Person: Ordovas-Montanes, Jose
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Ordovas-Montanes
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Jose
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Ordovas-Montanes, Jose
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Publication Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation(2014) Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Wood, John N.; von Andrian-Werburg, UlrichThe skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation1–4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear5,6. Here, we have exposed the skin of mice to imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation7,8. We show that a subset of sensory neurons expressing the ion channels TRPV1 and NaV1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors9–11, DDCs failed to produce IL-23 in IMQ exposed skin. Consequently, the local production of IL-23 dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response12. These findings indicate that TRPV1+NaV1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.Publication The Regulation of Immunological Processes by Peripheral Neurons(2015-09-23) Ordovas-Montanes, Jose; Winau, Florian; Kagan, Jon; Ginty, David; McGavern, DorianThe nervous system and the immune system are the primary sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to stimuli with the appropriate valence and magnitude to optimize host fitness. Furthermore, an alluring parallel concept is that both systems have the capacity to form memories of these encounters leading to optimized and adaptive future responses. Recent work in the fields of neuroscience and immunology has led to a high-resolution map of cell subsets within both systems. Here, we start to leverage these advances to explore the relationship between these two sensory systems at the level of discrete cell subsets in immunological disease and homeostasis with a focus on interactions at barrier tissues. This work stems from the initial hypothesis that sensory neurons for noxious stimuli, nociceptors, regulate inflammation by controlling production of key instructive and effector cytokines derived from tissue-resident immune cells. In our first investigation focused on the skin, we identified that NaV1.8+ TRPV1+ nociceptors, via interactions with dDCs, are essential in vivo regulators of interleukin-(IL)-23/IL-17 pathway cutaneous immune responses. This set of studies raised several intriguing questions including determining what the inputs and outputs of nociceptors are that regulate IL-23 production from dDCs and whether nociceptors play a role in distinct inflammatory contexts. In further experiments we determined that while TRPV1 itself is dispensable, nociceptor activity is essential to promote disease and local cytokine production. As we found that nociceptors are critical for cutaneous IL-23 production, we tested the effect of nociceptor ablation during a bacterial infection that depends on IL-23 for clearance. Surprisingly, the absence of NaV1.8+ nociceptors led to more severe skin pathology and bacterial dissemination suggesting that NaV1.8+ nociceptors are important for tissue protection and bacterial containment. In complementary studies assessing the role of nociceptors in atopic dermatitis (Type 2 inflammation), we found that TRPV1+ neurons did not regulate gross disease or the instructive cytokine thymic stromal lymphopoietin (TSLP), yet were required for full effector (IL-4) cytokine production. This suggests that nociceptors exert contextual specificity and are not exclusively pro-inflammatory in all cutaneous pathologies. Based on the role for nociceptors in regulating cutaneous IL-23 and subsequent inflammation, we hypothesized that TRPV1+ nociceptors would be important in regulating IL-23-driven pathologies in the gut. However, we found no appreciable role for nociceptors in either an acute innate colitis or a spontaneous microbiota-driven colitis. While colitis is characterized by its gastrointestinal pathology, it affects the body systemically and we noted that in both models, mice lacking TRPV1+ nociceptors maintained healthier weights than their nerve-replete counterparts. This opens future avenues for exploration on how sensing of inflammation by nociceptors influences microbial communities, systemic metabolism, and sickness behavior. In summary, we propose that sensory perception of inflammation by peripheral neurons exerts context-dependent effects on immunological processes. We speculate that there is the potential to uncover a modular design framework by which distinct lines of sensory neurons are triggered in specific settings and may contribute to regulating different aspects of inflammation through interactions with immune cell subsets.Publication Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells(2012) Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten; Daley, George; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, LuigiIn the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies.Publication Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection(Cold Spring Harbor Laboratory, 2020-03-23) Kazer, Samuel W.; Aicher, Toby P.; Muema, Daniel M.; Carroll, Shaina L.; Ordovas-Montanes, Jose; Maio, Vincent M.; Tu, Andy A.; Ziegler, Carly G.K.; Nyquist, Sarah K.; Wong, Emily; Ismail, Nasreen; Dong, Mary; Moodley, Amber; Berger Leighton, Bonnie; Love, J. Christopher; Dong, Krista L.; Leslie, Alasdair; Ndhlovu, Zaza; Ndung'u, Thumbi; Walker, Bruce; Shalek, AlexanderCellular immunity is critical for controlling intracellular pathogens, but the dynamics and cooperativity of the evolving host response to infection are not well defined. Here, we apply single-cell RNA-sequencing to longitudinally profile pre- and immediately post-HIV infection peripheral immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a strong transcriptional interferon response integrated across most cell types, with subsequent pro-inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With longitudinal sampling, we nominate key intra- and extracellular drivers that induce these programs, and assign their multi-cellular targets, temporal ordering, and duration in acute infection. Two individuals studied developed spontaneous viral control, associated with initial elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated proliferating natural killer (NK) cell subset. Our study presents a unified framework for characterizing immune evolution during a persistent human viral infection at single-cell resolution, and highlights programs that may drive response coordination and influence clinical trajectory.