SARS-CoV-2 infection, COVID-19 pathogenesis, and exposure to air pollution: What is the connection?

Abstract

Exposure to air pollutants has been previously associated with respiratory viral infections, including influenza, measles, mumps, rhinovirus, and respiratory syncytial virus. Epidemiological studies have also suggested that air pollution exposure is associated with increased cases of SARS-CoV-2 infection and COVID-19-associated mortality, although the molecular mechanisms by which pollutant exposure affects viral infection and pathogenesis of COVID-19 remain unknown. In this review, we suggest potential molecular mechanisms that could account for this association. We have focused on the potential effect of exposure to nitrogen dioxide (NO₂ ), ozone (O₃ ), and particulate matter (PM) since there are studies investigating how exposure to these pollutants affects the life cycle of other viruses. We have concluded that pollutant exposure may affect different stages of the viral life cycle, including inhibition of mucociliary clearance, alteration of viral receptors and proteases required for entry, changes to antiviral interferon production and viral replication, changes in viral assembly mediated by autophagy, prevention of uptake by macrophages, and promotion of viral spread by increasing epithelial permeability. We believe that exposure to pollutants skews adaptive immune responses toward bacterial/allergic immune responses, as opposed to antiviral responses. Exposure to air pollutants could also predispose exposed populations toward developing COIVD-19-associated immunopathology, enhancing virus-induced tissue inflammation and damage.

Keywords: air pollution; coronavirus; nitrogen dioxide; ozone; particulate matter; viral infection.

Figure 1

Coronavirus life cycle. To initiate entry, the spike (S) protein attaches to the host receptor angiotensin‐converting enzyme 2 (ACE2). Entry requires cleavage of the S protein by the cellular serine protease TMPRSS2 and cathepsins B/L. After fusion, viral RNA is released into the cell and translated into the polyproteins pp1a and pp1b, which are cleaved into nonstructural proteins, some of which form the replicase complex. Coronavirus replication and transcription are regulated by the replication‐transcription complex in rearranged internal host membranes or double‐membranous vesicles (DMVs). Genomic RNA and nested subgenomic mRNAs are produced using negative‐strand intermediates. Subgenomic mRNAs are translated into viral proteins, including the spike (S), envelope (E), and membrane (M) structural proteins. The structural proteins are translated and inserted into the endoplasmic reticulum (ER) and move into the ER‐Golgi intermediate compartment (ERGIC). Newly encapsidated viral genomes bud into the ERGIC, forming mature virions, which are transported in vesicles and released from cells via exocytosis.

Figure 2

Potential effects of pollutant exposure on the viral life cycle of SARS‐CoV‐2. Exposure to air pollutants may promote viral entry through a variety of mechanisms, including preventing antiviral activity of SP‐D and antimicrobial peptides, increasing levels of receptor ACE2, and promoting cleavage of TMPRSS2. The effects of exposure on viral uncoating are unknown. However, pollutants may promote TLR2 and TLR4 signaling, which is involved in bacterial immune responses, allowing evasion of antiviral responses. The effects of pollutant exposure on antiviral sensing mechanisms, including RIG‐I–like receptors, are unclear. Exposure to pollutants induces lipid peroxidation and production of ROS through activation of NAPDH oxidase and mitochondrial damage, reducing ATP generation, stimulating apoptosis, and inducing autophagy. Coronaviruses may use autophagy to generate DMVs for replication. Thus, pollutant exposure may promote viral replication. Moreover, pollutant‐induced ROS results in activation of proinflammatory redox‐sensitive transcription factors NF‐κB and AP‐1, promoting transcription of proinflammatory genes. PAHs also stimulate AhR activation, which can crosstalk with NF‐κB. Pollutant exposure also stimulates inflammasome activation. Thus, pollutant exposure enhances inflammation during viral infections.

Figure 3

Potential effects of pollutant exposure on SARS‐CoV‐2 infection and COVID‐19 pathogenesis. As illustrated in Figure 1, exposure to air pollutants may promote viral entry, replication, and assembly, and activate proinflammatory transcription factors, resulting in enhanced local inflammation. Furthermore, pollutant exposure reduces mucociliary clearance and decreases levels of tight junction proteins, promoting epithelial permeability, which can result in increased viral spread and inflammation because of the leaky epithelium. Prevention of macrophage uptake and defective natural killer (NK) cell function also promotes viral spread. Subsequent enhanced inflammation can stimulate neutrophil recruitment and further amplify inflammatory processes. Moreover, since pollutant exposure is believed to skew adaptive immune responses toward allergic/bacterial responses instead of antiviral immune responses, exposure may result in enhanced virus‐induced tissue damage and inflammation, promoting dysfunction of a variety of organs, including the lungs, heart, kidney, and brain, resulting in death.