SARS-CoV-2 and helminth co-infections, and environmental pollution exposure: An epidemiological and immunological perspective

Soil-transmitted helminths infect billions of people globally, particularly those residing in low- and middle-income regions with poor environmental sanitation and high levels of air and water pollution. Helminths display potent immunomodulatory activity by activating T helper type 2 (Th2) anti-inflammatory and Th3 regulatory immune responses. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus disease 2019 (COVID-19), can exacerbate Th1/Th17 pro-inflammatory cytokine production in humans, leading to a cytokine storm. Air pollutants (particulate matter, oxygen radicals, hydrocarbons and volatile organic compounds) and water pollutants (metals and organic chemicals) can also intensify Th1/Th17 immune response and could exacerbate SARS-CoV-2 related respiratory distress and failure. The present review focused on the epidemiology of SARS-CoV-2, helminths and fine particulate matter 2.5 µm or less in diameter (PM2.5) air pollution exposure in helminth endemic regions, the possible immunomodulatory activity of helminths against SARS-CoV-2 hyper-inflammatory immune response, and whether air and water pollutants can further exacerbate SARS-CoV-2 related cytokine storm and in the process hinder helminths immunomodulatory functionality. Helminth Th2/Th3 immune response is associated with reductions in lung inflammation and damage, and decreased expression levels of angiotensin-converting enzyme 2 (ACE2) receptors (SARS-CoV-2 uses the ACE2 receptors to infect cells and associated with extensive lung damage). However, air pollutants are associated with overexpression of ACE2 receptors in the epithelial cell surface of the respiratory tract and exhaustion of Th2 immune response. Helminth-induced immunosuppression activity reduces vaccination efficacy, and diminishes vital Th1 cytokine production immune responses that are crucial for combating early stage infections. This could be reversed by continuous air pollution exposure which is known to intensify Th1 pro-inflammatory cytokine production to a point where the immunosuppressive activities of helminths could be hindered. Again, suppressed activities of helminths can also be disadvantageous against SARS-CoV-2 inflammatory response. This “yin and yang” approach seems complex and requires more understanding. Further studies are warranted in a cohort of SARS-CoV-2 infected individuals residing in helminths and air pollution endemic regions to offer more insights, and to impact mass periodic deworming programmes and environmental health policies.

Environmental pollution, an activator of pro-inflammatory Th1 immune responses, is proposed to also exacerbate COVID-19 severity and insidiously dampen the immunomodulatory activity of helminths in COVID-19 patients (Dvorožňáková et al., 2016;Frontera et al., 2020;Saraswathy et al., 2018). Globally, around 92% of the world population breathes unhealthy levels of air pollution (World Health Organization, 2016). The WHO reported that air pollution accounts for over 6.5 million deaths worldwide annually. This is equivalent to 11.6% (1 in every 9 deaths) of all global deaths annually, and over 90% of deaths occurred in low and middle-income countries. Over 6.1 million deaths (94%) occurred due to air pollution-induced non-communicable diseases (chronic obstructive pulmonary disease, cardiovascular disease, lung cancer and stroke) (World Health Organization, 2016). Studies have associated air pollution, a potent oxidative stress and inflammation inducing agent, with adverse alterations in host immune system and cytokine production Pope et al., 2016;Saraswathy et al., 2018) and COVID-19 severity (Frontera et al., 2020) in humans. Drinking water pollutants (plastic components, plasticizers, metals, phthalates, bisphenol A and per-and polyfluoroalkyl substances) have also been reported to compromise the immune system which results in exacerbation of COVID-19 respiratory symptoms in humans (Quinete and Hauser-Davis, 2020).
Studies focusing on helminth and SARS-CoV-2 co-infections in areas affected with environmental pollution are scarce. The present review highlights the: (i) prevalence of SARS-CoV-2, helminths and fine particulate matter 2.5 µm or less in diameter (PM 2.5 ) air pollution exposure in helminth endemic regions, (ii) regulatory role of helminths, (iii) dysregulatory role of environmental pollution, and (iv) regulatory/ dysregulatory role of helminths and environmental pollution coexposure in response to SARS-CoV-2 immune responses and severity.

Overview on SARS-CoV-2
Coronaviruses are large, positive-stranded, enveloped RNA viruses. The viral envelope is associated with at least four structural proteins namely nucleocapsid nucleoprotein, membrane, envelope and spike proteins (Malik, 2020). To date, seven human coronaviruses have been identified which are known to cause mild [HKU1, NL63 and OC43 (Betacoronaviruses) and 229E (Alphacoronavirus)] and severe [Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS-CoV and SARS-CoV-2] respiratory illness and disease .
Patients with co-infections or co-morbidities such as obesity, human immunodeficiency virus (HIV) and tuberculosis, hypertension, metabolic syndrome, diabetes, cardiovascular disorders, kidney disease and respiratory disorders are most at risk of developing severe COVID-19 (Zhou et al., 2020). Patients with COVID-19 in Wuhan, China displayed symptoms of dyspnoea and lymphopenia and developed acute respiratory distress syndrome, acute cardiac injury, RNAaemia and secondary infection complications .
SARS-CoV-2 utilizes host cell factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), to enter cells (Hoffmann et al., 2020). The SARS-CoV-2 spike protein interacts with the ACE2 receptor to promote cell entry while the TMPRSS2 plays a role in SARS-CoV-2 spike protein priming and cleavage, allowing viral and cellular membrane fusion and entry of the virus into cells (Hoffmann et al., 2020).
ACE2, an 805-amino acids captopril-insensitive carboxypeptidase, is expressed in lung alveolar epithelial cells, nasal epithelial cells, arterial and venous endothelial cells, enterocytes and arterial smooth muscle cells. ACE2 is an important regulator in lung diseases, diabetes, hypertension and cardiovascular diseases (Alifano et al., 2020). TMPRSS2, a 70-kDa serine protease, is associated with several physiological and pathological processes namely digestion, blood coagulation, tissue remodelling, tumour cell invasion, inflammatory responses and apoptosis (Antalis et al., 2011).
ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells and shown to be most vulnerable to SARS-CoV-2 infection (Lukassen et al., 2020). Studies have speculated that binding of SARS-CoV-2 to ACE2 could negatively affect the overall functionality of ACE2, leading to the overproduction of reactive oxygen species and the pathophysiology of cardiovascular and respiratory failure (Alifano et al., 2020).
Studies have found that children have lower SARS-CoV-2 infection rate, display milder symptoms and have better clinical outcomes compared to adults (Ludvigsson, 2020). Researchers attributed this to lower ACE2 gene expression levels in nasal passage epithelial cells taken from children compared to adults. It was further concluded that ACE2 gene expression was age-dependent and increases with age into adulthood (Bunyavanich et al., 2020). Researchers also investigated whether lung ACE2 and TMPRSS2 expression levels in children and adults vary using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry. They also explored whether gene expression levels might influence milder SARS-CoV-2 symptoms in children. No significant changes in lung ACE2 and TMPRSS2 expression levels were observed between children and adults, even though the percentage of cells expressing TMPRSS2 were higher in adults. Alveolar type 2 (AT2) cells had the highest ACE2 expression while alveolar type 1 (AT1) cells in children and club cells in adults also showed noticeable expression. In both adults and children, AT1, AT2 and club cells were the main cell types with relatively high TMPRSS2 expression. It was concluded that lung ACE2 and TMPRSS2 expression levels was unlikely to be a major reasoning behind lower virus intrusion rate and milder symptoms in children, and unique features in children's underdeveloped immunity systems may play a far more pivotal role (Tao et al., 2020). A possible explanation is that children have decreased mononuclear and polymorphonuclear chemotaxis, and enhanced and trained innate and adaptive immune systems if they are frequently exposed to a broad spectrum of pathogens compared to adults (Tao et al., 2020).

SARS-CoV-2 variants
In comparison to the SARS-CoV outbreak in 2002 in Guangdong, China and MERS-CoV outbreak in 2012 in Jeddah, Saudi Arabia, the current SARS-CoV-2 which originated from Wuhan, China in 2019 is treacherously and potently more infectious in humans due to mutations in the SARS-CoV-2 spike glycoprotein (mediates viral entry into cells through cell receptor binding and membrane fusion) and nucleocapsid nucleoprotein (regulates viral replication and thus influences transcription and assembly) in addition to its ability to infect and reproduce in the upper respiratory tract (Lippi and Plebani, 2020).
Several mutations in the SARS-CoV-2 spike protein can greatly enhance viral infectivity and pathogenicity, and the Center for Disease Control and Prevention (CDC) classified these mutations as variants of concern and of high consequence. This includes the B.  et al., 2021). In April 2021, India report on the emergence of a more infectious SARS-CoV-2 variant, B.1.617, that has the ability to enhance viral replication and evade antibodies. The B.1.617 variant carries two mutations known as E484Q and L452R. The E484Q mutation mirrors E484K, a mutation found in the South African (B.1.351) and United Kingdom (B.1.1.7) variants, while the L452R mutation is also found in the highly transmissible Californian (B.1.427/ B.1.429) variants (The Indian Express, 2021). With the ongoing emergence and discovery of highly infectious SARS-CoV-2 variant strains, this could lead to changes in pathogenicity patterns in children, and trigger higher morbidity and mortality rates in adults.

SARS-CoV-2 and the gut microbiota
SARS-CoV-2 also infects the mature human intestinal cells, the ACE2 receptors-expressing enterocytes of the small intestines in particular, which may lead to gastrointestinal symptoms such as abdominal pain, vomiting and diarrhoea during the early phases of COVID-19 (Dhar and Mohanty, 2020;Kaźmierczak-Siedlecka et al., 2020). Intestinal ACE2 receptors act as a chaperone for membrane trafficking of the sodiumdependent neutral amino acid transporter B 0 AT1. In the intestinal epithelium, the B 0 AT1/ACE2 complex regulates the composition and function of the gut microbiota, leading to ambiguous changes in host immune responses against pathogens (Viana et al., 2020).

SARS-CoV-2, environmental pollution and cigarette smoking
Studies examining the effects of environmental pollution and cigarette smoking on COVID-19 severity are summarised in Table 1. Chronic exposure to air pollution [particulate matter (PM), nitrogen dioxide (NO 2 ), sulphur dioxide (SO 2 ), ozone (O 3 ), carbon monoxide (CO), polycyclic aromatic hydrocarbons and volatile organic compounds] can exacerbate SARS-CoV-2 related adverse health outcomes (respiratory distress and failure) and mortality rates (Domingo and Rovira, 2020;Konstantinoudis et al., 2021;Wu et al., 2020;Zhu et al., 2020;Bashir et al., 2020). Studies have postulated that the SARS-CoV-2 might have the ability to attach to airborne atmospheric particulates (PM 2.5-10 ) which could be a contributing factor towards the high prevalence of indirect transmission rates in humans (Sanità di Toppiet al., 2020). Frontera and colleagues (2020) proposed a "double-hit hypothesis". They found chronic exposure to PM 2.5 and NO 2 intensified SARS-CoV-2 related mortality rates. Chronic PM 2.5 exposure led to the overexpression of alveolar ACE2 receptor which was associated with high viral load in patients. This then led to the exhaustion of ACE2 receptors and impaired host defences. Chronic NO 2 exposure provided a second hit which caused a more severe form of SARS-CoV-2 in the ACE2 depleted lungs and was responsible for extensive lung damage (Frontera et al., 2020). Cigarette smoking and tobacco smoke exposure was also associated with increased ACE2 and TMPRSS2 expression which led to severe SARS-CoV-2 infections (Cai, 2020;Gülsen et al., 2020;Zhao et al., 2020). Woodby and colleagues (2021) hypothesized that air pollutants have the ability to promote SARS-CoV-2 entry and life cycle in the body through several mechanisms, including preventing antiviral activity of antimicrobial peptides and surfactant protein D, inhibition of mucociliary clearance, promoting TLR2 and TLR4 signalling that are specific for bacterial sensing, increasing ACE2 receptor expression levels, promoting TMPRSS2 cleavage, altering viral replication and assembly mediated by autophagy, modulating interferon production, preventing uptake by macrophages, and increasing epithelial permeability to promote viral spread (Woodby et al., 2021).

Table 1
Summary of studies focusing on the effects of environmental pollution and cigarette smoking on COVID-19 severity.

References
Aim of study Methodology Major findings Konstantinoudis et al., 2021 -Temporal association between long-term air pollution (NO 2 and PM 2.5 ) and COVID-19 mortality in England.
-Air pollution concentrations were retrieved between 2014 and 2018.
-Bayesian hierarchical models were used for data analysis.
Wu et al., 2020 -Temporal association between long-term PM 2.5 exposure and COVID-19 mortality in the U.S.A.
-COVID-19 death counts were collected from 3,000 counties in the U.S.A up to 22 April 2020.
-Zero-inflated negative binomial models were used for data analysis.
Zhu et al., 2020 -Temporal association between air pollution (PM 2.5 , PM 10 , NO 2 and O 3 ) and daily confirmed COVID-19 cases in China.
-Generalized Additive Models (GAM) were used for data analysis. -Retrospective study.
-Environmental pollution concentration and total confirmed cases and mortality of COVID-19 were retrieved between 4 March -24 April 2020.
-Kendall (K) and Spearman (S) correlation (r) tests were used for data analysis.  -COPD and ongoing smoking collectively worsen COVID-19 severity and outcomes. Cai, 2020 -To investigate the disparity related to tobacco use in lung ACE2 gene expression and its distribution among cell types in order to predict COVID-19 susceptibility.
-Cross-sectional study -Large-scale bulk transcriptomic datasets of normal lung tissue were retrieved to investigate the disparity related to smoking status in ACE2 gene expression.
-Single-cell transcriptomic datasets were retrieved to investigate the distribution of ACE2 gene expression among cell types.
-Former smoker's lung had higher ACE2 gene expression compared to non-smoker's lung.
-Bronchial epithelium: ACE2 is highly expressed in goblet cells and club cells of current smokers and non-smokers, respectively.
Helminthic infections (the most prevalent neglected tropical diseases) predominantly occur in the intestines as well as in the blood, lungs, liver and brain . Risk factors associated with soil-transmitted intestinal helminth infection are low socioeconomic status, poor availability of clean water, poor sanitation and poor hygiene . Mebendazole (most favoured), praziquantel, albendazole and diethylcarbamazine are some of the anthelmintic drugs used in the mass control and prevention of helminth infections (Dayan, 2003). Lately, ivermectin, an anti-parasitic and anthelmintic drug, was reported to inhibit the replication of SARS-CoV-2 in vitro (Caly et al., 2020).
Soil-transmitted helminth infections often tend to be mild or asymptomatic in humans however severe infections do occur leading to nutritional deficiencies, several allergy-related atopic diseases, mental delays, growth and development delays, organ failure and death (Cepon-Robins and Gildner, 2020).
Helminth infections can modify the gut microbiota composition in the intestines and exacerbate bacterial colitis (Su et al., 2018). They secrete excretory-secretory products that have antimicrobial activity (Abner et al., 2001;Brosschot and Reynolds, 2018), and also modify human production of anti-microbial peptides (Brosschot and Reynolds, 2018;Fricke et al., 2015). Helminths and Lactobacilli species have coevolved and display a mutualistic relationship with the aim of regulating mucosal immune responses in order to thrive in the intestinal environment; Lactobacilli species increases in abundance during chronic helminth infection and promotes the pathogenesis of persistent helminth infection (Brosschot and Reynolds, 2018). Nutritional deficiencies in the intestines and diminished epithelial glucose absorption are also associated with helminth infections (Brosschot and Reynolds, 2018;Shea-Donohue et al., 2001).
In a Malaysian cohort, helminth parasites (Ascaris species and Trichuris species) was associated with increased faecal abundance of Paraprevotellaceae (strongly associated with the Trichuris species), Alphaproteobacteria, Bacteroidales and Mollicutes, and enriched metabolic pathways involving amino acids and nucleotides biosynthesis in the microbiota. In helminth-negative patients, a high abundance of Bifidobacterium, and enriched xenobiotic and carbohydrate metabolism pathways was observed in the microbiota. Trichuris worms alone was associated with highly enriched pathways involved in nucleotide metabolism, and cell growth and death while Ascaris worms alone was correlated with reduced activity of carbohydrate metabolic pathways in the microbiota (Lee et al., 2014). In Zimbabwe, children infected with Schistosoma hematobium displayed increased faecal abundance of bacteria within the genus Prevotella (Kay et al., 2015).

Epidemiology of SARS-CoV-2, helminths and PM 2.5 air pollution in helminth endemic regions
The prevalence of SARS-CoV-2, helminths and PM 2.5 air pollution levels in helminth endemic WHO regions worldwide are summarized in Tables 3, 4 and 5. Data for helminths (World Health Organization, 2021a) and PM 2.5 air pollution (World Health Organization, 2021b) prevalence were retrieved from the WHO online website. Data for the prevalence of SARS-CoV-2 (total cases, total deaths and total recovered) was retrieved from the Worldometer online website that gives real time world statistics (Worldometer, 2021). Helminth endemic countries or territories are grouped into 6 WHO regions: Africa, The Americas, Eastern Mediterranean, European region, South East Asia and Western Pacific.
The Americas had the highest SARS-CoV-2 mortality rate (3,22%) followed by Sub-Saharan Africa (2,52%), Eastern Mediterranean (2,09%), Western Pacific (1,97%), South East Asia (1,33%) and European region (1,31%) (Tables 3-5). COVID-19 lethality rate deviate between continents, regions and countries, with notable higher rates in Europe and the United States of America (non-helminth endemic regions as specified by the WHO), regions that are economically developed with optimal health systems. On the contrary, helminth endemic regions with poor economies and inadequate health care facilities tend to have low COVID-19 lethality (Fonte et al., 2020). It was hypothesized that the immunomodulatory role of helminths could be a reason behind the low Table 2 Global prevalence and morphological characteristics of intestinal helminths (Lindquist and Cross, 2017;Parija et al., 2017).

Intestinal helminths
Global prevalence lethality rates. However, several other factors could also influence these outcomes such as age, population genetics, unavailability of diagnostic testing, SARS-CoV-2 mutations, and environmental humidity and temperature that oppose viral replication (Fonte et al., 2020). Both HIV and tuberculosis infections are independent risk factors for increasing COVID-19 mortality rates (WCDH and NICD, 2020); Sub-Saharan Africa has the highest prevalence of both infections in the world, and had the second highest COVID-19 mortality rate (Table 3). The harmful impacts of air pollution in adversely affecting host immune response and triggering the manifestation of severe SARS-CoV-2 infections will be discussed further later on.

Immunological features of soil-transmitted helminths, SARS-CoV-2 and environmental pollution
Cytokines are synthesized by a wide variety of immune cells, predominantly, by T cells, macrophages and neutrophils, which play an important role in promoting and regulating immune responses towards a broad spectrum of parasites, bacteria and viruses (Lucas et al., 2020).
Helminths display potent immunomodulatory activities via suppression of Th1 pro-inflammatory immune responses and activation of Th2 anti-inflammatory immune responses (Fonte et al., 2020). Helminths controls Th1 and Th2 immune responses by enhancing the activities of alternatively activated macrophages (AAMs), FOXP3+ Treg cells and regulatory B cells, leading to the release of anti-inflammatory cytokines (IL-10, TGF-β) (Fonte et al., 2020). Helminth-induced tissue injury activates the production of cytokine alarmins (ILC2, IL-25, IL-33), leading to the activation of Th2 cytokines production by Th2 cells, thymic stromal lymphopoietin (TSLP) cells, eosinophils and basophils Salgame et al., 2013). The production of cytokines IL-4, IL-5, IL-9 and IL-13, the primary mediators of Th2 responses, is triggered by IL-25 and IL-33. IL-12 production by dendritic cells, a major promoter of Th1 responses, is limited by TSLP (Fonte et al., 2020). Additionally, macrophages exposure to the Th2 cytokines IL-4 or IL-13 can result in the suppression and stimulation of the classically activated macrophages (M1) and alternatively activated macrophages (M2), respectively Salgame et al., 2013). Helminth-produced excretory-secretory antigens stimulate dendritic cells to produce immunoregulatory cytokines (IL-10 and TGF-β) and also inhibit dendritic cell synthesis of pro-inflammatory costimulatory molecules, cytokines and chemokines Salgame et al., 2013). Helminth infection can also stimulate regulatory dendritic cells to promote the synthesis and differentiation of Tregs, leading to the down-regulation of pro-inflammatory Th1 and Th17 responses (and its related cytokines IFN-γ, TNF-α, IL-12, IL-17, IL-23) by Th2 cytokines Fonte et al., 2020;Salgame et al., 2013). Th17 cells secrete IL-17A and IL-17F and produces IL-21 and IL-22, maintain the mucosal barrier, manages host defence against pathogens and also play a role in the induction of tissue inflammation and destruction (Guglani and Khader, 2010).

SARS-CoV-2 immune responses
Patients with COVID-19 initially display respiratory disease symptoms which can further lead to pneumonia and disseminated inflammation, and eventually resulting in the occurrence of a "cytokine storm" and multiple complications including sepsis-like syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome and failure of multiple organs (Azkur et al., 2020). The "cytokine storm", an indicator of disease severity and fatal outcomes, is stimulated by the activation of several white blood cells (monocytes, neutrophils, dendritic (Azkur et al., 2020;Behrens and Koretzky, 2017). Adverse changes in the gut microbiota, induced by SARS-CoV-2, stimulates COVID-19 disease severity and dysfunctional immune responses by intensifying the magnitude of several inflammatory chemokines, cytokines and tissue damage blood markers . The expression of cytokines and tissue reparative growth factors in patients with moderate, severe and critical COVID-19 is summarized in Fig. 1.
Lucas and colleagues (2020) identified specific immunological markers that occur early in patients with COVID-19 which strongly correlated with poor health outcomes and death. They associated increased levels of IFN-α before the first 12 days from symptom onset with lengthier hospital stays and death in patients with COVID-19. In addition, patients who eventually died of COVID-19 displayed significantly higher levels of IL-1Ra, IFN-α and IFN-λ, as well as chemokines (CCL1, MCP-1, CCL21, M-CSF, IL-2, IL-16) associated with the recruitment and survival of monocytes and T cells within the first 12 days from symptom onset (Lucas et al., 2020).

Environmental pollution-induced immune responses
Similar to SARS-CoV-2 and COVID-19, environmental pollution (air and water pollution) can also trigger the activation of several inflammation associated pathways and diseases, and adversely affects the host immune system (Quinete and Hauser-Davis, 2020;Saraswathy et al., 2018). Prolonged and chronic exposure to environmental pollution can lead to the exhaustion and diminished activity of Th2 immune response (Quinete and Hauser-Davis, 2020;Saraswathy et al., 2018). Air pollution is associated with the pathogenesis of several complications and diseases in the lungs (chronic obstructive pulmonary disease and asthma), heart (myocardial ischemia, atherosclerosis and hypertension), blood (increased coagulability, reduced oxygen saturation and peripheral thrombosis) and brain (cerebrovascular ischemia, neurodegeneration and impaired neurotransmitter signalling) (Quinete and Hauser-Davis, 2020;Saraswathy et al., 2018).
Water pollutants such as metals (copper, cadmium, mercury, lead, chromium and arsenic) and organic chemicals (polyfluoroalkyl substances, bisphenol A and phthalates) can also be immunotoxic and compromise the immune response of humans by dysregulating Th1 and Th2 cytokine production (Quinete and Hauser-Davis, 2020). They display endocrine disrupting properties and are associated with autoimmune diseases, and reproductive, developmental and neurological disorders (Quinete and Hauser-Davis, 2020).
In humans, high arsenic levels were correlated with increased incidences of allergies, asthma and parasitic infections, and significantly inhibited the secretion of IL-2, resulting in immunosuppression and favouring opportunistic infections (Quinete and Hauser-Davis, 2020;Soto-Peña et al., 2006). Increased IL-1β (chromium and mercury) and TNF-α (low mercury concentration), and decreased IL-6, IL-8, IL-10 and IFN-γ (chromium) and TNF-α and IL-1β (high mercury concentration) expression levels were noted in human PMBCs (Maria et al., 2000). BALB/c mice consuming water containing lead and copper displayed an upregulation of IFN-γ and IL-4 expression downregulated in the leadtreated group only (Radbin et al., 2014).
Human exposure to polyfluoroalkyl substances is associated with increased IL-4 and IL-5 levels, limited seroprotection from the influenza A virus subtype H3N2 and asthma (Dong et al., 2013;Looker et al., 2014;Quinete and Hauser-Davis, 2020;Zhu et al., 2016). Mice consuming water containing perfluorooctane sulfonate displayed significantly increased IL-6 levels (Fair et al., 2011;Quinete and Hauser-Davis, 2020), while another study noted a reduction in IL-2 and IFN-γ secretion in favour of IL-4 and IL-10 which indicated that perfluorooctane sulfonate exposure directly suppress cellular responses and enhances the activation of humoral responses (Quinete and Hauser-Davis, 2020;Zheng et al., 2011).
Both bisphenol A (an environmental estrogen) and phthalates are also implicated in airway inflammation, allergic sensitization and asthma (Nakajima et al., 2012;Quinete and Hauser-Davis, 2020). Mice drinking water containing butyl benzyl phthalate displayed increased susceptibility for Th2-mediated immune responses and no significant changes in Th1 immune responses was noted, leading to increased vulnerability in developing allergic asthma and immune-related diseases (Jahreis et al., 2018;Quinete and Hauser-Davis, 2020). Bisphenol A exposure was associated with highly intensified Th1 cellular immune response (IFN-γ) and suppression of IL-4 in mice. It was proposed that the estrogenic activity of bisphenol A stimulated the production of prolactin which affected cytokine expression profiles, leading to dysregulated Th1 cellular immune response (Quinete and Hauser-Davis, 2020;Youn et al., 2002).
Helminths play a crucial role in modifying the intestinal microbiota by promoting the rapid growth and development of several immuneregulating bacterial species. The anti-inflammatory Th2 cytokines produced by the intestinal microbiota was reported to minimize viral infection-induced lung tissue damage (Cepon-Robins and Gildner, 2020;McFarlane et al., 2017).
As mentioned, the SARS-CoV-2 bind directly to the ACE2 receptors in order to infect cells (Hoffmann et al., 2020). Studies associated heightened inflammation and activated Th2 immune response with increased and decreased levels of host ACE2 receptors, respectively (Cepon-Robins and Gildner, 2020;Jackson et al., 2020;Wrapp et al., 2020). Inflammatory conditions such as smoking, diabetes, respiratory disease and cardiovascular disease are associated with increased levels of ACE2 receptors (Butler et al., 2020;Cepon-Robins and Gildner, 2020;Sajuthi et al., 2020;Smith et al., 2020). Unlike non-allergic asthma, allergic asthma, which is initiated by activated Th2 immune response and linked with decreased ACE2 expression, was proposed to offer protection from severe COVID-19 symptoms and outcomes in humans (Cepon-Robins and Gildner, 2020;Jackson et al., 2020). Considering that helminths trigger Th2 immune response in the lung (Cepon-Robins and Gildner, 2020; Schwartz et al., 2018), this could also lead to decreased ACE2 levels in respiratory cells, diminished ability of SARS-CoV-2 to infect host cells and decreased viral load (Cepon-Robins and Gildner, 2020).
Patients with severe COVID-19 have very low levels of eosinophils (Cepon-Robins and Gildner, 2020; Tanni et al., 2020). Helminth infections activates the production of IL-5 which is directly associated with high eosinophils levels (Cepon-Robins and Gildner, 2020; Huang and Appleton, 2016;Sanderson, 1992). Eosinophils display immunoregulatory and antiviral effects in the body in response to combating helminth larvae in the lungs (Cepon-Robins and Gildner, 2020; Huang and Appleton, 2016;Lindsley et al., 2020). A strong Th2 immune response and high levels of eosinophils could be beneficial in fighting off early stages of SARS-CoV-2 infection, resulting in less tissue damage and reductions in viral loads (Cepon-Robins and Gildner, 2020;Lindsley et al., 2020;Rodriguez, 2020).

Disadvantages
Helminths are linked with nutritional deficiencies and anaemia which leads to compromised and dampened immune response against pathogens in humans (Abdoli, 2020;Bethony et al., 2006;Cepon-Robins and Gildner, 2020;Le et al., 2017). As mentioned previously, SARS-CoV-2 and species-specific helminths can adversely alter the gut microbiota composition by favouring and retarding the growth of opportunistic pathogens and short-chain fatty acid producing salutary bacteria, respectively which could lead manifestation of gastrointestinal infections, bacterial colitis and gut dysbiosis-related diseases (Lee et al., 2014;Su et al., 2018;Yeoh et al., 2021;Zuo et al., 2021;Zuo et al., 2020). These outcomes may be further aggravated if individuals are coinfected.
Chronic helminth infections can skew the host immune response toward anti-inflammatory Th2 immunity, leading to the suppression of vital pro-inflammatory Th1 immune response that is crucial for attacking intracellular pathogens as seen in cases with co-infections between helminths and tuberculosis . Helminthinduced immunosuppression could also lead to increased viral loads and disease severity (Abdoli, 2020;Cepon-Robins and Gildner, 2020). This is in accordance with human studies associating helminth infections in endemic regions with increased susceptibility and severity to malaria, HIV/AIDS and tuberculosis (Abdoli, 2020;Salgame et al., 2013).
Helminth-induced immunosuppression was reported to dampen Bacillus Calmette-Guérin (BCG), a vaccine for tuberculosis, vaccination efficacy (Abdoli, 2020;Elias et al., 2008). Lately, the BCG vaccine was proposed to be a candidate in protecting against severe COVID-19 (Abdoli, 2020;Redelman-Sidi, 2020). Studies using mice found helminth infections drastically reduced vaccination efficacy against the H1N1 influenza A virus due to the systemic and sustained expansion of IL-10-producing CD4 + CD49 + LAG-3 + type 1 regulatory T cells. The above observations remained the same even after termination of helminth infection, and blockade of the IL-10 receptor only partially restored anti-influenza vaccination efficacy (Abdoli, 2020;Hartmann et al., 2019). These findings suggest that helminth infections could inhibit the advancement of long-term immunity against SARS-CoV-2.

Concluding remarks
In conclusion, there is scarcity of studies focusing on: (i) the immunomodulatory role of helminths against SARS-CoV-2 pro-inflammatory Th1/Th17 immune response, and (ii) the insidious role of prolonged and chronic air and water pollution exposure on the functionality and immunomodulatory activity of helminths in the host, and in exacerbating pro-inflammatory Th1/Th17 cytokine production in patients with SARS-CoV-2.
Nonetheless, considering that helminths are potent activators of antiinflammatory Th2 immune response, studies have associated elevated Th2 related cytokines and tissue reparative growth factors with reductions in lung inflammation and damage, and decreased expression levels of ACE2 receptors (SARS-CoV-2 uses the ACE2 receptors to infect cells and associated with extensive lung damage), which could lead to reduced SARS-CoV-2 infection rate and low viral load in the host. However, this can be reversed if the individual is continuously being exposed to air pollution because studies have associated overexpression of ACE2 receptors in the epithelial cell surface of the respiratory tract with air pollution and exhaustion of Th2 immune response which could promote severe SARS-CoV-2 infection in high air pollution endemic regions.
Conversely, helminth-induced immunosuppression activity could also be disadvantageous by reducing vaccination efficacy, and diminishing vital Th1/Th17 immune response cytokine production that are crucial for combating early stage infections. However, this could be reversed by: (i) continuous air pollution exposure which is associated with exhaustion of Th2 immune response, or (ii) hyper-inflammatory disorders (obesity, diabetes, hypertension and metabolic disorders) which are known to intensify Th1/Th17 pro-inflammatory cytokine production to a point where the immunosuppressive activities of helminths could be hindered. Again, suppressed activities of helminths can also be disadvantageous against SARS-CoV-2 inflammatory response. This "yin and yang" approach seems complex and requires more understanding.
All the above suggest that environmental pollution could hinder the activity of helminths which could be both harmful and beneficial in patients with SARS-CoV-2. It is also known that chronic air pollution exposure exacerbates SARS-CoV-2 related adverse health outcomes (respiratory distress and failure). Further studies are warranted in a cohort of SARS-CoV-2 infected individuals residing in helminth and air pollution endemic regions to offer more clarification. Data from these studies could influence mass periodic deworming programmes and environmental health policies in order to minimise SARS-CoV-2 severity in affected regions. Fig. 2 highlights the hypothesized mechanisms on how air pollutants can promote SARS-CoV-2 entry and life cycle, the role of SARS-CoV-2 and air pollutants in stimulating Th1/ Th17 proinflammatory cytokine production and associated cytokine storm, the role of helminth infections in stimulating Th2 anti-inflammatory cytokine production and tissue reparative growth factors, and collectively on how helminths may modulate inflammation induced by SARS-CoV-2 and air pollutants.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Fig. 2. Immune response against SARS-CoV-2 and interaction with environmental pollution and helminths. Environmental pollutants may promote SARS-CoV-2 entry and replication by increasing ACE2 receptor expression, TLR2/ TLR4 sensing and epithelial permeability, decreasing the activity of antimicrobial peptides, surfactant protein D, macrophages and mucociliary clearance, and modulating the production of interferon. Both SARS-CoV-2 and environmental pollution can trigger the activation of pro-inflammatory Th1/ Th17 immune response, leading to the intensified production of inflammatory cytokines and chemokines and the manifestation of a cytokine storm. This scenario may be worsened if individuals have co-morbidities. Exhaustion/ diminished activity of tissue reparative/ pro-angiogenic growth factors occurs as disease severity and inflammation is aggravated. Helminths are potent stimulators of anti-inflammatory Th2/ Th3 immune response. Helminth induced intestinal penetration and tissue injury activates the production of alarmins, leading to the activation of Th2 associated cytokines (IL-4, IL-5, IL-9, IL13), B-cells, eosinophils, basophils, masts cells, M2 macrophages (responds to tissue fibrosis by stimulating the extracellular matrix and tissue reparative growth factors) and TSLP cells. Helminths associated excretorysecretory antigen products stimulates dendritic cells to promote the activation and production of M2 macrophages, FOXP3+, Treg cells, Breg cells, IL-10 (regulates Th1/Th17-cell immune responses) and TGF-β (regulator of haematopoiesis and tissue repair). Collectively, helminths are important immunomodulators and may have the potential to ameliorate SARS-CoV-2 and environmental pollution induced inflammation. Fig. 2 footnote: ACE2: Angiotensin-converting enzyme 2; Breg: Regulatory B cells; CCL: C-C motif chemokine ligand; CO: Carbon monoxide; CXCL: chemokine (C-X-C motif) ligand; ECM: Extracellular matrix; EGF: Epidermal growth factor; ESP: Excretory-secretory products; FOXP3+: forkhead box P3; G-CSF: Granulocyte colony-stimulating factor; GM-CSF: Granulocyte-macrophage colony-stimulating factor; GROα: Growth-regulated alpha protein; IFN: Interferon; IL: Interleukin; M1: classically activated macrophages; M2: alternatively activated macrophages; M-CSF: Macrophage colony-stimulating factor; NO 2 : Nitrogen dioxide; O 3 : Ozone; Pb: Lead; PDGF: Platelet-derived growth factor; PM: Particulate matter; RANTES: Regulated on Activation, Normal T Cell Expressed and Secreted; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; sCD40L: Soluble CD40 ligand; SO 2 : Sulphur dioxide; SP-D: Surfactant protein D; TGF-β: Transforming growth factor beta; Th1: T helper type 1 cells; Th2: T helper type 2 cells; Th3: T helper type 3 cells; Th17: T helper type 17 cells; TLR: Toll-like receptor; TNF-α: Tumour necrosis factor alpha; Treg: Regulatory T cells; VEGF: Vascular endothelial growth factor; VOC: Volatile organic compounds.

Acknowledgments
We would like to acknowledge the South African Medical Research Council (SAMRC) for funding.

Funding
Professor ZL Mkhize-Kwitshana was partially supported as a private investigator (PI) (and researchers PN, MNMM, KNB, NN and RP) by funding from the South African Medical Research Council (SAMRC) Mid-Career Scientist Programme (MCSP) Grant (no award/grant number), through its Division of Research Capacity Development under the RCDI programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders.