosols, large droplets and fomites, these results demonstrate that SARS-CoV and SARS-CoV-2 can remain infectious while traveling through the air. Efficient virus transmission between ferrets is in agreement with frequent SARS-CoV-2 outbreaks in mink farms. Although the evidence for virus transmission via the air between humans under natural conditions is absent or weak for SARS-CoV and SARS-CoV-2, ferrets may represent a sensitive model to study interventions aimed at preventing virus transmission.
Human influenza A viruses are known to be transmitted via the air from person to person. It is unknown from which anatomical site of the respiratory tract influenza A virus transmission occurs. Here, ...pairs of genetically tagged and untagged influenza A/H1N1, A/H3N2 and A/H5N1 viruses that are transmissible via the air are used to co-infect donor ferrets via the intranasal and intratracheal routes to cause an upper and lower respiratory tract infection, respectively. In all transmission cases, we observe that the viruses in the recipient ferrets are of the same genotype as the viruses inoculated intranasally, demonstrating that they are expelled from the upper respiratory tract of ferrets rather than from trachea or the lower airways. Moreover, influenza A viruses that are transmissible via the air preferentially infect ferret and human nasal respiratory epithelium. These results indicate that virus replication in the upper respiratory tract, the nasal respiratory epithelium in particular, of donors is a driver for transmission of influenza A viruses via the air.
Many respiratory viruses of humans originate from animals. For instance, there are now eight paramyxoviruses, four coronaviruses and four orthomxoviruses that cause recurrent epidemics in humans but ...were once confined to other hosts. In the last decade, several members of the same virus families have jumped the species barrier from animals to humans. Fortunately, these viruses have not become established in humans, because they lacked the ability of sustained transmission between humans. However, these outbreaks highlighted the lack of understanding of what makes a virus transmissible. In part triggered by the relatively high frequency of occurrence of influenza A virus zoonoses and pandemics, the influenza research community has started to investigate the viral genetic and biological traits that drive virus transmission via aerosols or respiratory droplets between mammals. Here we summarize recent discoveries on the genetic and phenotypic traits required for airborne transmission of zoonotic influenza viruses of subtypes H5, H7 and H9 and pandemic viruses of subtypes H1, H2 and H3. Increased understanding of the determinants and mechanisms of respiratory virus transmission is not only key from a basic scientific perspective, but may also aid in assessing the risks posed by zoonotic viruses to human health, and preparedness for such risks.
This review summarizes recent discoveries on the genetic and phenotypic traits required for airborne transmission of zoonotic influenza viruses of subtypes H5, H7 and H9 and pandemic viruses of subtypes H1, H2 and H3.
Graphical Abstract Figure.
This review summarizes recent discoveries on the genetic and phenotypic traits required for airborne transmission of zoonotic influenza viruses of subtypes H5, H7 and H9 and pandemic viruses of subtypes H1, H2 and H3.
Mathilde Richard works in the field of virology, more specifically on the evolution and pathogenesis of influenza viruses. In this mSphere of Influence article, she reflects on how the two articles ..."Structure of Influenza A Polymerase Bound to the Viral RNA Promoter" by A. Pflug, D. Guilligay, S. Reich, and S. Cusack (Nature 516:355-360, 2014, https://doi.org/10.1038/nature14008) and "Structural Insight into Cap-Snatching and RNA Synthesis by Influenza Polymerase" by S. Reich, D. Guilligay, A. Pflug, H. Malet, I. Berger, et al. (Nature 516:361-366, 2014, https://doi.org/10.1038/nature14009) made an impact on her by providing new grounds to study the influenza virus polymerase and its role in virus biology and evolution.
Influenza viruses cause a remarkable disease burden and significant morbidity and mortality worldwide, and these impacts vary between seasons. To understand the mechanisms associated with these ...differences, a comprehensive approach is needed to characterize the impact of influenza genomic traits on the burden of disease. During 2016⁻2017, a year with severe A(H3N2), we sequenced 176 A(H3N2) influenza genomes using next generation sequencing (NGS) for routine surveillance of circulating influenza viruses collected via the French national influenza community-based surveillance network or from patients hospitalized in the intensive care units of the University Hospitals of Lyon, France. Taking into account confounding factors, sequencing and clinical data were used to identify genomic variants and quasispecies associated with influenza severity or vaccine failure. Several amino acid substitutions significantly associated with clinical traits were found, including NA V263I and NS1 K196E which were associated with severity and co-occurred only in viruses from the 3c.2a1 clade. Additionally, we observed that intra-host diversity as a whole and on a specific set of gene segments increased with severity. These results support the use of whole genome sequencing as a tool for the identification of genetic traits associated with severe influenza in the context of influenza surveillance.
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Highly pathogenic avian influenza viruses (HPAIVs) cause severe hemorrhagic disease in terrestrial poultry and are a threat to the poultry industry, wild life, and human health. HPAIVs arise from low ...pathogenic avian influenza viruses (LPAIVs), which circulate in wild aquatic birds. HPAIV emergence is thought to occur in poultry and not wild aquatic birds, but the reason for this species-restriction is not known. We hypothesized that, due to species-specific tropism and replication, intrahost HPAIV selection is favored in poultry and disfavored in wild aquatic birds. We tested this hypothesis by co-inoculating chickens, representative of poultry, and ducks, representative of wild aquatic birds, with a mixture of H7N7 HPAIV and LPAIV, mimicking HPAIV emergence in an experimental setting. Virus selection was monitored in swabs and tissues by RT-qPCR and immunostaining of differential N-terminal epitope tags that were added to the hemagglutinin protein. HPAIV was selected in four of six co-inoculated chickens, whereas LPAIV remained the major population in co-inoculated ducks on the long-term, despite detection of infectious HPAIV in tissues at early time points. Collectively, our data support the hypothesis that HPAIVs are more likely to be selected at the intrahost level in poultry than in wild aquatic birds and point towards species-specific differences in HPAIV and LPAIV tropism and replication levels as possible explanations.
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A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial-endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of ...the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear.Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial-endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber.We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial-endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4.Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection.
Central nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) ...H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions-PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS.
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Highly Pathogenic Avian Influenza Viruses (HPAIVs) arise from low pathogenic precursors following spillover from wild waterfowl into poultry populations. The main virulence determinant of HPAIVs is ...the presence of a multi-basic cleavage site (MBCS) in the hemagglutinin (HA) glycoprotein. The MBCS allows for HA cleavage and, consequently, activation by ubiquitous proteases, which results in systemic dissemination in terrestrial poultry. Since 1959, 51 independent MBCS acquisition events have been documented, virtually all in HA from the H5 and H7 subtypes. In the present article, data from natural LPAIV to HPAIV conversions and experimental in vitro and in vivo studies were reviewed in order to compile recent advances in understanding HA cleavage efficiency, protease usage, and MBCS acquisition mechanisms. Finally, recent hypotheses that might explain the unique predisposition of the H5 and H7 HA sequences to obtain an MBCS in nature are discussed.
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