Are we there yet? understanding interactions between respiratory viral infections, atopy, and the microbiome

Introduction

Atopic diseases are most prevalent in Western countries; however, their incidence continues to increase in low- and middle-income countries as urbanization and adoption of Western lifestyles expand (1). In 2024, allergic rhinitis was the most common atopic condition among Americans, affecting 25.2% of adults and 20.6% of children, followed by atopic dermatitis (7.7% of adults and 12.7% of children), asthma (8.7% of adults and 6.2% of children), and food allergies (6.7% of adults and 5.3% of children). Approximately 20% of the global population is affected by at least one atopic disease, and these conditions represent the most common chronic diseases of childhood (1–4). Beyond their high prevalence, atopic diseases impose a substantial economic burden, increase healthcare utilization, contribute to poorer health outcomes, and significantly diminish quality of life (5, 6). A better understanding of the mechanisms underlying their development is therefore critical for improving prevention and treatment strategies.

Respiratory viral infections are the leading cause of acute respiratory illness in infants and young children and have been associated with long-term respiratory morbidity, including recurrent wheezing, asthma, and recurrent respiratory infections (7). Observational studies have previously linked respiratory viral infections during infancy with an increased risk of allergic sensitization and subsequent atopic disease (8, 9). Consequently, respiratory viral infections have been proposed as a potential driver of allergic disease development (10). More recent investigations, however, suggest that the relationship between respiratory viral infection and atopy is more complex than previously appreciated. Emerging evidence suggests that immune pathways associated with atopy may protect against the development of post-viral airway disease, highlighting the need to better define the mechanisms underlying these interactions.

The increasing prevalence of atopic diseases is likely multifactorial, involving not only infectious triggers but also genetic susceptibility, the microbiome, and environmental exposures (5). Although much of the mechanistic evidence has been observed in animal models, a growing body of human studies has begun to validate many of these findings and reveal important similarities in the underlying immune pathways. This review summarizes the current evidence from both animal models and human studies on the development of atopic sensitization and allergic disease and highlights areas requiring further investigation and the implications for future therapeutic strategies.

Impact of respiratory viral infections on atopy

Respiratory viral infections early in life have been associated with an increased risk of wheeze and even asthma. In early studies it was found that infants hospitalized with a severe RSV infection in the first 2–10 months of life were at a much-increased risk of developing asthma and even allergic sensitization. This same cohort was found to have increased atopic disease if they had severe RSV infection (11, 12). Being infected by RSV was insufficient to drive the atopic disease, as nearly all infants have been infected by RSV by 2 years of age. Other studies have demonstrated a seasonal relationship between recurrent wheeze, with increased recurrent wheeze in those infants born such that they were 2–6 months old during the RSV season (13, 14).

However, not all studies have shown a strong association between RSV and asthma, and indeed it seems that the stronger association is simply with the development of wheeze. In fact, studies have shown that this association is strongest shortly after the viral infection and appears to disassociate as the child ages (15–18).

Why RSV would have such an age restriction is curious. Most studies have proposed it is related to impaired Type I Interferon (IFN) production at these young ages, suggesting that increased type I IFN during the RSV infection might prevent the subsequent risk of wheeze (19). Other studies have demonstrated that the RSV induced risk for wheeze is only in those without pre-existing atopy, which could also explain the age predilection (20, 21). Unlike RSV, human Rhinovirus (hRV) has been demonstrated to drive the development of asthma and recurrent wheeze in those children who already have pre-existing atopy (and usually at an older age) (21–23) (Figure 1). The mechanisms by which these viruses (hRV and RSV) drive development of wheeze and/or atopic disease is still an active area of research, for which animal models are often used.

Animal models have suggested that infection with RSV drives type 2 innate lymphoid cells into the airways, which can lead to airway hyper-reactivity and mucous cell metaplasia (24, 25). However, RSV does not normally infect mice (it is not a natural rodent pathogen), which raises concerns over how applicable these findings are to humans. We and others have demonstrated that infection with murine parainfluenza virus-1 (Sendai virus, SeV, a natural rodent pathogen related to RSV) drives a well characterized pathway leading to post-viral airway disease (airway hyper-reactivity and mucous cell metaplasia) that likely lasts for the life of the animal (26–28).

This pathway starts with infection of the airway epithelium, which leads to recruitment of CD49d expressing neutrophils, who are maintained in the airway by LTD4 binding to CysLTR expressed on the neutrophils. These neutrophils then drive expression of FceRI, the high affinity receptor for IgE, on airway conventional dendritic cells (cDC). At the same time IgE is produced against SeV, and SeV is still present in the lungs. The crosslinking of anti-SeV IgE by SeV leads to production of CCL28 by the cDC. This recruits CCR10 expressing lymphocytes (Th2 and ILC2 cells), which produce IL-13 and drive the post-viral airway disease (29, 30). Exposure to a non-viral antigen in the middle of the antiviral immune response is sufficient to drive production of IgE against the non-viral antigen, suggesting the mice also develop atopy as a result of the infection (27). Over time NK cells interact with airway macrophages to drive an IL-13 dependent alternative activation of the macrophages. These macrophages then continue to produce IL-13 leading to the continued existence of the post-viral airway disease (31).

Components of these pathways have been demonstrated in humans—specifically the presence of CD49d expressing neutrophils with severe disease, production of IgE against respiratory viruses, increased cDC expression of FceRI, and production of CCL28 when FceRI is crosslinked on the cDC. While the mouse model is dependent upon production of antiviral IgE, it is not clear whether this applies to humans (28). Indeed, a human study found that treatment with anti-IgE reduced asthma exacerbations during respiratory viral seasons (32). The reduction in IgE was associated with an increased production of type I IFN from plasmacytoid dendritic cells (pDC), suggesting that atopy led to impaired antiviral immunity and that drove the asthma exacerbation (33–36). However, another study where subjects were treated with or without anti-IgE and then experimentally infected with hRV does not support this hypothesis. In this study, treatment with anti-IgE was associated with reduced asthma symptoms, but instead of having lower viral titers (presumably due to increased type I IFN) the subjects treated with anti-IgE had higher viral titers (37, 38). Clearly additional research is needed to better elucidate the relationship between respiratory viral infections and the development of atopy.

Impact of atopy on respiratory viral infections

As indicated, atopy appears to have an ability to modulate the antiviral immune response in the lungs. Increased IgE will impair pDC production of type I IFN, although whether that has a significant effect on the antiviral immune response is less clear. There are some data to support the ability of atopy to be protective of severe respiratory infections in humans. In particular, during the 2009 H1N1 influenza pandemic having asthma was associated with reduced mortality and need for mechanical ventilation. Complicating this finding, though, was the fact that those with asthma received more systemic corticosteroids and were probably treated differently in the hospital than those without asthma (39, 40). During the COVID-19 pandemic several studies suggested that those with atopy had less severe disease than those without, and in fact some studies suggested that having atopy actually was protective from even getting COVID-19 (41).

Animal models have demonstrated a very significant effect of atopy on the lung antiviral immune response (Figure 1, bottom panel). Several studies have demonstrated that making mice atopic (primarily by using the house dust mite model) they become resistant to normally lethal infections with influenza or SeV (42–44). The mechanisms of this protection are less well defined. One study demonstrated that the protection required TGFbRII expression, while we initially found that neuregulin-1 is overproduced in atopic mice and treatment with neuregulin-1 in non-atopic mice protects them from a lethal viral infection (44, 45). However, our subsequent work suggests that the atopic effect on survival does not depend on (and is disparate from) neuregulin-1 (46). In fact, atopy might not be the critical factor in survival in the mouse models, as low dose lipopolysaccharide has been shown to provide a survival advantage in respiratory viral infection models, an effect that depended upon lung resident macrophages (47).

In addition to macrophages, neutrophils have been implicated in the atopic effect on the antiviral immune response. IL-4 treated neutrophils have increased phagocytosis, and we have shown that in atopic mice airway neutrophils contain increased genomic SeV RNA compared to neutrophils from non-atopic mice. Indeed, atopic mice have reduced SeV titers, and this effect can be reversed by depleting neutrophils or blocking IL-4 (48). This likely has significance for humans, as a study of preschool children found that the systemic neutrophil response to a viral infection was more effective in those with allergic disease (49).

Microbiome, respiratory viral infections and atopy

Respiratory tract infections may alter the composition of the airway microbiome both during and after infection. Conversely, the existing airway microbiome may influence an individual's susceptibility to subsequent respiratory tract infections. During the first three years of life, hypopharyngeal colonization with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis has been associated with an increased risk of developing bronchitis and pneumonia at age four years. Early colonization with Streptococcus species has been associated with an increased risk of earlier onset of lower respiratory tract infections, whereas Moraxella colonization is associated with an earlier onset of upper respiratory tract infections (50) (Figure 2). The interactions between the microbiome and respiratory viruses leading to immunomodulation with an impact on the host response is an understudied area; however, emerging evidence suggests that this axis (microbiome-respiratory virus) may contribute to the pathogenesis of atopic diseases (51). Furthermore, commensal bacteria colonizing the respiratory tract have been reported to be altered in viral infection subsequently affecting the immune response and contributing to development of post-viral airway disease (52). Although it is worth noting that a recent prospective study of young children (mean age 8.63 yrs) with asthma found the nasal microbiome dominated by commensal bacteria, which provided greater protection against respiratory viral infection (53).

The influence of respiratory viruses, such as RSV, RV, IAV or SARS-CoV-2 on the nasopharyngeal and gut microbiome, or vice-versa, is unclear. Beyond the respiratory tract and environmental exposures, the gut microbiome has been increasingly recognized as a potential modulator of both local and distant immune responses, a relationship associated with lung function termed the gut-lung axis (54) (Figure 2). Furthermore, studies have evaluated how alterations in immune cells in response to viral infections can alter the gut microbiome. Earlier mouse studies discovered that CD8+ cell depletion increased food intake and prevented infection-induced anorexia which reversed gut microbiome changes normally seen in RSV. Furthermore, RSV infection also caused a shift in lipid metabolism due to changes in fecal gut metabolome along with an increase in sphingolipids, polyunsaturated fatty acids, and short chain fatty acids. All these factors may potentially be contributing to protective anti-inflammatory responses post viral exposure (55). Alternatively, when viruses interact with respiratory epithelium, they create a proinflammatory state which can shift towards Th2 inflammation leading to allergies and atopy (56). The proinflammatory state, as was seen in COVID-19, can lead to gut microbiome dysbiosis, which further exacerbates systemic inflammation (57). Recent publications have explored the alteration in commensal bacteria or respiratory microbiota when exposed to respiratory viruses leading to post viral lung injury possibly driving atopy. As with the case with influenza, specifically H1N1, there was a shift from Actinobacter to Gammaproteobacteria, which metabolize proinflammatory products leading to chronic lung diseases. Chronic inflammation driven by IL-13-mediated hypersecretion of mucus and airway hyperreactivity can be observed with influenza infection and post-RSV one year after infection. The virus-induced alteration in the respiratory tract microbiota may result in this shift towards a Th2 response and contribute to post-viral wheeze and asthma (52).

Studies have demonstrated that decreased microbiome biodiversity and dysbiosis are the largest contributors leading to decreased pathogenic microorganism clearance and immune system dysfunction, with increased dysbiosis contributing to more severe clinical atopic disease (54, 58). In patients affected by SARS-CoV-2, alterations in the gut microbiome occured due to cytokine storm leading to a leaky gut, which worsened both clinical presentation and long-term outcomes (59). Reduced gut microbiome diversity is also associated with decreased T regulatory cells and increased interferon gamma production, contributing to increased mortality with exposure to respiratory viral infections (60). Host gut microbiome analyses in children with a history of bronchiolitis demonstrated that specific bacterial species (i.e., Bacteroides vulgatus, Eisenbergiella massiliensis, and Butyricimonas virosa) were differentially associated with forced expiratory volume in one second (FEV1), while the presence of Ruminococcus bromii and Alistipes indistinctus were found to have a protective effect on children with risk factors for asthma (61).

While viral infections may alter the developing microbiome, emerging studies suggest that pre-existing microbial differences may also influence susceptibility to atopy. Landmark birth cohort studies have demonstrated that alterations in the early-life gut microbiome can precede development of childhood asthma, supporting a potential role for dysbiosis in shaping immune maturation and subsequent allergic risk (62). In addition, experimental evidence suggests that specific microbial taxa, including supplementation with Lactobacillus, may influence airway immune defense against both allergens and viral infection (63). Genetics play a role as well, as at least one study demonstrated that in infants without any microbial stimulation, only those with an inherited risk of asthma (mothers with asthma) developed asthma by 5 years of age (64). Together, these findings suggest that the microbiome may function also as important modifier of antiviral immunity and susceptibility to atopic disease. Metagenomic analyses of atopic patients have identified potential genetic influences on gut microbiome composition; however, these associations are regarded as a component of a larger complex, multifactorial, and dynamic ecosystem that is not yet comprehensively understood.

Conclusion

As assessed in the review, there are multiple factors, including pre-existing atopy, the gut microbiome, and environmental factors, that contribute to the immune system's function. It is imperative to look beyond the initial hypothesis that early childhood viral infections drive development of atopy, but rather whether pre-existing atopy can serve as a protective evolutionary change to protect against significant morbidity and mortality with viral illness. As we continue to elucidate the biochemical mechanisms underlying these pathways in mouse models, it will be important to identify analogous human pathways and utilize this information to develop targeted therapeutic treatments when atopy becomes pathologic and viral illness becomes fatal. The aim of this review is to comprehensively discuss what has been researched in the field to suggest what gaps should be considered for exploration in the future. Although viral illnesses were previously thought to contribute to the development of atopy, emerging evidence suggests that immune pathways in previously sensitized individuals may confer protection against severe respiratory disease. Moreover, emerging evidence suggest that the gut-lung axis with gut microbiota communicating through immune pathways and metabolites such as short-chain fatty acids plays a pivotal role in modulating the axis between atopy and respiratory viral responses. Disruption of gut microbial balance has been linked to reduced pulmonary immunity and increased susceptibility to respiratory viral infections.

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Footnotes

Edited by: Giovanni Paoletti, Humanitas University, Italy

Reviewed by: Bhuwaneswaran Vijayam, Newcastle University Medicine Malaysia, Malaysia