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Review
. 2021 Oct 26:2:738987.
doi: 10.3389/falgy.2021.738987. eCollection 2021.

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

Jodie Ackland  1 , Alastair Watson  1   2   3 , Tom M A Wilkinson  1   2   4 , Karl J Staples  1   2   4
Affiliations
Review

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

Jodie Ackland et al. Front Allergy. .

Abstract

Asthma is a heterogeneous, chronic respiratory disease affecting 300 million people and is thought to be driven by different inflammatory endotypes influenced by a myriad of genetic and environmental factors. The complexity of asthma has rendered it challenging to develop preventative and disease modifying therapies and it remains an unmet clinical need. Whilst many factors have been implicated in asthma pathogenesis and exacerbations, evidence indicates a prominent role for respiratory viruses. However, advances in culture-independent detection methods and extensive microbial profiling of the lung, have also demonstrated a role for respiratory bacteria in asthma. In particular, airway colonization by the Proteobacteria species Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) is associated with increased risk of developing recurrent wheeze and asthma in early life, poor clinical outcomes in established adult asthma and the development of more severe inflammatory phenotypes. Furthermore, emerging evidence indicates that bacterial-viral interactions may influence exacerbation risk and disease severity, highlighting the need to consider the impact chronic airway colonization by respiratory bacteria has on influencing host responses to viral infection. In this review, we first outline the currently understood role of viral and bacterial infections in precipitating asthma exacerbations and discuss the underappreciated potential impact of bacteria-virus crosstalk in modulating host responses. We discuss the mechanisms by which early life infection may predispose to asthma development. Finally, we consider how infection and persistent airway colonization may drive different asthma phenotypes, with a view to identifying pathophysiological mechanisms that may prove tractable to new treatment modalities.

Keywords: asthma; bacteria; co-infection; early-life; exacerbation; inflammation; virus.

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Conflict of interest statement

KS reports grants from AstraZeneca outside the conduct of the study. TW reports grants and personal fees from AstraZeneca, personal fees and other from MMH, grants and personal fees from GSK, grants and personal fees from AZ, personal fees from BI, grants and personal fees from Synairgen, outside the submitted work. 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.

Figures

Figure 1
Figure 1
Overview of inflammatory pathways in asthma. Inflammation in asthma is defined as Type (T)2-high or T2-low. T2-high inflammation is characterized by T2 cytokines such as interleukin (IL)-4, IL-5, IL-9, and IL-13. These cytokines can be released by T helper (Th) 2 cells or innate lymphoid group 2 cells (ILC2s). Th2 cells are stimulated by IL-4 whereas ILC2s are stimulated by IL-25, IL-33, or Thymic Stromal Lymphopoietin (TSLP). The T2 cytokines promote the cellular features of T2 inflammation including eosinophil recruitment and activation, B cell proliferation, IgE class switching, and mast cell activation. Although T2 inflammation is generally responsive to steroids, it results in the classical pathophysiological features of asthma including airway hyperresponsiveness, remodeling, and eosinophilia. T2-low responses are often associated with T1 or T17 inflammation. T1 inflammatory responses are regarded as important for defense against intracellular pathogens and are driven by Th1 cells, which are activated upon stimulation by either IL-27 or IL-12. Th1 cells release IL-2, IFN-γ, or TNF-α which activates macrophages and promotes microbial killing. Macrophages also participate in positive feedback through production of IL-12/IL-18, CXCL9, CXCL10, and CXCL11 to amplify T1 inflammation. T17 responses are induced through IL-23 stimulation of Th17 cells. Th17 cells release IL-21 and IL-17 which can either autoregulate Th17 cell differentiation or can act upon epithelial cells or macrophages to release IL-1β, IL-8, CXCL1, and IL-6 to promote neutrophil recruitment and activation. T17 responses are associated with the neutrophilic asthma phenotypes, inflammasome activation, and steroid-resistance in asthma. Created using BioRender.com.
Figure 2
Figure 2
Overview of the impact of infection in early life asthma development, on chronic inflammation in established asthma and during asthma exacerbations. The development and stability of the microbiome in early life is associated with allergen exposure, mode of delivery, feeding method, and antibiotic use. The composition of the microbiome is associated with the number of RTIs during infancy, which is subsequently associated with increased risk of asthma development in later life. Microbial dysbiosis resulting in microbiome profiles enriched in Proteobacteria particularly is associated with development of asthma and aberrant immune responses in later life. During established asthma, chronic colonization of the airway by Proteobacteria is associated with modulation of airway inflammation. NTHi persistent airway colonization causes inflammatory responses switching to T17, neutrophilic inflammation, increased inflammasome activation, which is linked to increased steroid-resistance. As a possible consequence of chronic bacterial colonization, baseline immunity in asthma is altered, including decreased antiviral immunity (IFN responses) and macrophage function (phagocytic ability). Viral infection is established due to delayed antiviral responses, which causes increased asthma symptoms, resulting in a virally driven exacerbation. Different viruses cause different disease pathology (e.g., increased cellular cytotoxicity following IAV infection compared to RV) and induction of T2-low (IAV) or T2-high (RV) responses. Bacterial infection also causes exacerbations and are likely contributors to exacerbation symptoms following viral infection, as bacterial outgrowth occurs due to impaired phagocytosis and macrophage immune response sensitization induced by viral infection. Again, different bacteria induce different responses, with Mcat reported to induce a mixed T1/2/17 response, whereas NTHi drives a T1/T17 pro-inflammatory response. Co-infection can augment inflammation and asthma symptoms, which may impact on treatment failure/success during exacerbation. Created using BioRender.com.
Figure 3
Figure 3
Factors contributing to infection-induced exacerbations. The role of infection in exacerbations are likely to be multifactorial, with several host, pathogen, and environmental factors impacting on the contribution of infection to an exacerbation. Each factor may be multi-directional and directly or indirectly impact on another factor, highlighting the complex mechanisms involved in exacerbations. Created using BioRender.com.
Figure 4
Figure 4
Summary of the diverse potential mechanisms contributing to and influencing infection-induced exacerbations. (A) The role of bacteria in exacerbations are not well-known but inflammatory profiles associated with exacerbations appear to be pathogen dependent. (i) NTHi infection results in upregulation of pro-inflammatory mediators and is associated with persistent infection, neutrophilic inflammation and steroid-resistance. Chronic NTHi airway colonization may occur as a result of macrophage impairment in phagocytosis. (ii) On the other hand, exacerbations with Mcat are associated with acquisition of a new Mcat strain and is associated with both neutrophilic and eosinophilic inflammation. (B) Viral induced exacerbations can induce the hallmarks of asthma exacerbations through upregulation of T2 responses. (iii) Epithelial cells and macrophages contribute to IL-33, IL-25, and TSLP release, resulting in ILC2 or Th2 release of IL-4, IL-5, and IL-13 to upregulate eosinophils and B cells, which produce IgE and subsequently activate mast cells, all of which induce airway hyperresponsiveness, remodeling, and mucus hypersecretion. (iv) Conversely, some viruses have been shown to induce IL-8, CXCL5, and CXCL1 release, resulting in neutrophilic inflammation and epithelial damage via neutrophil production of NETs. (v) Influenza infection can impact on macrophage function or result in macrophage depletion, which along with mucus plugging, and may render the airway susceptible to persistent bacterial infection, and may further act to exacerbate airway inflammation. Underlying host factors such as (vi) impaired host antiviral immunity may result in an altered baseline immune profile that contributes to a dysregulated host response, whereas (vii) allergen sensitization or exposure may synergistically augment inflammation and increase cell lysis and damage during viral infection. Created using BioRender.com.
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