Mucosal Immunology

Chemotherapy and radiotherapy frequently lead to intestinal damage. The mechanisms governing the repair or regeneration of intestinal damage are still not fully elucidated. Intraepithelial lymphocytes (IELs) are the primary immune cells residing in the intestinal epithelial layer. However, whether IELs are involved in intestinal epithelial injury repair remains unclear. Here, we found that IELs rapidly infiltrated the intestinal crypt region and are crucial for the recovery of the intestinal epithelium post-chemotherapy...

Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains TH 1 cell proliferation and promotes host protective Type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris...

Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species. Our previous work suggested that the gut microbiota influenced iNKT cell functions during dextran sulfate sodium-induced colitis in mice...

Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using AMG-517) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, TNF-α production by MCs, eosinophil infiltration and activation, and CCL11 (eotaxin-1) expression in fibroblasts...

Air pollution significantly impacts the aggravation of asthma. Exposure to acrylamide, a volatile organic compound in tobacco smoke, is associated with elevated risks of allergy-related outcomes among active smokers. As group 2 innate lymphoid cells (ILC2s) can act as an environmental sensor and significantly contribute to protease allergen-induced lung inflammation, we aimed to elucidate the causal relationship and how inhaled acrylamide worsens allergic lung inflammation via ILC2s. Intranasal acrylamide exposure at nanomolar levels significantly enhanced allergen-induced or recombinant mouse interleukin-33-induced lung inflammation in C57BL/6 mice or Rag1-/- mice, respectively...

Our understanding of the quality of cellular and humoral immunity conferred by coronavirus disease 2019 (COVID-19) vaccination alone versus vaccination plus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two dose primary series and then experienced an Omicron BT...

The fungus Candida albicans can cause mucosal infections including oropharyngeal candidiasis (OPC) in immunocompromised patients. In humans, an increased risk of fungal infections correlates with thrombocytopenia. However, our understanding of platelets and megakaryocytes in mucosal fungal infections is almost entirely unknown. When megakaryocyte- and platelet-depleted mice were infected with OPC, the tongue showed higher fungal burden, due to decreased neutrophil accumulation. Protection depended on a distinct population of oral-resident megakaryocytes...

Streptococcus pneumoniae (Spn) is a common pathogen causing a secondary bacterial infection following influenza which leads to severe morbidity and mortality during seasonal and pandemic influenza. Therefore, there is an urgent need to develop bacterial vaccines that prevent severe post-influenza bacterial pneumonia. Here, an improved Yersinia pseudotuberculosis strain (designated as YptbS46) possessing an Asd+ plasmid pSMV92 could synthesize high amounts of the Spn pneumococcal surface protein A (PspA) antigen and monophosphoryl lipid A as an adjuvant...

The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis (TB), a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated M.tb growth within human alveolar macrophages...

Tuberculosis is the leading cause of death for people living with HIV (PLWH). We hypothesized that altered functions of innate immune components in the human alveolar lining fluid of PLWH (HIV-ALF), drive susceptibility to Mycobacterium tuberculosis (M.tb) infection. Our results indicate a significant increase in oxidation of innate proteins and chemokine levels, and significantly lower levels and function of complement components and Th1/Th2/Th17 cytokines in HIV-ALF vs. control-ALF (non-HIV infected people)...

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of PD-L1, a ligand for the inhibitory receptor PD-1. We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses...

Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell intrinsic DOCK8 was required for maintenance of antigen-specific IgA secreting plasma cells (PCs) in the gut lamina propria...

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of IgA in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced Dextran Sulfate Sodium Salt (DSS)-induced colitis...

SARS-CoV-2 initially infects cells in the nasopharynx and oral cavity. The immune system at these mucosal sites plays a crucial role in minimizing viral transmission and infection. To develop new strategies for preventing SARS-CoV-2 infection, this study aimed to identify proteins that protect against viral infection in saliva. We collected 551 saliva samples from 290 healthcare workers who had tested positive for COVID-19, before vaccination, between June and December 2020. The samples were categorized based on their ability to block or enhance infection using in vitro assays...

Dry eye disease (DED) is a prevalent chronic eye disease characterized by an aberrant inflammatory response in ocular surface mucosa. The immunological alterations underlying DED remain largely unknown. In this study, we employed single-cell transcriptome sequencing of conjunctival tissue from environment-induced DED mice to investigate multicellular ecosystem and functional changes at different DED stages. Our results revealed an epithelial subtype with fibroblastic characteristics and proinflammatory effects emerging in the acute phase of DED...

The oral cavity harbors a diverse microbiota that plays a significant role in maintaining homeostasis. Disruption of this balance can lead to various oral diseases, including periodontitis. Accumulating evidence suggests a connection between periodontitis and extra-oral diseases such as cardiovascular disease, rheumatoid arthritis, obesity, and diabetes. During periodontitis, oral bacteria enter the bloodstream directly, impacting extra-oral organs. Furthermore, recent studies have uncovered another pathway, the direct oral-gut axis, where oral bacteria translocate to the gut through an enteral route, influencing gut microbiota and metabolism...

The relationship between gastrointestinal tract infection, the host immune response and clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including magnitude of systemic antibody induction. Combining two prospective cohort studies, ISARIC4C and INSTINCT, we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures...

The intestine is home to an intertwined network of epithelial, immune, and neuronal cells as well as the microbiome, with implications for immunity, systemic metabolism, and behaviour. While the complexity of this microenvironment has long since been acknowledged, recent technological advances have propelled our understanding to an unprecedented level. Notably, the microbiota and non-immune or structural cells have emerged as important conductors of intestinal immunity, and by contrast, cells of both the innate and adaptive immune systems have demonstrated non-canonical roles in tissue repair and metabolism...

Type-3 innate lymphoid cells (ILC3) respond to localised environmental cues to regulate homeostasis and orchestrate immunity in the intestine. The intestinal epithelium is an important upstream regulator and downstream target of ILC3 signalling, however the complexity of mucosal tissues can hinder efforts to define specific interactions between these two compartments. Here, we employ a reductionist co-culture system of murine epithelial small intestinal organoids (SIO) with ILC3 to uncover bi-directional signalling mechanisms that underlie intestinal homeostasis...

Commensal-specific CD4+ T cells are expanded in inflammatory bowel disease (IBD) patients compared to healthy individuals. How and where commensal-specific CD4+ T cells get activated is yet to be fully understood. We used CBir1 TCR-transgenic CD4+ T cells, specific to a commensal bacterial antigen, and different mouse models of IBD to characterize the dynamics of commensal-specific CD4+ T cells activation. We found that CBir1 T cells proliferate following intestinal damage and cognate antigen presentation is mediated by CD11c+ cells in the colon-draining mesenteric lymph nodes (cMLNs)...