Influenza viruses and coronaviruses: Knowns, unknowns, and common research challenges

Abstract

The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.

Fig 1. Factors potentially affecting the production, fate, and infectivity of virus-laden aerosols.

Only few (mostly environmental and viral factors) have been documented so far. Multidisciplinary progress in this research field will help improve mitigation measures when a new pandemic respiratory virus emerges. Created with BioRender.com. LRT, lower respiratory tract; URT, upper respiratory tract; UV, ultraviolet.

Fig 2. Growing pool of structural data available for influenza viruses and coronaviruses.

The number of 3D structures available in the Protein Data Bank (https://www.rcsb.org, 17 October 2021) for each of the indicated category of viral proteins has been recorded separately for the 1981 to 2014 and the 2015 to 2021 period (the latter corresponding to an extended use of new generation detectors and cryo-EM, gray background). SARS-CoV-2 protein structures were counted separately (inset on the right). The years when the Relenza, Tamiflu and Xofluza inhibitors were approved by the FDA are indicated. RdRp, RNA-dependent RNA polymerase: PB1, PB2, and PA proteins of influenza viruses; nsp7, nsp8, nsp10, nsp12, and nsp14 proteins of corona viruses. Proteases: nsp3 and nsp5. * corresponds to the publication years of the first HA and NA X-ray structure, which preceded by several years their deposition in the PDB. HA, hemagglutinin; NA, neuraminidase; S, Spike; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig 3. Cellular and animal models available for IAV and SARS-CoV-2 infections [–176].

An estimation of the performance to the criteria indicated on the left is provided with the following color code: dark blue (very good), light blue (good), orange (poor), red (very poor), gray (not documented), no color (irrelevant). ^a All transmission routes including aerosol and direct contact routes. ^b NHP have been very rarely used in transmission studies; however, it was reported that H1N1pdm09 influenza viruses can efficiently transmit between marmosets [177]. 2D/3D, two- or three-dimensional; HAE, human airway epithelium; Hu mice, humanized mice (refers to mice grafted with human immune cells in the case of IAV and to mice grafted with human lung tissue in the case of SARS-CoV-2); IAV, influenza A virus; NHP, nonhuman primate; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; Tg mice, transgenic mice.