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. 2023 Jan 9;192(1):3–14. doi: 10.1093/toxsci/kfad003

Air pollution and respiratory infections: the past, present, and future

Alexys Monoson 1, Evangeline Schott 2, Kerry Ard 3, Brita Kilburg-Basnyat 4, Robert M Tighe 5, Sonal Pannu 6, Kymberly M Gowdy 7,✉
PMCID: PMC10025881  PMID: 36622042

Abstract

Air pollution levels across the globe continue to rise despite government regulations. The increase in global air pollution levels drives detrimental human health effects, including 7 million premature deaths every year. Many of these deaths are attributable to increased incidence of respiratory infections. Considering the COVID-19 pandemic, an unprecedented public health crisis that has claimed the lives of over 6.5 million people globally, respiratory infections as a driver of human mortality is a pressing concern. Therefore, it is more important than ever to understand the relationship between air pollution and respiratory infections so that public health measures can be implemented to ameliorate further morbidity and mortality. This article aims to review the current epidemiologic and basic science research on interactions between air pollution exposure and respiratory infections. The first section will present epidemiologic studies organized by pathogen, followed by a review of basic science research investigating the mechanisms of infection, and then conclude with a discussion of areas that require future investigation.

Keywords: lung, inflammation, COVID-19, pneumonia, air pollution

Ambient levels of criteria air pollutants continue to rise despite regulations by organizations like the United States Environmental Protection Agency (EPA) (EPA, 2022) and the European Environment Agency (EEA, 2022). According to the World Health Organization (WHO), 9 out of 10 individuals currently live in areas with ambient air pollution that exceeds the current local regulations (WHO, 2022). These elevated air pollution levels have important health consequences and continue to be a significant global public health concern. Air pollution is associated with more than 7 million premature deaths globally every year (IQAir, 2020; WHO, 2022). Beyond mortality, air pollution exposure can exacerbate chronic cardiopulmonary diseases, and can increase susceptibility to respiratory infections (WHO, 2022). As air pollution levels continue to rise despite global regulations on air quality, human morbidity and mortality are also expected to increase. Therefore, concurrent with efforts to improve air quality, research is required to better understand mechanisms driving adverse health effects from air pollution exposure that can be the focus of intervention strategies. The recent COVID-19 pandemic has again brought attention to respiratory infections, particularly the association and mechanisms between air pollution and enhanced infection risk/severity. Associations between air pollution exposure and enhanced respiratory infection severity have been well established in population and laboratory mechanistic studies. The earliest observation was in 1937 where an autopsy study noted evidence of alveolar carbon pigmentation, consistent with air pollution exposure, in individuals who died from pneumonia (Haythorn and Meller, 1938). Consistent with this observation, studies from the Great Smog of London event in 1952 demonstrated a direct correlation between increased ambient particulate matter (PM) and the incidence of pneumonia with an 80% increase in mortality when compared with the previous year and approximately 3500–4000 additional deaths in the 5 years following the event (Bell et al., 2004; Greater London Authority, 2002). Similar associations are being observed with the COVID-19 pandemic (Aggarwal et al., 2021; Bashir et al., 2020; Bianconi et al., 2020; Bilal et al., 2020; Bowe et al., 2021; Chakrabarty et al., 2021; Coker et al., 2020; Cole et al., 2020; De Angelis et al., 2021; Dragone et al., 2021; Fang et al., 2021; Fattorini and Regoli, 2020; Fiasca et al., 2020; Hendryx and Luo, 2020; Jiang et al., 2020; Konstantinoudis et al., 2021; Lembo et al., 2021; Liang et al., 2020; Lin et al., 2020; Liu et al., 2021), suggesting broad implications of air pollution exposure and respiratory infections. Now, more than ever, it is important to understand both the epidemiologic and mechanistic relationships between air pollution and respiratory infection to ameliorate future morbidity and mortality from respiratory infections.

This article will aim to provide a review of the literature regarding air pollution and pulmonary infections. The first section will highlight recent epidemiologic research, primarily focusing on the impact of the criteria air pollutants (O3, CO, PM2.5, NO2, SO2, and Pb) on pneumonia. Studies will be classified by pathogen and will focuse on data related to bacterial, fungal, and viral infections. We will provide a comprehensive review of both epidemiological and laboratory studies as well as an overview of the current mechanisms by which air pollution affects the immune response critical for clearing infections. This article will also highlight the emerging studies of criteria air pollutants and the incidence of SARS-CoV-2 infection, the respiratory virus responsible for the current COVID-19 pandemic. Lastly, we will attempt to identify areas that require further investigation on mechanisms driving susceptibility and severity of respiratory infections from air pollution.

Epidemiological findings of air pollution and infection

Acute respiratory infections are one of the top 5 leading causes of all-causes of global mortality (WHO, 2022). According to the WHO, 17% of deaths from acute lower respiratory infections (ie, pneumonia) are attributable to ambient air pollution (WHO, 2022). Pneumonia may be caused by several organisms including viruses, bacteria, and fungi. A diagnosis of pneumonia is made clinically by the examination of patient symptoms, a physical exam, and radiographic evidence. Because of this, the causative organism is often not identified. Several studies have defined associations between pneumonia diagnosis and ambient air pollutants concentrations. For example, increased PM2.5 concentrations were associated with increased emergency department (ED) visits and admissions for ‘pneumonia’ in New York state (Croft et al., 2019). A similar study was conducted in Utah, where elevated PM2.5 was associated with more ED visits, hospitalizations, and mortality from pneumonia (Pirozzi et al., 2018). Similar observations have been defined in national studies. Dominici et al. observed that an increase of PM2.5 by 10 μg/m3 was associated with a 5.4% increase in the rate of respiratory tract infections (Dominici et al., 2006). These associations are not unique to PM2.5 as they have been noted with other criteria air pollutants. For example, for every 1 ppb increase in O3, there was a 0.41% increase in admissions for pneumonia in the United States (Medina-Ramon et al., 2006). There also have been multiple epidemiological studies conducted in populations in Asia and Europe where NO2, O3, and PM10 have been associated with increased risk of diagnosis and hospital admission for pneumonia (Ciencewicki and Jaspers, 2007; MacIntyre et al., 2014; Qiu et al., 2021). These studies, as well as others (Croft et al., 2020; MacIntyre et al., 2014; Zhang et al., 2019), clearly demonstrate that changes in air pollution levels lead to a greater incidence of morbidity and mortality from pneumonia.

 

 

Influenza and respiratory syncytial virus infections

Although pneumonia is a diagnosis that is nonspecific for a causative pathogen, epidemiological data support that changes in air quality increase incidence of viral-specific respiratory infections like influenza and respiratory syncytial virus (RSV). For example, an increase of one standard deviation in the EPA’s air quality index results in over 4000 additional hospitalizations for influenza in the U.S. every year (Croft et al., 2020). When examining the effects of specific criteria air pollutants, increases in PM2.5 in New York City were associated with a 6% excess rate of influenza-related ED visits (Croft et al., 2020). Similar trends have been seen with other criteria air pollutants. In Brazil, China, and Australia, increased O3 levels were associated with an increased risk of influenza and ED visits (Ali et al., 2018; Martins et al., 2002; Wong et al., 2009). Song et al. (2021) observed a correlation between SO2, CO, NO2, PM2.5, and PM10 levels and influenza diagnoses across China between 2004 and 2017. Similar trends have been reported with RSV, a virus known to cause severe lower respiratory infections in young children. Among the criteria air pollutants, increases in PM10, PM2.5, NO2, CO, and SO2 levels correlated with RSV diagnosis and ED visits for RSV in Korea, China, and Israel (Pompilio and Di Bonaventura, 2020; Croft et al., 2019; Yitshak-Sade et al., 2017). Taken together, these data indicate that changes in ambient levels of multiple criteria air pollutants influence the incidence and severity of respiratory viral infections.

Bacterial pneumonias

Unlike the incidence of viral pneumonia and/or respiratory virus infections, the association between bacterial pneumonia and air pollution levels has not been as extensively studied. However, there are some sentinel studies suggesting similar associations. For example, in China, levels of O3, PM10, NO2, and PM2.5, SO2 are independently associated with an increased risk of infection and admission for pneumonia secondary to Mycoplasma pneumoniae (Bono et al., 2016; Chen et al., 2020; Zhang et al., 2019). Similarly, in the United States, SO2 was associated with increased rates of pneumococcal disease that spread to the bloodstream, caused by the bacteria Streptococcus pneumoniae (Kim et al., 1996). The lack of population studies associating air pollution with bacterial pneumonia is likely due to the clinical difficulty in identifying a causative organism. While diagnoses of viral infections often rely on PCR testing that can be easily obtained via nasal swab or rapid blood test, bacterial pneumonias are often diagnosed via culture of respiratory sputum. Sputum samples are often difficult to collect; as patients must either be able to expectorate productively or undergo invasive sampling with bronchoscopy (BAL). Lastly, diagnoses of the specific causative organism are done by assays that are not high throughput and can sometimes take days to obtain results. Despite these challenges, data reported thus far indicate that air pollutants increase the incidence of bacterial pneumonias.

The association between air pollution and tuberculosis (TB; caused by infection from the bacteria Mycobacterium tuberculosis) is particularly important in developing countries where TB infections contribute to millions of deaths annually (IQAir, 2020). Many developing countries have both a high incidence of TB as well as high levels of air pollutants. However, a large meta-analysis by Popovic et al. (2019) found a correlation between TB and air pollution levels across Asia, Europe, and North America. Although this article demonstrated the strongest correlation between TB outcomes and PM2.5, other studies have shown associations with PM10, PM2.5, NO2, and SO2 (Hwang et al., 2014; Lai et al., 2016). Interestingly, levels of criteria air pollutants are not only associated with an increased risk of TB but also with an increased risk of drug-resistant infection. In Shandong province, China, 725 culture-positive cases of TB were examined and compared with ambient levels of PM2.5, PM10, O3, and CO. PM2.5, PM10, and CO were all associated with an increased incidence of multidrug-resistant TB infection (Yao et al., 2019). However, the biological mechanisms by which this occurs are still unknown.

Fungal pneumonias

Fungal pneumonias are rare when compared with bacterial and viral pneumonia but have high morbidity and mortality compared to these more common pneumonias. Air pollution can also impact the severity of fungal pneumonias. Aspergillus, a fungi readily found both indoors and outdoors on surfaces ranging from soil to starchy foods, can cause pulmonary disease in humans, the most severe of which is invasive aspergillosis (Liu et al., 2018). In a study of a large Taiwanese database, Liu et al. (2018) demonstrated an association between PM2.5 levels and incidence of invasive aspergillosis, suggesting that air pollution exposure may augment the severity of fungal pneumonias. However, these fungal pneumonias often occur in patients who are immunosuppressed. This includes individuals with HIV who are at risk for severe respiratory infections from the fungus Pneumocystis jirovecii (PJP). In HIV-positive patients with low CD4 counts, elevated ambient levels of NO2, SO2, PM10, and O3 are associated with increased PJP hospital admission rates (Alvaro-Meca et al., 2015; Djawe et al., 2013). Knowing that air pollution can increase the severity of fungal infections in these susceptible populations indicates that more studies are needed to understand why this association occurs.

SARS-CoV-2 infection

The COVID-19 pandemic is one of the greatest public health crises of modern times and, according to the WHO, it has caused more than 615 million infections and 65 million deaths across the globe as of October 2022 (WHO, 2022). In an effort to stop the spread of the virus, many countries implemented lockdown policies. As people were confined to their homes, most ambient levels of criteria air pollutants were significantly reduced (Venter et al., 2020). Regardless of this reduction in air pollutants, the incidence and mortality of COVID-19 continued to correlate with air pollution levels (Wu et al., 2020). This association has been outlined in Table 1. A nationwide cross-sectional study comparing county-wide, long-term PM2.5 levels with mortality from COVID-19 concluded that a 1-μg/m3 increase in PM2.5 was associated with an 8% increase in mortality (Liang et al., 2020). In the United Kingdom, increased PM2.5 levels were associated with a 12% increase in new COVID-19 cases (Travaglio et al., 2021). These findings have been noted in other countries as well as with other air pollutants (ie, NO2, O3, PM2.5, and PM10) (Cole et al., 2020; Fattorini and Regoli, 2020). For example, in Wuhan China, levels of PM (both PM2.5 and PM10) were temporally associated with COVID-19 mortality (Yao et al., 2020a). Thus far, these population-based studies demonstrate associations between air pollutants and COVID-19 incidence and mortality; however, as the pandemic continues and new SARS-CoV2 strains emerge, more studies are required to assess whether these associations will continue and how they are modified by new variants. Additionally, the source of these pollutants (eg, industrial, vehicles, and biomass) may vary among the different areas examined and could potentially alter the pollutant and pathogen interactions in these population studies.

Table 1.

Epidemiological studies of air pollution and COVID-19 outcomes

Pollutant(s) studied Results Study location(s) Reference
PM2.5 and PM10 PM2.5 and/or PM10 are positively associated with COVID-19 mortality and/or case fatality. Afghanistan, Bangladesh, Chile, China, France, India, Indonesia, Italy, Mexico, Nepal, Netherlands, Pakistan, Sri Lanka, United Kingdom, United States (Aggarwal et al., 2021; Bashir et al., 2020; Berg et al., 2021; Bianconi et al., 2020; Borro et al., 2020; Coker et al., 2020; Cole et al., 2020; De Angelis et al., 2021; Fang et al., 2021; Gupta et al., 2021; Hendryx and Luo, 2020; Hou et al., 2021; Jain et al., 2021; Jiang and Xu, 2021; Kolluru et al., 2021; Konstantinoudis et al., 2021; Liang et al., 2020; Lopez-Feldman et al., 2021; Magazzino et al., 2020; Mele and Magazzino, 2021; Meo et al., 2021a, b, c; Sahoo, 2021; Valdes Salgado et al., 2021; Yao et al., 2020a, b; Zhou et al., 2021)
PM2.5 and/or PM10 are positively associated with COVID-19 incidence. Canada, Chile, China, India, Italy, Netherlands, Saudi Arabia, United Kingdom, United States (Bashir et al., 2020; Bianconi et al., 2020; Borro et al., 2020; Cole et al., 2020; De Angelis et al., 2021; Fang et al., 2021; Fattorini and Regoli, 2020; Hadei et al., 2021; Hendryx and Luo, 2020; Jiang et al., 2020; Kolluru et al., 2021; Li et al., 2020; Ma et al., 2021; Meo et al., 2021a, b, c, d; Pei et al., 2021; Pozzer et al., 2020; Stieb et al., 2020; Travaglio et al., 2021; Valdes Salgado et al., 2021; Xu et al., 2022; Zhang et al., 2021; Zhou et al., 2021; Zhu et al., 2020; Zoran et al., 2020b)
PM2.5 and/or PM10 are positively associated with COVID-19 prevalence. Italy (Petroni et al., 2020)
PM2.5 and/or PM10 levels are positively associated with COVID-19 hospitalizations. Malaysia, United States (Bowe et al., 2021; Mendy et al., 2021; Nor et al., 2021)
PM2.5 and/or PM10 levels are positively associated with COVID-19 epidemic growth rate or transmission. Italy, Spain, United States (Chakrabarty et al., 2021; Lolli et al., 2020; Saez et al., 2020; Setti et al., 2020)
No significant association between PM2.5 and/or PM10 and epidemic growth rate. Japan (Azuma et al., 2020)
No significant association between PM2.5 and COVID-19 mortality. United States (Liang et al., 2020)
PM2.5 is negatively associated with COVID-19 incidence. Germany (Ogen, 2020)
NO2 NO2 is positively associated with COVID-19 mortality and/or case fatality. France, Germany, India, Italy, Netherlands, Spain, United Kingdom, United States (Bashir et al., 2020; Cole et al., 2020; Frontera et al., 2020; Liang et al., 2020; Mele and Magazzino, 2021; Meo et al., 2021a; Ogen, 2020; Travaglio et al., 2021)
NO2 is positively associated with COVID-19 incidence. China, Iran, Italy, United Kingdom, United States (Fattorini and Regoli, 2020; Fiasca et al., 2020; Jiang et al., 2020; Li et al., 2020; Ma et al., 2021; Pozzer et al., 2020; Sahoo, 2021) (Bashir et al., 2020; Hadei et al., 2021; Meo et al., 2021a; Travaglio et al., 2021; Zhang et al., 2021; Zhu et al., 2020)
NO2 is positively associated with COVID-19 epidemic growth rate. Spain (Saez et al., 2020)
No significant association between NO2 and COVID-19 mortality and/or case fatality. China, United States (Adhikari and Yin, 2020; Hou et al., 2021)
No significant association between NO2 and COVID-19 incidence. Saudi Arabia (Adhikari and Yin, 2020; Meo et al., 2021d)
No significant association between NO2 and COVID-19 prevalence. Italy (Filippini et al., 2020)
No significant association between NO2 and COVID-19 epidemic growth rate. Japan (Azuma et al., 2020)
NO2 is negatively associated with COVID-19 mortality. Italy (De Angelis et al., 2021)
NO2 is negatively associated with COVID-19 incidence. Italy (De Angelis et al., 2021; Zoran et al., 2020a)
CO and CO2 CO and/or CO2 are positively associated with COVID-19 mortality. China, India, United Kingdom, United States (Kolluru et al., 2021; Mele and Magazzino, 2021; Meo et al., 2021a, b, c)
CO and/or CO2 are positively associated with COVID-19 incidence. China, Italy, Saudi Arabia, United Kingdom, United States (Jiang et al., 2020; Kolluru et al., 2021; Li et al., 2017, 2020; Meo et al., 2021a, b; Pozzer et al., 2020; Zhu et al., 2020)
CO and/or CO2 are negatively associated with COVID-19 mortality. China (Jiang and Xu, 2021)
O3 O3 is positively associated with COVID-19 mortality. India, Italy, United Kingdom, United States (Kolluru et al., 2021; Meo et al., 2021a, b, c; Travaglio et al., 2021; Tripepi et al., 2021)
O3 is positively associated with COVID-19 incidence. China, India, Iran, Italy, Saudi Arabia, United Kingdom, United States (Adhikari and Yin, 2020; Fattorini and Regoli, 2020; Hadei et al., 2021; Jiang et al., 2020; Kolluru et al., 2021; Meo et al., 2021a, b, c, d; Tripepi et al., 2021; Xu et al., 2022; Zhu et al., 2020; Zoran et al., 2020a)
O3 is positively associated with COVID-19 prevalence. Italy (Petroni et al., 2020)
No significant association between O3 and COVID-19 mortality and/or case fatality rate. China, United States (Adhikari and Yin, 2020; Hou et al., 2021; Liang et al., 2020)
No significant association between O3 and COVID-19 incidence. China (Zhang et al., 2021)
O3 is negatively associated with COVID-19 incidence. Italy (Pozzer et al., 2020)
SO2 SO2 is positively associated with COVID-19 mortality. Netherlands, United States (Bashir et al., 2020; Cole et al., 2020)
SO2 is positively associated with COVID-19 incidence. China, United States (Bashir et al., 2020; Jiang et al., 2020; Ma et al., 2021)
No significant association between SO2 and mortality and/or case fatality rate. China (Hou et al., 2021)
SO2 is negatively associated with COVID-19 mortality. China (Jiang and Xu, 2021)
SO2 is negatively associated with COVID-19 incidence. India (Sahoo, 2021)
NH3 NH3 is positively associated with COVID-19 incidence. Italy (Pozzer et al., 2020)
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Original epidemiological studies found through searches of Google Scholar and PubMed were included. Review articles, articles examining only conglomerate measures of air pollution, and articles in preprint at the time of search were excluded.

Despite the strengths and number of studies reporting the associations between air pollution and respiratory infections, there are confounders for these datasets that can influence the interpretation of the data. For instance, most of these studies examine large and diverse populations that include patients from a variety of different socioeconomic statuses, demographics, medical comorbidities, and housing and work conditions. This population diversity can make statistical analysis difficult; particularly when accounting for covariates that could be effect modifiers. Additionally, most of the epidemiological studies focus on specific susceptible populations, including the elderly or children, thus raising the question of whether they are broadly applicable to all age groups. A final consideration, as noted above, is that diagnosis of pneumonia and specific pathogens can be challenging due to misdiagnosis and inherent difficulties in obtaining specimens for testing as well as different assay methods. Despite these barriers, the available data support strong associations between elevated air pollution exposure and increased incidence and severity of pulmonary infections.

Laboratory studies defining associations between air pollution and respiratory infections

Laboratory studies have been conducted to uncover the causal relationships between air pollution and respiratory infections; each with inherent strengths and weaknesses. These studies have used a number of different study designs to investigate relationships. The first of these are in vivo human modeling. In these studies, human volunteers are exposed to a low, controlled level of the air pollutant and lung or nasal cells are harvested via bronchoalveolar lavage, nasal lavage, or nasopharyngeal brushings. After the cells have been isolated, they can be exposed to a pathogen of interest. Effects have been defined in human alveolar macrophages and respiratory epithelial cells using this method. These methods have demonstrated mechanisms by which air pollutants alter cellular responses to respiratory infection (Becker et al., 2002; Jaspers et al., 2005). However, this type of study design does have limitations, including single pollutant evaluation, examining cells outside of the microenvironment that can influence biological responses, as well as eliminating systemic immune responses to pathogen. To address some of these concerns, investigators have also used rodent exposure models. Rodent models have a number of benefits including allowing for a broader range of exposure concentrations and durations than in humans, and enabling direct infection with pathogens, assessments over a variety of time points, and evaluation of whole-organism responses including systemic translocation of infection. The major limitations of rodent models are that they are generally performed on a single genetic strain that lacks the genetic diversity of human populations. In addition, they have different fractional deposition of pollutants throughout the upper and lower airways than human models, rodent studies are typically performed on young healthy mice without preexisting respiratory disease, and until recently, most rodent studies were performed on a single sex. In contrast, the majority of people who suffer from pneumonia tend to have underlying medical conditions such as chronic cardiac or lung diseases or are at the extremes of age (eg, children or the elderly). This can lead to difficulty in translating observations between rodent models and humans, though they remain an important model for defining causal relationships. A final study design is the use of in vitro human cells. This typically involves the use of either a transformed cell line or primary cells isolated from human volunteers that are exposed in vitro to a combination of air pollutants and pathogens. This method can facilitate mechanistic research on how that cell type responds to a pollutant and pathogen but has some of the same drawbacks as the cells used from in vivo human exposure models.

Using these various study designs, several mechanisms have been defined for how air pollution impacts respiratory infections. This review focuses on 4 principal mechanisms including (1) augmented inflammation within the lining of the respiratory tract disrupting normal innate barrier defenses; (2) disruption of macrophage pathogen clearance functions; (3) alterations in the expression of cellular receptors used by pathogens to cause infection; and (4) modulation of the commensal bacteria in the lung leading to a favorable environment for pathogenic infections. Below, we review the current laboratory findings of these 4 mechanisms of air pollution and their association with increased susceptibility and/or severity of respiratory infection. Additionally, a graphical description of these proposed mechanisms can be found in Figure 1.

Figure 1.

Figure 1.

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Molecular mechanisms by which air pollution increases susceptibility to respiratory infections. Pollutants that have been shown to increase susceptibility or exacerbate pulmonary infections include PM, sulfur dioxide, diesel exhaust, ozone, and nitrogen dioxide. It is thought that inhalation of these pollutants increases the amount of PAMPs, danger associated molecular patterns (DAMPs), and reactive oxygen species which can alter function and responses of the resident lung cells including the alveolar macrophage and epithelial cells. (A) Known air pollution-induced alterations in the alveolar macrophage include (1) decreased phagocytosis; (2) increased expression of PRRs; and increased production of proinflammatory cytokines. (B) Known air pollution-induced alterations in epithelial cells include (1) increased cell death; (2) augmented inflammatory cyto/chemokine production; (3) disruption of normal innate barrier defenses; (4) alterations in the expression of cellular receptors used by pathogens to cause infection; and (5) modulation of the commensal bacteria in the lung leading to a favorable environment for pathogenic infections. These air pollution-induced changes to the lung can lead to increased pathogen burden and mortality associated with infection. Created with BioRender.com.

 

 

Air pollution disruption of barrier functions

Inflammation of the respiratory tract can disrupt a number of innate protective barriers that normally limit or prevent infection. One of these barriers is the epithelial lining fluid (ELF), a protective layer of fluid that physically traps pathogens and contains a number of resident immune cells and compounds important in host defense and anti-oxidant responses including mucins, surfactant/surfactant proteins, glutathione, uric acid, superoxide dismutase, and ascorbate (Cross et al., 1994; Kelly, 2003; Kelly et al., 1996). A number of air pollutants (PM2.5, O3, and NO2) have been shown to induce oxidative stress and thereby decrease host defense responses (Chauhan and Johnston, 2003; Ciencewicki and Jaspers, 2007; Dellinger et al., 2001; Kelly, 2003). This appears to result in depletion of host defense and anti-oxidant components in ELF as has been observed in samples isolated from human and rodent airspaces (Behndig et al., 2009; Kelly, 2003; Kelly and Tetley, 1997). Depletion of ELF factors such as surfactant proteins, defensins, and/or club cell secretory protein (CCSP) has also been noted in models of air pollution to enhance susceptibility to respiratory infections. For example, diesel exhaust and O3 exposure deplete the lung of important host defense molecules including CCSP, surfactant protein A (SP-A), and surfactant protein D (SP-D), which directly impact susceptibility to respiratory infection (Ciencewicki et al., 2007; Gowdy et al., 2008). Another lung innate defense function altered by air pollution exposure is mucociliary clearance. Respiratory cilia move debris and potential pathogens trapped in mucus from the lower respiratory tract into the oropharynx where they can be swallowed or expectorated. Not only do cilia have reduced motion following air pollution exposure, but mucous becomes less viscous, significantly decreasing mucociliary clearance and increasing susceptibility to infection (Grose et al., 1980; Pedersen, 1990; Saldiva et al., 1992; Xiao et al., 2013). Air pollutants can also affect the integrity of the epithelial barrier. When exposed to PM, the tight junctions of the alveolar epithelium are disrupted by reactive oxygen-mediated destruction of zona occludens-1 (ZO-1) and occludin proteins (Caraballo et al., 2011; Wang et al., 2012). Disruption of tight junctions impacts the integrity of the alveolar-epithelial barrier, potentially facilitating the entry of pathogens into the respiratory interstitium.

Air pollution alters macrophage functions

The second mechanism by which air pollution may lead to increased susceptibility to respiratory infections is by causing macrophage dysfunction. Macrophage functions are critical to pulmonary host defense. These include phagocytosing pathogens, facilitating antigen presentation, and pathogen destruction via oxygen-dependent pathways. In addition, macrophages produce cyto/chemokines that recruit other important host-defense immune cells (Becker et al., 2005). To identify pathogens, macrophages use pathogen-associated molecular patterns (PAMPs) on microbes that are recognized by pattern recognition receptors (PRRs) including toll-like receptors 2 and 4 (TLR2 and TLR4). Air pollution can regulate the expression of PRRs as evidenced by the downregulation of TLR4 in human alveolar macrophages exposed to PM (Morrow, 1988). This impact on PRRs can then decrease the ability of macrophages to recognize invading pathogens. In addition to having a decreased ability to recognize pathogens, macrophages have decreased motility, altered phagocytosis, and augmented cytokine and chemokine production following air pollutant exposure (Becker and Soukup, 1999; Chauhan and Johnston, 2003; Kienast et al., 1996; Rylance et al., 2015). Although the majority of research has shown that exposure to air pollutants leads to decreased pathogen clearance by macrophages, a recent study by Vose et al. (2021) reported that exposure to wood smoke particles altered macrophage phenotypes leading to increased clearance of influenza infection and decreased markers of clinical severity. This suggests that different types of lung macrophages or exposures may result in different effects on respiratory infections. Despite this, macrophages are a principal target of air pollutants impacting lung infection, and more studies are needed to understand the underlying mechanisms.

Immune response alterations following air pollution exposure

Air pollution modifies cellular receptors used by pathogens to cause infection. Diesel exhaust, NO2, and O3 have been shown to increase the surface expression of intercellular adhesion molecule 1 (ICAM-1) (Ciencewicki et al., 2007; Pathmanathan et al., 2003; Spannhake et al., 2002; Takahashi et al., 1995). ICAM-1 is the primary cellular attachment for a number of viruses, including rhinovirus (Greve et al., 1989). Similarly, S. pneumoniae binds to host epithelial cells via platelet-activating factor receptor (PAFR) and exposure to PM10 has been shown to increase PAFR levels and bacterial attachment (Mushtaq et al., 2011). Similarly, both NO2 and PM2.5 have been shown to increase the expression of angiotensin converting enzyme-2 (ACE-2) in the respiratory epithelium, which is a cellular receptor for SARS-CoV-2 (Aztatzi-Aguilar et al., 2015; Hamming et al., 2004; Hoffmann et al., 2020; Lin et al., 2018; Paital and Agrawal, 2021). Despite this, a direct causal relationship between air pollution and SARS-CoV-2 infection in laboratory models has yet to be demonstrated.

In addition to increasing the expression of cellular receptors that pathogens use to gain access to cells, air pollutants can also augment the immune response leading to greater lung inflammation/injury which can perpetuate the systemic dissemination of pathogens. For example, respiratory epithelial cells recognize pathogens through a number of receptors, including toll-like receptors. When rodents are exposed to diesel exhaust prior to influenza infection, the preexposure to air pollution upregulated pulmonary expression of toll-like receptor-3 (TLR3) and increased airspace levels of IL-6, IFN-γ, and TNF-α (Ciencewicki et al., 2007). In most biological models of infection, an augmented immune response is beneficial to the host defense response by promoting pathogen clearance; however, in the context of air pollution, the increased inflammation is mostly coupled with increased pathogen burden. However, it is unclear why this paradox following air pollution exposure happens and few studies have addressed this. It has been shown that this augmented inflammatory response by air pollutants can lead to a disruption of the balance of proteases/antiproteases, allowing for a direct increase in viral entry into cells and/or host susceptibility (Kesic et al., 2012). However, emerging literature has also reported that air pollution exposure can modulate the adaptive immune responses by changing T cell polarization (ie, decreased regulatory T cells and Th22 polarization, increased Th17 and/or Th2 skewing) which results in prolonged inflammation and pathogen load in the lung (Deiuliis et al., 2012; Jaligama et al., 2018, 2017; Kumar et al., 2021; Li et al., 2022). Whether these adaptive immune changes are driven by increased pulmonary inflammation or direct effects on the adaptive immune response still remains unknown.

Air pollution disruption of the microbiome

The 4th mechanism of pollution-mediated respiratory infections is an alteration of the microenvironment within the airways promoting a more hospitable environment for pathogens to survive/proliferate. An important aspect of this is the formation of biofilm, which is clinically important due to its ability to confer antibiotic resistance (Hussey et al., 2017; Woo et al., 2018). When S. pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa are directly exposed to PM in vivo and in vitro, there is a significant increase in both biofilm thickness and complexity (Hussey et al., 2017; Li et al., 2017; Woo et al., 2018). Specifically, when Pseudomonas was exposed to PM, the biofilm it established had increased cellular adhesion to respiratory cells (Woo et al., 2018). This increased adhesion allows for increased pathogen uptake and/or entry and subsequent infection. In addition, when Streptococcus bacteria is exposed to PM, the bacteria had a higher rate of dissemination from the nasopharynx to the lungs, where it may lead to pneumonia (Yadav et al., 2020). Additionally, following air pollution exposure, there is not only a change in the 16S rRNA in the lung, with bacterial diversity decreasing, but also a significant increase in Proteobacteria in the lungs (Li et al., 2017). This dysbiosis of the lung microbiome with a decrease in commensal bacterial diversity as well as an increase in bacterial species is known to be pathogenic (Li et al., 2017; Wang et al., 2019; Yu et al., 2016).

Limitations

Though the laboratory research and mechanisms discussed above support the epidemiological findings of pollution-associated respiratory infections, there are still areas where further investigations are warranted. Currently, most human and rodent models used to evaluate the interaction of air pollution and infection are from young and otherwise healthy subjects/specimens. These healthy subjects are mostly used for both financial reasons and safety concerns. In contradiction to these commonly used models, most epidemiological findings report that susceptible populations (children and >65 years of age) are most at risk for air pollution-induced health effects. Furthermore, many of these current controlled human laboratory studies that are performed rely on collecting cellular samples (ie, BAL) which are difficult and complicated to collect and can confer an increased risk for complications. Due to these constraints, majority of the research models used for the study of pollution-associated respiratory infections are relatively limited in mechanism and may not accurately reflect the populations that are most susceptible. Lastly, most laboratory studies only examine a single air pollutant whereas epidemiological studies include exposure to a wide array of environmental exposures. Recent studies have reported that these exposures interact with each other, affecting the immune response in a way that is difficult to replicate in a controlled setting (Hathaway et al., 2021; Majumder et al., 2021a, b). Additionally, there may be interactions with criteria air pollutants and unregulated air toxins (ie, ultrafine particles, acrolein, and biomass). Many of these unregulated toxins have been implicated in pathogen susceptibility in laboratory studies (Brocke et al., 2022; Jaligama et al., 2017; Kumar et al., 2021; Rebuli et al., 2019) but very few are considered in population-based studies. Therefore, evaluating coexposures in the context of susceptibility to infection may yield differential results to the data that are already available. In conclusion, although current data support pollution-mediated damage to innate immune barriers, macrophages, and cellular receptors, the research community has just begun to understand the mechanisms behind pollution-associated respiratory infections and there is a need for more studies to better understand this interaction.

Conclusion and future directions

As highlighted by the current COVID-19 pandemic, respiratory infections are an important cause of human morbidity and mortality and a significant public health threat. Addressing these pandemic and future events will require a detailed understanding of factors that regulate infection risk and severity. Highlighted in this review, air pollution is an important factor impacting respiratory infection risk and severity. This is supported both by population associations in epidemiologic studies and causal mechanistic studies. Despite these observations, there remain gaps in our understanding. Resolving these gaps will be critical as the prevalence and severity of respiratory infections are expected to increase air pollution levels, despite regulations will continue to rise. Addressing this will require collaborations between different environmental health disciplines that will address interactions between respiratory infection and the environment. In addition, more transdisciplinary research is needed that leverages the strengths and weaknesses of population-based research with basic mechanistic studies to identify novel mechanisms by which air pollution alters respiratory infections, risk factors for these effects, and intervention strategies that target this risk. Ultimately, these measures would improve public health and limit morbidity and mortality associated with respiratory infection.

Declaration of conflicting interests

Dr. Brita Kilburg-Basnyat is currently employed by Arcus Biosciences, Inc but completed the majority of her contributions (concept and intellectual contributions) during her postdoctoral scholar position at East Carolina University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Contributor Information

Alexys Monoson, Department of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.

Evangeline Schott, Department of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.

Kerry Ard, School of Environment and Natural Resources, The Ohio State University, Columbus, Ohio 43210, USA.

Brita Kilburg-Basnyat, Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina 27834, USA.

Robert M Tighe, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Sonal Pannu, Department of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.

Kymberly M Gowdy, Department of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.

Funding

National Institute of Environmental Health Sciences (R01ES028829 to K.M.G., R01ES027574 to R.M.T.).

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