Post-viral lung diseases: the microbiota as a key player

Abstract

Viral infections of the respiratory tract can lead to chronic lung injury through immunopathological mechanisms that remain unclear. Communities of commensal bacteria colonising the respiratory tract, known as the respiratory tract microbiota, are altered in viral infections, which can contribute to inflammation, lung epithelial damage and subsequent development of lung disease. Emerging evidence on post-viral lung injury suggests an interplay between viral infections, immune responses and airway microbiota composition in the development of viral-induced lung diseases. In this review, we present the clinical characteristics of post-viral lung injury, along with the underlying immunopathological mechanisms and host-bacteria interactions, with a focus on influenza virus, respiratory syncytial virus and coronaviruses. Additionally, considering the important role of the airway microbiota in viral-induced pulmonary sequelae, we suggest key areas for future research on respiratory microbiota involvement in the development of post-viral lung diseases.

FIGURE 1

Host–bacteria interactions in post-viral lung diseases. Viral infections can lead to disruption of the respiratory tract microbiota. The latter plays a key role in the immunopathological mechanisms leading to post-viral lung diseases: disbalanced microbiota can lead to altered immune response, which in turn may affect bacterial community composition through the release of cytokines and interleukins. This vicious circle is further enhanced by the generated chronic inflammatory state and can lead to post-viral lung disease.

FIGURE 2

Host–bacterial interactions in post-influenza lung disease. In the post-acute influenza infection, lung alveolar and interstitial CD68⁺ macrophages produce an elevated amount of interleukin (IL)-13, enhancing mucus production and airway hyperreactivity [20]. This nutrient-rich environment provides advantageous conditions for Pseudomonas aeruginosa growth, perpetrating a vicious circle of chronic inflammation [34, 35]. Influenza RNA remnants might intensify this persistent inflammatory state [19]. P. aeruginosa promotes IL-22 degradation, protecting itself from the host's immunity and counteracting the protective role of IL-22 in lung epithelial repair after pandemic 2009 influenza A (H1N1) infection [37]. Club cells surviving acute H1N1 infection produce pro-inflammatory mediators such as CXCL10, CCL5 and CCL20, inducing lung tissue damage [21]. The observed post-acute inflammatory state is also characterised by an increased bacterial diversity, with a shift towards enhanced Gammaproteobacteria and increased Streptococcus, Staphylococcus, Prevotella and Fusobacterium [27, 29, 38].

FIGURE 3

Host–bacterial interactions in post-respiratory syncytial virus (RSV) wheezing/asthma, from acute infection to chronic disease. In the acute phase of infection, the presence of Moraxella catarrhalis was linked to elevated sputum IL-10 and IL-6 levels, and Haemophilus was associated with increased CXCL8 levels and RSV RNA remnants [52, 60]. In addition, a shift in the Th1/Th2 response could be observed, with an increase in interleukin (IL)-4 and IL-10 levels, as well as a reduction in interferon (IFN)-γ and IL-12 nasal levels, which is also observed in asthma, illustrating the interplay between immune system and microbiota [57]. In the post-acute state, an increase in nasal interleukin and cytokine (IL-6, IL-7, IL-10, IL-13, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), IFN-γ, CCL5, CXCL8) was associated with post-RSV wheezing or asthma [51, 52]. IL-13 downregulates IL-12 levels, contributing to the persistence of RSV antigens in the lungs [53]. IL-13 also contributes to airway hyperreactivity and mucus production, the latter being additionally associated with high tumour necrosis factor (TNF)-α, IL-4, IL-5 and IL-9 levels [54]. The increased abundance in M. catarrhalis and Streptococcus in the post-acute state supports the notion of a remodelling of the airway microbiota after RSV infection, all in all leading to a persistent inflammatory state, with Lactobacillus (not shown) having a potential protective role during the acute disease [61, 62].

FIGURE 4

Host–bacterial interactions and post-COVID lung sequelae. During acute disease, increased abundance in Veillonella, Prevotella and Leptotrichia was associated with persistent respiratory symptoms. Veillonella and Leptotrichia produce lipopolysaccharide (LPS) with pro-inflammatory effects, contributing to chronic inflammation [98]. The enrichment in Veillonella might additionally be explained by a translocation of Veillonella into the lungs through disruption of the gut–lung axis [25, 28]. The overrepresentation of Prevotella might be driven by viral-induced inflammation and subsequent micro-aspiration of this bacterial species, leading to undesired lung tissue remodelling [11, 98, 99]. In the post-acute phase, an increase in activated CD8⁺ T-cells contributes to inflammation and lung tissue damage [93]. The persistence of SARS-CoV-2 RNA remnants may additionally activate the immune system [88]. Cytokines involved in epithelial repair and fibrosis (matrix metalloproteinase-3, epidermal growth factor receptor ligand AREG, TGFA and KRT19) are upregulated, along with markers related to epithelial damage and cell death (lactate dehydrogenase, albumin, EPCAM, CASP3, CXCL9, CXCL10, CXCL11 and interleukin (IL)-7) [92]. Inflammatory molecules, such as IL-1β, interferon (IFN)-β, IFN-λ1, IFN-γ and IL-6 are also increased in long COVID syndrome [93]. This persistent inflammatory state may be related to the decrease in Prevotella [11]. The increase in Fusobacterium might further contribute to inflammation and lung tissue damage [100]. Finally, decreased bacterial diversity in the gut might impair immune cell activation in the lungs through the gut–lung axis [101]. ARDS: acute respiratory distress syndrome; eNO: exhaled nitric oxide.