Although mammalian secretory immunoglobulin A (sIgA) targets mucosal pathogens for elimination, its interaction with the microbiota also enables commensal colonization and homeostasis. This paradoxical requirement in the control of pathogens versus microbiota raised the question of whether mucosal (secretory) Igs (sIgs) evolved primarily to protect mucosal surfaces from pathogens or to maintain microbiome homeostasis. To address this central question, we used a primitive vertebrate species (rainbow trout) in which we temporarily depleted its mucosal Ig (sIgT). Fish devoid of sIgT became highly susceptible to a mucosal parasite and failed to develop compensatory IgM responses against it. IgT depletion also induced a profound dysbiosis marked by the loss of sIgT-coated beneficial taxa, expansion of pathobionts, tissue damage, and inflammation. Restitution of sIgT levels in IgT-depleted fish led to a reversal of microbial translocation and tissue damage, as well as to restoration of microbiome homeostasis. Our findings indicate that specialization of sIgs in pathogen and microbiota control occurred concurrently early in evolution, thus revealing primordially conserved principles under which primitive and modern sIgs operate in the control of microbes at mucosal surfaces.

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The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in electrical activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α + cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α + cells were TCRαβ T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses observed with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses. neuroimmunology | olfactory sensory neurons | teleost | viral immunity | TrkA

Thyroid hormone (TH) is an ancestral signal linked to seasonal life history transitions throughout vertebrates. TH action depends upon tissue-localized regulation of levels of active TH (triiodothyronine, T3), through spatiotemporal expression of thyroid hormone deiodinase (dio) genes. We investigated the dio gene family in juvenile Atlantic salmon (Salmo salar) parr, which prepare for seaward migration in the spring (smoltification) through TH-dependent changes in physiology. We identified two type 2 deiodinase paralogs, dio2a and dio2b, responsible for conversion of thyroxine (T4) to T3. During smoltification, dio2b was induced in the brain and gills in zones of cell proliferation following increasing day length. Contrastingly, dio2a expression was induced in the gills by transfer to salt water (SW), with the magnitude of the response proportional to the plasma chloride level. This response reflected a selective enrichment for osmotic response elements (OREs) in the dio2a promoter region. Transcriptomic profiling of gill tissue from fish transferred to SW plus or minus the deiodinase inhibitor, iopanoic acid, revealed SW-induced increases in cellular respiration as the principal consequence of gill dio2 activity. Divergent evolution of dio2 paralogs supports organ-specific timing of the TH-dependent events governing the phenotypic plasticity required for migration to sea.

Many organisms can generate alternative phenotypes from the same genome, enabling individuals to exploit diverse and variable environments. A prevailing hypothesis is that such adaptation has been favored by gene duplication events, which generate redundant genomic material that may evolve divergent functions. Vertebrate examples of recent whole-genome duplications are sparse although one example is the salmonids, which have undergone a whole-genome duplication event within the last 100 Myr. The life-cycle of the Atlantic salmon, Salmo salar, depends on the ability to produce alternating phenotypes from the same genome, to facilitate migration and maintain its anadromous life history. Here, we investigate the hypothesis that genome-wide and local gene duplication events have contributed to the salmonid adaptation. We used high-throughput sequencing to characterize the transcriptomes of three key organs involved in regulating migration in S. salar: Brain, pituitary, and olfactory epithelium. We identified over 10,000 undescribed S. salar sequences and designed an analytic workflow to distinguish between paralogs originating from local gene duplication events or from whole-genome duplication events. These data reveal that substantial local gene duplications took place shortly after the whole-genome duplication event. Many of the identified paralog pairs have either diverged in function or become noncoding. Future functional genomics studies will reveal to what extent this rich source of divergence in genetic sequence is likely to have facilitated the evolution of extreme phenotypic plasticity required for an anadromous life-cycle.

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Mucosal surfaces require balancing different physiological roles and immune functions. In order to effectively achieve multifunctionality, mucosal epithelia have evolved unique microenvironments that create unique regional immune responses without impairing other normal physiological functions. Whereas examples of regional immunity are known in other mucosal epithelia, to date, no immune microenvironments have been described in the nasal mucosa, a site where the complex functions of olfaction and immunity need to be orchestrated. In this study we identified for the first time the presence of CD8α+ cells in the rainbow trout (Oncorhynchus mykiss) nasal epithelium. Nasal CD8α+ cells display a distinct phenotype suggestive of CD8+ T cells with high integrin β2 expression. Importantly, nasal CD8α+ cells are located in clusters at the mucosal tip of each olfactory lamella but scattered in the neuroepithelial region. The grouping of CD8α+ cells may be explained by the greater expression of CCL19, ICAM-1, and VCAM-1 in the mucosal tip compared to the neuroepithelium. Whilst viral antigen uptake occurred via both tip and lateral routes, tip resident MHC-II+ cells are located significantly closer to the lumen of the nasal cavity than their neuroepithelial counterparts, therefore having quicker access to invading pathogens. Our studies reveal for the first time compartmentalized mucosal immune responses within the nasal mucosa of a vertebrate species, a strategy that likely optimizes local immune responses while protecting olfactory sensory functions.

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