Host/Pathogen Interactions and the Role of the Barriers: On the Edge Between Health and Multifactorial/Complex Diseases

Microbial agents, whether pathogens, pathobionts, or commensals, have a multifaceted role in the pathogenesis of multifactorial diseases, with a particular emphasis on immune cell activation, antigen recognition, and trafficking through distinct tissues’ barriers. The microbial colonization and immune education begin in utero, through another barrier able to influence immune cell phenotypes and shaping future responses to both infection and vaccination. The complexity of T cell responses, shaped by the cross-reactivity of T cell receptors to a diverse repertoire of microbial epitopes, challenges the classical infectious disease paradigm wherein a single pathogen is associated with a specific disease. Instead, sequential or concurrent microbial exposures may be required to elicit disease, either by priming T cells or modulating their trafficking properties through direct (cis) or indirect (trans) mechanisms. Genetics and epigenetics combined with microbial exposure are shown to influence immune cell migration to target organs and the permeabilization of the barriers, including the blood brain barrier and the central nervous system, thereby contributing to neurodegenerative disorders. Two models, cis- and trans-regulation, by which microbes can alter T cell trafficking and immune homeostasis, crossing tissue barriers and offering mechanistic insight into the microbial contribution to inflammatory disease flares. These findings open new avenues for therapeutic intervention, including targeted vaccination, microbiota modulation, and antimicrobial therapies. However, challenges remain in identifying causal microbial drivers, mitigating risks associated with immunomodulation, and preventing adverse outcomes such as antimicrobial resistance or unintended immune activation. Future challenges will be the integration of approaches combining immunogenetics, single-cell sequencing, and systems immunology to better define pathogen specific contributions to complex immune-mediated diseases.