Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract

Abstract

Influenza viruses cause annual epidemics and occasional pandemics of respiratory tract infections that produce a wide spectrum of clinical disease severity in humans. The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and has since caused a pandemic. Both viral and host factors determine the extent and severity of virus-induced lung damage. The host's response to viral infection is necessary for viral clearance but may be deleterious and contribute to severe disease phenotypes. Similarly, tissue repair mechanisms are required for recovery from infection across the spectrum of disease severity; however, dysregulated repair responses may lead to chronic lung dysfunction. Understanding of the mechanisms of immunopathology and tissue repair following viral lower respiratory tract infection may broaden treatment options. In this Review, we discuss the pathogenesis, the contribution of the host response to severe clinical phenotypes and highlight early and late epithelial repair mechanisms following influenza virus infection, each of which has been well characterized. Although we are still learning about SARS-CoV-2 and its disease manifestations in humans, throughout the Review we discuss what is known about SARS-CoV-2 in the context of this broad knowledge of influenza virus, highlighting the similarities and differences between the respiratory viruses.

Fig. 1. Patient-related risk factors for severe influenza virus and SARS-CoV-2 infections.

a | Estimates of yearly influenza virus infections worldwide and in the United States (2018–2019 season). b | Risk factors associated with severe influenza virus infection in epidemiological and genetic studies. c | Global estimated number of cases and deaths from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. d | Risk factors identified thus far to be associated with severe coronavirus disease 2019 (COVID-19). Type 2 bias, bias towards type 2 immune responses.

Fig. 2. Mechanisms of host resistance and tolerance in lung structural cells.

Recent studies have identified structural cells in the lung (epithelial, endothelial and mesenchymal) as crucial regulators of host immune responses. Cells in the lower respiratory tract must effectively communicate to promote effective viral clearance while limiting damage to endothelial cells of the blood vessels (red) and epithelial cells of the alveoli (blue), which together carry out gas exchange. Each cell type, and their phenotypically distinct subsets, contributes to disease resistance and tolerance host strategies through diverse mechanisms indicated in the boxes. The balance of these resistance and tolerance mechanisms ultimately determines the outcome and long-term consequences of respiratory viral infection. AREG, amphiregulin; ECM, extracellular matrix; FGF, fibroblast growth factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL-6, interleukin 6.

Fig. 3. Cellular tropism of influenza virus and SARS-CoV-2.

a | The haemagglutinin (HA) protein of influenza viruses preferentially binds sialosaccharides on the surface of pulmonary epithelial cells. Whereas human influenza viruses prefer sialic acids (SAs) linked to galactose by α(2,6) linkage (SAα2,6Gal), avian influenza viruses prefer SAα2,3Gal. These are distributed in a gradient in the human respiratory tract. Immunohistochemistry staining demonstrates intracellular localization of influenza viruses in epithelial cells at three sites from mice challenged with influenza A virus. b | The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on the surface of certain olfactory and respiratory epithelial cells distributed along the human respiratory tract after activation by a cellular protease, such as transmembrane serine protease 2 (TMPRSS2) (other proteases, including cathepsin L, neuropilin 1 and furin are involved in activation). Histopathological images in part a courtesy of P. Vogel.

Fig. 4. Alveolar epithelial repair along the severity continuum.

The regeneration of alveolar tissue and restoration of function is essential for survival following a severe respiratory infection. Recent studies have demonstrated that the extent and severity of influenza virus infection determines the quality of alveolar epithelial repair. Repair by self-renewing type II alveolar cells occurs during less severe infection and is efficient. During infection with extensive tissue damage when type II alveolar cells are ablated, additional epithelial progenitor cells (p63⁻ and p63⁺) mobilize to mediate repair. WNT and NOTCH signalling pathways determine localized differentiation of these progenitor cells. In severe damage, mobilization of p63⁺ progenitors can result in dysplastic alveolar repair characterized by the formation of cyst-like structures with high expression of Krt5 leading to reduced lung function. This dysplastic repair may lead to persistent lung dysfunction.