Exposure to air pollution, including gaseous pollution and particulate matter (PM) pollution, is a leading contributor to the Global Burden of Disease (GBD 2015 Risk Factors Collaborators, 2016). In recent years, more and more attention has been paid to the impact of PM pollution on public health. PM is a complex mixture of solids and liquids suspended in the air, which can be classified by its aerodynamic diameter as PM₁₀ (<10 μm, inhalable particulate matter), PM_2.5 (<2.5 μm, fine particulate matter) and PM_0.1 (<0.1 μm, ultrafine particulate matter). PM originates from natural sources (such as dust, sea salt, and wildfires) and anthropogenic emissions (such as vehicles, household wood and coal burning as well as power plants and industry), and the latter accounts for most of the PM pollution (Cho et al., 2018). The components of PM are extremely complex, including inorganic components (such as heavy and transition metals, elemental carbon, and sulfuric/nitric/ammonia salts), organic components (such as polycyclic aromatic hydrocarbons) and biological components (such as fungi, spores, and viruses) (Zhang et al., 2015; Cho et al., 2018). There are certain differences in the source and composition of different types of particulate matter, and the harm to public health varies as well (Figure 1). Among them, PM_2.5 was considered to be the most harmful one. PM_2.5 has a large surface area and can adsorb a variety of toxic and harmful substances (Hsu et al., 2016). Because of its small particle size, it can penetrate deep into the lungs and deposit in the terminal bronchioles and alveoli with breath, and even enter the circulatory system through the gas-blood barrier (Pinkerton et al., 2000; Schulze et al., 2017). Exposure to PM_2.5 can endanger multiple organs in the body, and even lead to systemic adverse effects (Chauhan and Johnston, 2003). Among them, the most common are the respiratory and cardiovascular systems (Xing et al., 2016). This review focuses on the respiratory system, the primary target organ for PM_2.5 exposure.

PM_2.5 may be the environmental risk factor that poses the greatest public health hazard. The GBD 2015 ranks PM_2.5 as the fifth leading risk factor for death, with exposure to PM_2.5 causing 4.2 million deaths (7.6% of global deaths) and loss of 10.31 million disability-adjusted life-years (DALYs) (4.2% of global DALYs) (Cohen et al., 2017). As claimed by the World Health Organization (WHO), 9 out of every 10 people in urban areas are exposed to high levels of PM_2.5 (annual average concentration >10 μg/m³) from outdoor air pollution, and about 3 billion people using non-renewable fuels are exposed to serious indoor air pollution (World Health Organization [WHO], 2019). According to the Air Quality Life Index (AQLI), sustained exposure to an additional 10 μg/m³ of PM_2.5 reduces life expectancy by 0.98 years¹. In addition, an increase of 10 μg/m³ per day of PM_2.5 concentration increases 0.29% of overall non-accidental mortality and 0.22% of respiratory disease mortalities (Chen et al., 2017).

A large number of epidemiological studies have shown that PM_2.5 exposure is closely related to a variety of respiratory diseases (Jo et al., 2017; Wang C. et al., 2019). It is noteworthy that exposure to PM_2.5 increases the susceptibility to respiratory infections. For instance, numerous clinical studies have found that PM_2.5 exposure is positively correlated with the number of outpatient visits, emergency visits, and hospitalizations for acute upper or lower respiratory infections (Li et al., 2017; Xia et al., 2017; Strosnider et al., 2019). Related animal models also support the notion that PM_2.5 exposure increases susceptibility to the lung infection (Yang et al., 2001; Sigaud et al., 2007; Zhao et al., 2014). However, the underlying mechanisms remain elusive. We speculate that PM_2.5 exposure may impair the host defense of the respiratory system, making the body more susceptible to infection. The purpose of this article is to review the existing epidemiological and experimental evidence to support the above hypothesis and to summarize the possible underlying mechanisms.

The respiratory system is the primary route for inhaled PM_2.5. Exposure to PM_2.5 can cause the development and progression of acute and chronic lung diseases, such as tracheal and pulmonary inflammation (Kampa and Castanas, 2008; Jedrychowski et al., 2013; Ge et al., 2018), asthma and its acute exacerbations (Habre et al., 2014; Zheng et al., 2015), chronic obstructive pulmonary disease (COPD) and its acute exacerbations (Faustini et al., 2013; Tsai et al., 2013). We are concerned with the fact that PM_2.5 exposure increases the susceptibility to respiratory infections.

Outpatient, emergency, and hospitalization-related data on respiratory infections confirmed that PM_2.5 exposure was positively associated with the increased respiratory infections. Li et al. (2017) studied the effects of air pollution on outpatients’ acute respiratory outcomes and their study indicated that PM_2.5 exposure was positively correlated with outpatient visits for upper respiratory tract infection (URTI). A study in the U.S. state of Georgia also showed that pediatric emergency visits for URTI were associated with PM_2.5 concentrations (Strickland et al., 2016). Another study reported that PM_2.5 was significantly associated with emergency room visits for respiratory diseases, particularly for URTI and lower respiratory tract infection (LRTI) (Xu et al., 2016). Recently, Strosnider et al. (2019) confirmed that PM_2.5 exposure was positively correlated with emergency visits for multiple respiratory diseases, including respiratory infections. In addition, Xia et al. (2017) studied the association between different types of air pollution and respiratory hospitalization and found that short-term exposure of PM_2.5 was positively correlated with the number of hospitalizations for acute respiratory infections. Similarly, another four studies also supported a significant positive correlation between PM_2.5 and the number of hospitalizations for URTI and LRTI (Belleudi et al., 2010; Li et al., 2018; Liu et al., 2019b; Zhang D. et al., 2019).

The effect of PM_2.5 exposure on respiratory infections is not immediate, but there is a certain lag effect. For example, PM_2.5 exposure was positively associated with an increase in hospitalization for acute respiratory infections, but this correlation was delayed by 7–13 days (Xia et al., 2017). Liang et al. (2014) analyzed the time curve of PM_2.5 concentration and human influenza in Beijing urban area from 2008 to 2011, and proved that there was a significant correlation between PM_2.5 exposure and influenza, but this correlation showed a 1–2 months delay. In a study of 150,000 cases, Horne et al. (2018) investigated the relationship between PM_2.5 and the health status of patients with acute LRTI and discovered that the association of PM_2.5 exposure with respiratory syncytial virus (RSV) infection occurred in 2–4 weeks. The hysteresis effects varied in different studies. Therefore, when investigating the association between PM_2.5 exposure and respiratory infections, researchers may need to choose the appropriate follow-up time.

Exposure to PM_2.5 increases the susceptibility to respiratory infections, especially in children and the elderly, as well as the vulnerable groups with hereditary or underlying diseases. A study on the relationship between PM_2.5 and the health status of patients with acute LRTI revealed that about 77% of the subjects were infants aged 0–2 years. RSV and influenza virus were the main pathogens (Horne et al., 2018). Another study on risks of respiratory infections associated with air pollution in China showed that children under the age of 14 were the predominantly susceptible population of acute respiratory infections caused by air pollution, accounting for 80% of hospitalized cases of respiratory system infections in the study (Xia et al., 2017). Similarly, Liu et al. (2019b) found that students aged 6–17 years were more vulnerable to PM_2.5 exposure. The maternal exposure to air pollution before birth may result in an impaired lung development and increase the risk of respiratory system infections (Pinkerton and Joad, 2006; Jedrychowski et al., 2013). In addition, by analyzing the association between PM_2.5 pollution and hospital emergency room visits for total and cause-specific respiratory diseases in urban areas in Beijing, Xu et al. (2016) found that people over 60 years of age demonstrated a higher risk of respiratory disease (including URTI and LRTI) after PM_2.5 exposure. Exposure to PM_2.5 is more likely to cause respiratory infections in people with congenital immune deficiencies due to hereditary diseases. For instance, exposure to PM_2.5 in patients with cystic fibrosis has been reported to be associated with the acquisition of Pseudomonas aeruginosa (P. aeruginosa). During the follow-up period, each additional PM_2.5 exposure of 10 μg/m³ increased the risk of 24% P. aeruginosa acquisition (Psoter et al., 2015). Another study has found that each additional PM_2.5 exposure of 10 μg/m³ increased the risk of methicillin-resistant Staphylococcus aureus (MRSA) by 68% (Psoter et al., 2017).

In vivo studies have shown that as a risk factor for respiratory infection, PM_2.5 exposure, can prime the lung for greater susceptibility to pathogens by impairing the respiratory host defense. Yang et al. (2001) found that PM exposure suppressed macrophage function and slowed the pulmonary clearance of Listeria monocytogenes (L. monocytogenes) in rats. Another research discovered that the colony-forming units (CFUs) of P. aeruginosa detected in the lung were significantly greater in the PM-exposed mice compared to the control mice (Liu et al., 2019a). Zhao et al. (2014) found that prior PM_2.5 exposure markedly increased the susceptibility of rats to subsequent Staphylococcus aureus (S. aureus) infection. Similarly, Duan et al. (2013) found that PM_2.5 exposure increased the susceptibility of rats to Klebsiella pneumoniae (K. pneumoniae) infection. Sigaud et al. (2007) and Migliaccio et al. (2013) established an exposure model in mice and subsequently infected with Streptococcus pneumoniae (S. pneumoniae). They found that PM exposure reduced bacterial clearance in the lungs of mice. In addition, Ma et al. (2017) discovered that exposure to PM_2.5 lowers influenza virus resistance. We summarized the in vivo experimental studies of PM_2.5 on respiratory host defense (Table 1).

In vitro experiments have also confirmed that PM_2.5 exposure increased the susceptibility of respiratory infection. For example, PM_2.5-pretreated A549 cells have a significantly increased risk of infection with Mycobacterium tuberculosis (M. tuberculosis) (Rivas-Santiago et al., 2015), and PM can disrupt the airway epithelium through oxidative burst to promote P. aeruginosa infection (Liu et al., 2019a). Similarly, Chen et al. (2018) found that PM suppressed airway antibacterial defense, causing an increased susceptibility to P. aeruginosa. In addition, adhesion is the key to microbial invasion of the respiratory tract. PM increased the binding of S. pneumoniae to both primary alveolar macrophages (AMs) and the murine macrophage cell line J774 A.1 but decreased internalization of bacteria (Zhou and Kobzik, 2007). Mushtaq et al. (2011) have discovered that urban PM increased the adhesion of S. pneumoniae to human tracheal epithelial cells. We also summarized the in vitro experimental studies of PM_2.5 on respiratory host defense (Table 2).

PM_2.5 exposure impairs the host defense of respiratory system causing the body more susceptible to infection. We dissect the underlying mechanisms from the following three aspects: defective airway epithelial host defense functions, alterations in respiratory microecology, insufficiency and dysfunction of immune cells (Figure 2).

In summary, there are sufficient epidemiological evidences from outpatient, emergency and hospitalization-related data that exposure to PM_2.5 increases susceptibility to respiratory infections. However, studies on the association between PM_2.5 exposure and age, gender, and specific pathogens remain controversial. In the future, a meta-analysis of existing research can be attempted to further confirm the susceptible population of PM_2.5 exposure to respiratory infections. We notice that there is a lag effect in the association between PM_2.5 exposure and respiratory infections. This may be due to the variations of the average incubation period of different pathogens. We also note that only a few epidemiological studies have reported the relationship between PM_2.5 exposure and the infection rates of specific pathogens associated with respiratory infections. Is there a specific pathogen preference for respiratory infections caused by PM_2.5 exposure? This still requires the unremitting efforts of the researchers.

In vivo and in vitro studies have shown that PM_2.5 exposure is beneficial to the adhesion, colonization and growth of microorganisms, but it is not conducive to the removal from the body. However, most of the current in vivo experiments establish a PM_2.5 exposure animal model by intratracheal instillation. This model usually affects the lower respiratory tract and is prone to uneven distribution in the lung lobes. Concentration and enrichment of PM_2.5 aerosol combined with the oral-inhalation or whole-body exposure system may be the best model for simulating human exposure. In recent years, an emerging technology has appeared, combing versatile aerosol concentration enrichment system (VACES) with oral-inhalation or whole-body exposure system. The advantages and disadvantages of these two models are shown in Table 3. Furthermore, current in vitro experiments are limited to epithelial cells- and alveolar macrophage-mediated innate immune responses, lacking attention to adaptive immune responses. Either in vivo or in vitro, the exposure doses currently used in the study are usually based on the corresponding toxicity experiments. How can such exposure levels represent real-world or clinical scenarios?

PM_2.5 exposure may impair the host defense system of respiratory system, making the organism susceptible to infection. In brief, the possible mechanisms include defective airway epithelial host defense functions, alterations of the respiratory tract microecology, and insufficient number or dysfunction of immune cells (Figure 2). However, there is still a lack of robust research on molecular mechanisms. Further efforts are desperately needed to elucidate the underlying mechanisms at the molecular level.

XT conceived and designed the manuscript. LY, CL, and XT wrote the manuscript and critically revised it. CL and XT generated the figures. XT provided guidance and edited the manuscript.

The 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.