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

['Olivier Terrier', 'Cnrs Resaflu', 'Groupement De Recherche Sur Les Virus Influenza', 'Ciri', 'Centre International De Recherche En Infectiologie', 'Team Virpath', 'Inserm', 'Université Claude Bernard Lyon', 'Cnrs', 'Ens De Lyon']

Date: 2022-02 

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.

The years 2020 to 2021 are characterized by an outstanding and worldwide research effort aimed at mitigating the Coronavirus Disease 2019 (COVID-19) pandemic, leading to >145,000 published articles and >2,900 completed or underway clinical trials ( https://www.covid-trials.org ). Experience and research work related to previous outbreaks, including the emergence of the H1N1pdm09 influenza virus in 2009, was also leveraged. As a result, safe and effective vaccines [ 1 ] as well as monoclonal antibody–based treatments [ 2 ] have been developed in less than 1 year. At the same time, the COVID-19 crisis exposed the weaknesses of our preparedness and response to pandemics and highlighted large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza A viruses (IAVs), the 2 major zoonotic respiratory viruses with pandemic potential. Here, we sought to identify common challenges of influenza virus and CoV research that should be addressed in order to become better prepared for upcoming pandemics.

1. Emergence, transmission, and adaptation to humans

1.1. Mapping of animal reservoirs and intermediate hosts Wild waterfowl are the main reservoir for IAVs, with poultry and swine being evolutionary intermediaries and possibly “mixing vessels” for the transmission to humans [3]. Human CoVs come from wild animal reservoirs as well, especially bats as in the case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or rodents [4,5]. They are thought to emerge in humans through an intermediate mammalian host, possibly domesticated or tamed or hunted, e.g., dromedary camels for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and civets for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) [4]. However, the direct animal progenitor of SARS-CoV-2 remains elusive to date [6]. Neither the emergence of H1N1pdm09 virus nor that of SARS-CoV-2, the viruses responsible for the 2 last pandemics (Table 1), were preceded by a disease outbreak in an animal population. This fits with phylogenetic data suggesting that viruses potentially “preadapted” to humans could have evolved and circulated undetected in wild or domesticated animals for years [7,8]. This situation, along with the genetic plasticity of IAVs and CoVs, as well as the diversity of animal species that could potentially represent prepandemic reservoirs, makes it an unrealistic goal to identify all viruses with pandemic potential before they emerge in humans. PPT PowerPoint slide

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TIFF original image Download: Table 1. Basic features of H1N1pdm09 and SARS-CoV-2 viruses. https://doi.org/10.1371/journal.ppat.1010106.t001 However, once a cluster of human zoonotic cases has been detected, the capacity to rapidly characterize the animal origin, route of transmission, and site of emergence of the pathogen is essential for informed public health decisions and early control of the outbreak. Such a capacity requires extensive and long-term surveillance data sets on the spatial and temporal dynamics of viruses in their reservoir and intermediate host species. With regard to IAVs, major progress has been achieved in recent years. Tracking of the epidemiology and evolution of highy pathogenic avian IAVs has improved due to the rise in whole genome sequencing [9] and initiatives on sharing sequencing data such as the GISAID database [10]. Genomic surveillance was integrated with the collaborative expertise of virologists, ornithologists, ecologists, and mathematical modelers to identify bird species, time periods, habitats, and geographies that are associated with increased risks of transmission to humans and therefore require an active surveillance of wild and domestic animals [11,12]. This approach should be further developed and extended to CoVs. Zooanthroponosis, as exemplified by the transmission of the H1N1pdm09 and SARS-CoV-2 human viruses back to animal species [13,14], should be closely monitored. Indeed, such spillover events can lead to the selection of variants at the time of cross-species transmission, such as SARS-CoV-2 variants isolated in mink farms from the Netherlands and Denmark, which showed amino acid substitutions in the spike protein possibly increasing its affinity for the mink angiotensin converting enzyme 2 (ACE2) receptor [15], or to the accumulation and fixation of mutations over time, as observed upon introduction of the human H1N1pdm09 virus in swine [16]. Ultimately, these events can lead to the establishment of novel animal virus lineages with subsequent risks for animal and human health [17]. To this end, taking advantage of recent developments in next generation sequencing technologies, such as the Oxford Nanopore MinION, in-field collection of genomic and metagenomic data should be intensified and combined with complementary approaches such as syndromic surveillance and serological surveys in farmed species [18–20]. Finally, research aiming at further understanding the molecular determinants for the host range and host switching potential of IAVs and CoVs will help identify high-risk viruses. This knowledge, together with surveillance data, should ultimately serve to feed and refine the risk assessment tools that have already been implemented for IAVs, such as the World Health Organization’s (WHO) Tool for Influenza Pandemic Risk Assessment (TIPRA) and the Centers for Disease Control and Prevention’s (CDC) Influenza Risk Assessment Tool (IRAT) [21], and adapt them to CoVs.

1.2. Understanding how selective pressures are shaping viral evolution IAVs and CoVs harbor single-stranded RNA genomes (negative or positive sense, respectively). High mutation rates occur during replication, which allows them to evolve rapidly [22,23]. There is much evidence that CoVs can limit their mutation rates due to a proofreading mechanism of their polymerase [24,25]. However, it is unclear to what extent this proofreading mechanism is limiting CoVs diversification in an epidemiological context [23,26]. Both viral families also undergo evolutionary shortcuts (reassortment of genomic segments for IAVs and homologous recombination for CoVs), which may favor the emergence of pandemic viruses. For instance, the H1N1pdm09 virus was a complex reassortant harboring genomic segments of swine, avian, and human IAVs origin [7]. SARS-CoV-2 is characterized by a polybasic cleavage site in the spike glycoprotein that was possibly acquired from another bat CoV through recombination [27]. Interestingly, recurrent occurrence of short deletions are currently being observed in the spike glycoprotein of SARS-CoV-2 [28,29] and in the hemagglutinin glycoprotein of H1N2 swine IAVs [30,31]. Depending on the nature of the host barrier and the level of preexisting immunity in the human population, CoVs or IAVs transmitted from animals to humans can show different patterns of pathogenicity and human-to-human transmissibility, which will result in different evolutionary pressures acting on the viruses. For instance, the emerging SARS-CoV-2 and H1N1pdm09 IAV were both less deadly and more transmissible among humans than the SARS-CoV, MERS-CoV, and zoonotic H5N1/H7N9 IAVs, but SARS-CoV-2 and the 2009 influenza pandemic virus differed in that the mortality was the highest in people older than 70 years for the former but not the latter [32]. Improving the accuracy of phylogenetic methods that infer the evolutionary history of the emerging viruses by sequence comparison with samples derived from the reservoir and intermediate hosts (see Section 1.1) will help characterize the pattern of host species jump. For the H1N1pdm09 as well as the SARS-CoV-2 viruses, real-time monitoring of the emerging virus evolution has been a key component of the pandemic response, not only to track transmission chains and evaluate the reproductive number [33,34] but also to infer the spatiotemporal spread of the virus country-wide or worldwide and evaluate the efficacy of mitigation measures [35,36]. A major challenge is to ensure the representativeness of sequences and to improve the predictive value of data-driven mathematical models so that they accurately anticipate how the course of the pandemic will be affected by the rise of new viral variants and by the implementation of mitigation measures [37,38]. Another challenge in the field is to combine phylogenetic and phenotypic data (e.g., virulence, transmissibility, escape from the antibody or T-cell response), in order to better understand how selective pressures and trade-offs are shaping viral evolution at both the intra- and interhost levels. For instance, the often mentioned hypothesis that virulence and transmissibility are inversely correlated and that this trade-off determines evolutionary trajectories remain to be verified for emerging IAVs and CoVs [39]. While the H1N1pmd09 remained genetically stable several years after its emergence, it has taken less than 1 year to see SARS-CoV-2 variants with distinct phenotypes from the progeny virus emerge, possibly due to differences in the nature and effects of cross-immunity. An hypothesis is that some early SARS-CoV-2 variants may have emerged from immunocompromised patients with long-lasting infection and, possibly, treatment with plasma from convalescent patients or recombinant antibodies [40]. Which mutations are evolutionary neutral or are associated with immune escape, increased replication, or increased transmissibility remains to be fully evaluated. Mutations on the viral spike protein are best characterized so far. Notably, the N501Y mutation, shared by the 4 main variants of concern (B.1.1.7, P.1, B.1.351 and B.1.1.529), increases the spike’s affinity of the ACE2 receptor and could thereby increase transmissibility, whereas the E484K mutation, found in the P.1 and B.1.351 variants, decreases binding of neutralizing antibodies and could thereby favor immune escape (for a review, see [41,42]). Unraveling the evolutionary drivers of IAVs and CoVs genetic diversity will help improve policy responses as well as the design of vaccines and antiviral therapies in the future.

[END]

[1] Url: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010106

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