Mucosal Immunity: The Key to Combating Enteroviruses and Beyond

Figures

• 

  Figure 1. Panel A represents how dendritic cells (DCs) interact with both effector T cells and regulatory T (Treg) cells in response to commensal bacteria under normal conditions. In Panel B, the focus is on either anti‐inflammatory or proinflammatory reactions under normal conditions or during instances of infection or inflammation. Normally, such conditioning might also result from the sampling of commensal bacteria or exposure to self‐antigens or dietary proteins, leading to immune responses that are effectively “quieted” through tolerance mechanisms involving Treg cells or the action of IgA in immune exclusion. A smaller subset of another type of DCs might also migrate to the mesenteric lymph nodes under normal conditions. These cells, having possibly avoided prior conditioning, could push T helper cells toward Th1 or Th17 profiles. Although present in minor quantities, these cells do not cause disease under normal conditions but could serve as early warning systems upon encountering pathogenic bacteria/viral pathogens or in situations where abnormal reactions to soluble proteins lead to disease manifestations, such as in food allergies.

• 

  Figure 2. At mucosal surfaces, protection is afforded through various immune responses. Effector B and T cells that are antigen‐specific circulate in the bloodstream and identify mucosal high endothelial venules (HEVs) to migrate into the mucosal tissue. B cells undergo final differentiation into plasma cells, predominantly generating dimeric IgA. This IgA is then secreted as SIgA into the mucosal secretions, where it plays a vital role in intercepting pathogens and antigens, thus preventing their invasion of the mucosa. Additionally, neutralizing IgG antibodies are found within the mucosal tissues, which may originate from either local plasma cells or be diffused from the blood through the fenestrated capillaries in the vicinity. Specific cytotoxic T lymphocytes (CTLs) or the process of antibody‐dependent cell‐mediated cytotoxicity (ADCC), which involves a partnership between natural killer (NK) cells and antibodies, can eliminate infected cells. Moreover, dendritic cells (DCs) and macrophages can capture pathogens and transport them to the draining lymph nodes for further immune response.

• 

  Figure 3. Mucosal immune response to enterovirus infection and enterovirus evasion mechanisms. This diagram depicts the host immune response at mucosal surfaces and the strategies used by the enteroviruses to counteract it. (1) Viral entry: Enteroviruses, like PV, enter through M cells and infect epithelial cells. (2) Innate immune detection: Viral RNA is identified by PRRs such as TLR3 and RIG‐I, which signal through TRIF and MAVS, activating IRF3 and IRF1 to produce type I and III interferons (IFN‐I/III). (3) Immune response: Interferon signaling promotes dendritic cell maturation and migration to lymphoid tissues, initiating adaptive immunity, resulting in SIgA production and T‐cell activation. (4) Viral evasion: Enteroviral proteases 2A and 3C impede antiviral signaling by cleaving crucial molecules like TRIF and MAVS, reducing interferon production and immune responses. (5) Clinical outcome: Effective interferon responses limit viral replication to mucosal tissues, while impaired signaling allows for viral spread, resulting in viremia. The inset contrasts local containment with widespread dissemination in cases of impaired responses, with red pathways indicating viral antagonism and…