Recent Insights into Cellular Crosstalk in Respiratory and Gastrointestinal Mucosal Immune Systems

The human body is continuously threatened by pathogens, and the immune system must maintain a balance between fighting infection and becoming over-activated. Mucosal surfaces cover several anatomically diverse organs throughout the body, such as the respiratory and gastrointestinal tracts, and are directly exposed to the external environment.Various pathogens invade the body through mucosal surfaces, making the mucosa the frontline of immune defense. The immune systems of various mucosal tissues display distinctive features that reflect the tissues' anatomical and functional characteristics. This review discusses the cellular components that constitute the respiratory and gastrointestinal tracts; in particular, it highlights the complex interactions between epithelial and immune cells to induce Ag-specific immune responses in the lung and gut. This information on mucosal immunity may facilitate understanding of the defense mechanisms against infectious agents that invade mucosal surfaces, such as severe acute respiratory syndrome coronavirus 2, and provide insight into effective vaccine development.

Recent Insights into Cellular Crosstalk in Respiratory and Gastrointestinal Mucosal Immune Systems

The human body is continuously threatened by pathogens, and the immune system must maintain a balance between fighting infection and becoming over-activated. Mucosal surfaces cover several anatomically diverse organs throughout the body, such as the respiratory and gastrointestinal tracts, and are directly exposed to the external environment.Various pathogens invade the body through mucosal surfaces, making the mucosa the frontline of immune defense. The immune systems of various mucosal tissues display distinctive features that reflect the tissues' anatomical and functional characteristics. This review discusses the cellular components that constitute the respiratory and gastrointestinal tracts; in particular, it highlights the complex interactions between epithelial and immune cells to induce Ag-specific immune responses in the lung and gut. This information on mucosal immunity may facilitate understanding of the defense mechanisms against infectious agents that invade mucosal surfaces, such as severe acute respiratory syndrome coronavirus 2, and provide insight into effective vaccine development.

N-terminal Domain of the Spike Protein of Porcine Epidemic Diarrhea Virus as a New Candidate Molecule for a Mucosal Vaccine

Porcine epidemic diarrhea virus (PEDV) is a contagious coronavirus infecting pigs that leads to significant economic losses in the swine industry. Given that PEDV infection occurs in gut epithelial cells mainly via the fecal-oral route, induction of PEDV-specific immune responses in the mucosal compartment is required for protective immunity against viral infection. However, an effective mucosal vaccine against the currently prevalent PEDV strain is not available. In this study, we demonstrated that the N-terminal domain (NTD) of the spike (S) protein of PEDV represents a new vaccine candidate molecule to be applied via the mucosal route. We first established an Escherichia coli expression system producing the partial NTD (NTD231–501) of the PEDV S protein. Orally administered NTD231–501 protein specifically interacted with the apical area of M cells in the follicle-associated epithelium of Peyer's patch. Additionally, the NTD protein induced antigen-specific immune responses in both the systemic and mucosal immune compartments when administered orally. Collectively, we propose the NTD of the PEDV S protein to be a candidate mucosal vaccine molecule.

Oral administration of red ginseng powder fermented with probiotic alleviates the severity of dextran-sulfate sodium-induced colitis in a mouse model / 中国天然药物

Red ginseng is a well-known alternative medicine with anti-inflammatory activity. It exerts pharmacological effects through the transformation of saponin into metabolites by intestinal microbiota. Given that intestinal microflora vary among individuals, the pharmacological effects of red ginseng likely vary among individuals. In order to produce homogeneously effective red ginseng, we prepared probiotic-fermented red ginseng and evaluated its activity using a dextran sulfate sodium (DSS)-induced colitis model in mice. Initial analysis of intestinal damage indicated that the administration of probiotic-fermented red ginseng significantly decreased the severity of colitis, compared with the control and the activity was higher than that induced by oral administration of ginseng powder or probiotics only. Subsequent analysis of the levels of serum IL-6 and TNF-α, inflammatory biomarkers that are increased at the initiation stage of colitis, were significantly decreased in probiotic-fermented red ginseng-treated groups in comparison to the control group. The levels of inflammatory cytokines and mRNAs for inflammatory factors in colorectal tissues were also significantly decreased in probiotic-fermented red ginseng-treated groups. Collectively, oral administration of probiotic-fermented red ginseng reduced the severity of colitis in a mouse model, suggesting that it can be used as a uniformly effective red ginseng product.

The development of mucosal vaccines for both mucosal and systemic immune induction and the roles played by adjuvants

Vaccination is the most successful immunological practice that improves the quality of human life and health. Vaccine materials include antigens of pathogens and adjuvants potentiating the effectiveness of vaccination. Vaccines are categorized using various criteria, including the vaccination material used and the method of administration. Traditionally, vaccines have been injected via needles. However, given that most pathogens first infect mucosal surfaces, there is increasing interest in the establishment of protective mucosal immunity, achieved by vaccination via mucosal routes. This review summarizes recent developments in mucosal vaccines and their associated adjuvants.

Yersinia enterocolitica Exploits Signal Crosstalk between Complement 5a Receptor and Toll-like Receptor 1/2 and 4 to Avoid the Bacterial Clearance in M cells

In the intestinal mucosal surface, microfold cells (M cells) are the representative gateway for the uptake of luminal antigens. At the same time, M cells are the primary infection site for pathogens invading mucosal surface for their infection. Although it is well recognized that many mucosal pathogens exploit the M cells for their infection, the mechanism to infect M cells utilized by pathogens is not clearly understood yet. In this study, we found that M cells expressing complement 5a (C5a) receptor (C5aR) also express Toll-like receptor (TLR) 1/2 and TLR4. Infection of Yersinia enterocolitica, an M cell-invading pathogen, synergistically regulated cyclic adenosine monophosphate-dependent protein kinase A (cAMP-PKA) signaling which are involved in signal crosstalk between C5aR and TLRs. In addition, Y. enterocolitica infection into M cells was enhanced by C5a treatment and this enhancement was abrogated by C5a antagonist treatment. Finally, Y. enterocolitica infection into M cells was unsuccessful in C5aR knock-out mice. Collectively, we suggest that exploit the crosstalk between C5aR and TLR signaling is one of infection mechanisms utilized by mucosal pathogens to infect M cells.

Expression of the ATP-gated P2X7 Receptor on M Cells and Its Modulating Role in the Mucosal Immune Environment

Interactions between microbes and epithelial cells in the gastrointestinal tract are closely associated with regulation of intestinal mucosal immune responses. Recent studies have highlighted the modulation of mucosal immunity by microbe-derived molecules such as ATP and short-chain fatty acids. In this study, we undertook to characterize the expression of the ATP-gated P2X7 receptor (P2X7R) on M cells and its role in gastrointestinal mucosal immune regulation because it was poorly characterized in Peyer's patches, although purinergic signaling via P2X7R and luminal ATP have been considered to play an important role in the gastrointestinal tract. Here, we present the first report on the expression of P2X7R on M cells and characterize the role of P2X7R in immune enhancement by ATP or LL-37.

Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines

Vaccination is one of the most successful applications of immunology and for a long time has depended on parenteral administration protocols. However, recent studies have pointed to the promise of mucosal vaccination because of its ease, economy and efficiency in inducing an immune response not only systemically, but also in the mucosal compartment where many pathogenic infections are initiated. However, successful mucosal vaccination requires the help of an adjuvant for the efficient delivery of vaccine material into the mucosa and the breaking of the tolerogenic environment, especially in oral mucosal immunization. Given that M cells are the main gateway to take up luminal antigens and initiate antigen-specific immune responses, understanding the role and characteristics of M cells is crucial for the development of successful mucosal vaccines. Especially, particular interest has been focused on the regulation of the tolerogenic mucosal microenvironment and the introduction of the luminal antigen into the lymphoid organ by exploiting the molecules of M cells. Here, we review the characteristics of M cells and the immune regulatory factors in mucosa that can be exploited for mucosal vaccine delivery and mucosal immune regulation.

Targeted Delivery of VP1 Antigen of Foot-and-mouth Disease Virus to M Cells Enhances the Antigen-specific Systemic and Mucosal Immune Response

Application of vaccine materials through oral mucosal route confers great economical advantage in animal farming industry due to much less vaccination cost compared with that of injection-based vaccination. In particular, oral administration of recombinant protein antigen against foot-and-mouth disease virus (FMDV) is an ideal strategy because it is safe from FMDV transmission during vaccine production and can induce antigen-specific immune response in mucosal compartments, where FMDV infection has been initiated, which is hardly achievable through parenteral immunization. Given that effective delivery of vaccine materials into immune inductive sites is prerequisite for effective oral mucosal vaccination, M cell-targeting strategy is crucial in successful vaccination since M cells are main gateway for luminal antigen influx into mucosal lymphoid tissue. Here, we applied previously identified M cell-targeting ligand Co1 to VP1 of FMDV in order to test the possible oral mucosal vaccination against FMDV infection. M cell-targeting ligand Co1-conjugated VP1 interacted efficiently with M cells of Peyer's patch. In addition, oral administration of ligand-conjugated VP1 enhanced the induction of VP1-specific IgG and IgA responses in systemic and mucosal compartments, respectively, in comparison with those from oral administration of VP1 alone. In addition, the enhanced VP1-specific immune response was found to be due to antigen-specific Th2-type cytokine production. Collectively, it is suggested that the M cell-targeting strategy could be applied to develop efficient oral mucosal vaccine against FMDV infection.

Mucosal Immune System and M Cell-targeting Strategies for Oral Mucosal Vaccination

Vaccination is one of the most effective methods available to prevent infectious diseases. Mucosa, which are exposed to heavy loads of commensal and pathogenic microorganisms, are one of the first areas where infections are established, and therefore have frontline status in immunity, making mucosa ideal sites for vaccine application. Moreover, vaccination through the mucosal immune system could induce effective systemic immune responses together with mucosal immunity in contrast to parenteral vaccination, which is a poor inducer of effective immunity at mucosal surfaces. Among mucosal vaccines, oral mucosal vaccines have the advantages of ease and low cost of vaccine administration. The oral mucosal immune system, however, is generally recognized as poorly immunogenic due to the frequent induction of tolerance against orally-introduced antigens. Consequently, a prerequisite for successful mucosal vaccination is that the orally introduced antigen should be transported across the mucosal surface into the mucosa-associated lymphoid tissue (MALT). In particular, M cells are responsible for antigen uptake into MALT, and the rapid and effective transcytotic activity of M cells makes them an attractive target for mucosal vaccine delivery, although simple transport of the antigen into M cells does not guarantee the induction of specific immune responses. Consequently, development of mucosal vaccine adjuvants based on an understanding of the biology of M cells has attracted much research interest. Here, we review the characteristics of the oral mucosal immune system and delineate strategies to design effective oral mucosal vaccines with an emphasis on mucosal vaccine adjuvants.