Suchergebnisse

Reactive oxygen species (ROS)- and calcium- dependent signaling pathways play well-established roles during plant innate immunity. Chloroplasts host major biosynthetic pathways and have central roles in energy production, redox homeostasis, and retrograde signaling. However, the organelle's importance in immunity has been somehow overlooked. Recent findings suggest that the chloroplast also has an unanticipated function as a hub for ROS- and calcium-signaling that affects immunity responses at an early stage after pathogen attack. In this opinion article, we discuss a chloroplastic calcium-ROS signaling branch of plant innate immunity. We propose that this chloroplastic branch acts as a light-dependent rheostat that, through the production of ROS, influences the severity of the immune response. ; S.S. is financially supported by FWO and, together with P.W., by a grant from the Ghent University Special Research Fund (grant 01J11311). This work was supported by the Ghent University Multidisciplinary Research Partnership "Ghent BioEconomy" (01MRB510W), the Belgian Science Policy Office (IAP7/29). P.K. and M.T. are supported by grants from the Austrian Science Fund (FWF project P 25359-B21) and the European Union's Seventh Framework Program (ITN CALIPSO, GA 2013-607607). N.S.C. is supported by funding from the European Union Marie Curie Actions (IIF-331392) and the Ministerio de Economía of the Spanish Government (AGL2010-21870). ; Peer reviewed

PURPOSE: Cannabis use is increasing due to recent legislative changes. In addition, cannabis is often used in conjunction with alcohol. The airway epithelium is the first line of defense against infectious microbes. Toll-like receptors (TLR) recognize airborne microbes and initiate the inflammatory cytokine response. How cannabis use in conjunction with alcohol affects pulmonary innate immunity mediated by TLRs is unknown. METHODS: Samples and data from an existing cohort of individuals with alcohol use disorders (AUDs), along with samples from additional participants with cannabis use alone and with AUD were utilized. Subjects were categorized into the following groups: no alcohol use disorder (AUD) or cannabis use (Control) (n=46), AUD only (n=29), Cannabis use only (n=39) and AUD and Cannabis use (n= 29). The participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and airway epithelial brushings. We measured IL-6, IL-8, TNF and IL-10 levels in BAL fluid, and performed real time PCR for TLR1–9 on the airway epithelial brushings. RESULTS: We found significant increases in TLR2 with AUD alone, cannabis use alone and cannabis use with AUD compared to control. TLR5 was increased in cannabis users compared to control, TLR6 was increased in cannabis users and cannabis users with AUD compared to control, TLR7 was increased in cannabis users compared to control, and TLR9 was increased compared to control. In terms of cytokine production, IL-6 was increased in cannabis users compared to control. IL-8 and IL-10 were increased in AUD only. CONCLUSIONS: AUD and cannabis use have complex effects on pulmonary innate immunity that promote airway inflammation.

S. A. G. was funded through the Weston Brain Institute International Fellowship in Neuroscience. J. G. P. was funded by Fulbright Canada, Weston Canada, and Brain Canada through the Canada Brain Research Fund, a public–private partnership established by the Government of Canada. M. R. B. was funded through the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts. J. H., M. R., and M. E. W. were funded through Medical Research Council (MRC) grant number G0901254/1.

Acknowledgments The authors would like to thank Andrew Gewirtz (Georgia State University, Atlanta, GA, USA) and Adam Cunningham (University of Birmingham, Edgbaston, Birmingham, UK) for generously providing the germ-free and conventional TLR5KO mice, respectively. The authors also wish to acknowledge a significant contribution to the inception of the work, experimental work, interpretation of results, and writing of the manuscript by Denise Kelly, as well as the support from RESAS (Rural and Environmental Science and Analytical Services) of the Scottish Government. EM and VF were supported by the Marie Curie Initial training network Fellowships funded by the EU (grant #215532). The authors acknowledge a generous support of Prof. Harry Flint and Dr. Sylvia Duncan in the microbiological part of this work. The skilled technical support of Gillian Campbell and Pauline Young at RINH Genomics is also gratefully acknowledged. ; Peer reviewed ; Publisher PDF

The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.

International audience ; BACKGROUND:Ebolavirus species Zaire (ZEBOV) causes highly lethal hemorrhagic fever, resulting in the death of 90% of patients within days. Most information on immune responses to ZEBOV comes from in vitro studies and animal models. The paucity of data on human immune responses to this virus is mainly due to the fact that most outbreaks occur in remote areas. Published studies in this setting, based on small numbers of samples and limited panels of immunological markers, have given somewhat different results.METHODOLOGY/PRINCIPAL FINDINGS:Here, we studied a unique collection of 56 blood samples from 42 nonsurvivors and 14 survivors, obtained during the five outbreaks that occurred between 1996 and 2003 in Gabon and Republic of Congo. Using Luminex technology, we assayed 50 cytokines in all 56 samples and performed phenotypic analyses by flow cytometry. We found that fatal outcome was associated with hypersecretion of numerous proinflammatory cytokines (IL-1β, IL-1RA, IL-6, IL-8, IL-15 and IL-16), chemokines and growth factors (MIP-1α, MIP-1β, MCP-1, M-CSF, MIF, IP-10, GRO-α and eotaxin). Interestingly, no increase of IFNα2 was detected in patients. Furthermore, nonsurvivors were also characterized by very low levels of circulating cytokines produced by T lymphocytes (IL-2, IL-3, IL-4, IL-5, IL-9, IL-13) and by a significant drop of CD3+CD4+ and CD3+CD8+ peripheral cells as well as a high increase in CD95 expression on T lymphocytes.CONCLUSIONS/SIGNIFICANCE:This work, the largest study to be conducted to date in humans, showed that fatal outcome is associated with aberrant innate immune responses and with global suppression of adaptive immunity. The innate immune reaction was characterized by a "cytokine storm," with hypersecretion of numerous proinflammatory cytokines, chemokines and growth factors, and by the noteworthy absence of antiviral IFNα2. Immunosuppression was characterized by very low levels of circulating cytokines produced by T lymphocytes and by massive loss of peripheral ...

International audience ; BACKGROUND:Ebolavirus species Zaire (ZEBOV) causes highly lethal hemorrhagic fever, resulting in the death of 90% of patients within days. Most information on immune responses to ZEBOV comes from in vitro studies and animal models. The paucity of data on human immune responses to this virus is mainly due to the fact that most outbreaks occur in remote areas. Published studies in this setting, based on small numbers of samples and limited panels of immunological markers, have given somewhat different results.METHODOLOGY/PRINCIPAL FINDINGS:Here, we studied a unique collection of 56 blood samples from 42 nonsurvivors and 14 survivors, obtained during the five outbreaks that occurred between 1996 and 2003 in Gabon and Republic of Congo. Using Luminex technology, we assayed 50 cytokines in all 56 samples and performed phenotypic analyses by flow cytometry. We found that fatal outcome was associated with hypersecretion of numerous proinflammatory cytokines (IL-1β, IL-1RA, IL-6, IL-8, IL-15 and IL-16), chemokines and growth factors (MIP-1α, MIP-1β, MCP-1, M-CSF, MIF, IP-10, GRO-α and eotaxin). Interestingly, no increase of IFNα2 was detected in patients. Furthermore, nonsurvivors were also characterized by very low levels of circulating cytokines produced by T lymphocytes (IL-2, IL-3, IL-4, IL-5, IL-9, IL-13) and by a significant drop of CD3+CD4+ and CD3+CD8+ peripheral cells as well as a high increase in CD95 expression on T lymphocytes.CONCLUSIONS/SIGNIFICANCE:This work, the largest study to be conducted to date in humans, showed that fatal outcome is associated with aberrant innate immune responses and with global suppression of adaptive immunity. The innate immune reaction was characterized by a "cytokine storm," with hypersecretion of numerous proinflammatory cytokines, chemokines and growth factors, and by the noteworthy absence of antiviral IFNα2. Immunosuppression was characterized by very low levels of circulating cytokines produced by T lymphocytes and by massive loss of peripheral ...