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Asthma is a complex, heterogeneous condition that affects over 350 million people globally. It is characterised by bronchial hyperreactivity and airways inflammation. A subset display marked airway neutrophilia, associated with worse lung function, higher morbidity and poor response to treatment. In these individuals, recent metagenomic studies have identified persistent bacterial infection, particularly with non-encapsulated strains of the Gram-negative bacterium Haemophilus influenzae. Here we review knowledge of non-typeable H. influenzae (NTHi) in the microbiology of asthma, the immune consequences of mucosal NTHi infection, various immune evasion mechanisms, and the clinical implications of NTHi infection for phenotyping and targeted therapies in neutrophilic asthma. Airway neutrophilia is associated with production of neutrophil chemokines and proinflammatory cytokines in the airways, including interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-17A and tumour necrosis factor. NTHi adheres to and invades the lower respiratory tract epithelium, inducing the NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes. NTHi reduces expression of tight-junction proteins, impairing epithelial integrity, and can persist intracellularly. NTHi interacts with rhinoviruses synergistically via upregulation of intracellular cell adhesion molecule 1 and promotion of a neutrophilic environment, to which NTHi is adapted. We highlight the clinical relevance of this emerging pathogen and its relevance for the efficacy of long-term macrolide therapy in airways diseases, we identify important unanswered questions and we propose future directions for research.

Mucosal associated invariant T (MAIT) cells were first identified as specific for bacterial, mycobacterial, and fungal organisms, which detect microbially-derived biosynthetic ligands presented by MHC-related protein 1 (MR1). More recently two unexpected, additional roles have been identified for these ancient and abundant cells: a TCR-depen-dent role in tissue repair and a TCR-independent role in antiviral host defence. Data from several classes of viral disease shows their capability for activation by the cytokines interleukin (IL)-12, IL-15, IL-18, and type I interferon. MAIT cells are abundant at mucosal surfaces, particularly in the lung, and it seems likely a primary reason for their striking evolutionary conservation is an important role in early innate defence against respiratory infections, including both bacteria and viruses. Here we review evidence for their TCR-independent activation, observational human data for their activation in influenza A virus, and in vivo murine evidence of their protection against severe influenza A infection, mediated at least partially via IFN-gamma. We then survey evidence emerging from other respiratory viral infections including recent evidence for an important adjuvant role in adenovirus infection, specifically chimpanzee adenoviruses used in recent coronavirus vaccines, and data for strong associations between MAIT cell responses and adverse outcomes from coronavirus-19 (COVID-19) disease. We speculate on potential translational implications of these findings, either using corticosteroids or inhibitory ligands to suppress deleterious MAIT cell responses, or the potential utility of stimulatory MR1 ligands to boost MAIT cell frequencies to enhance innate viral defences.

The prototype ORACLE scale based on two simple measures of type 2 airway inflammation (blood eosinophils and FENO) quantifies the excess risk conferred by raised biomarkers that is removed by type-2 anti-inflammatory treatment in trial populations

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Summary MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8+ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8+ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair., Graphical Abstract, Highlights • Activation of human MAIT cells is TCR-dependent or TCR-independent and enhanced by TL1A • TCR-dependent and TCR-independent triggering induces distinct transcriptional responses • TCR-dependent triggering of MAIT cells induces a tissue-repair program • Data integration with in vivo studies in mice indicates a shared transcriptome, Leng et al. explore the consequences of activation of human MAIT cells via their TCR and/or cytokines, including the gut-associated TNF-superfamily member TL1A. TCR triggering reveals a transcriptional program linked to tissue-repair functions seen in vivo, consistent with a homeostatic role for these cells in epithelia.