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dc.contributor.authorHelenius, Iiro Taneli
dc.contributor.authorKrupinski, Thomas
dc.contributor.authorTurnbull, Douglas W.
dc.contributor.authorGruenbaum, Yosef
dc.contributor.authorSilverman, Neal S.
dc.contributor.authorJohnson, Eric A.
dc.contributor.authorSporn, Peter H. S.
dc.contributor.authorSznajder, Jacob I.
dc.contributor.authorBeitel, Greg J.
dc.date2022-08-11T08:09:08.000
dc.date.accessioned2022-08-23T16:19:01Z
dc.date.available2022-08-23T16:19:01Z
dc.date.issued2009-10-23
dc.date.submitted2009-12-15
dc.identifier.citationProc Natl Acad Sci U S A. 2009 Nov 3;106(44):18710-5. Epub 2009 Oct 21. <a href="http://dx.doi.org/10.1073/pnas.0905925106">Link to article on publisher's site</a>
dc.identifier.issn1091-6490 (Electronic)
dc.identifier.doi10.1073/pnas.0905925106
dc.identifier.pmid19846771
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34947
dc.description.abstractElevated CO(2) levels (hypercapnia) frequently occur in patients with obstructive pulmonary diseases and are associated with increased mortality. However, the effects of hypercapnia on non-neuronal tissues and the mechanisms that mediate these effects are largely unknown. Here, we develop Drosophila as a genetically tractable model for defining non-neuronal CO(2) responses and response pathways. We show that hypercapnia significantly impairs embryonic morphogenesis, egg laying, and egg hatching even in mutants lacking the Gr63a neuronal CO(2) sensor. Consistent with previous reports that hypercapnic acidosis can suppress mammalian NF-kappaB-regulated innate immune genes, we find that in adult flies and the phagocytic immune-responsive S2* cell line, hypercapnia suppresses induction of specific antimicrobial peptides that are regulated by Relish, a conserved Rel/NF-kappaB family member. Correspondingly, modest hypercapnia (7-13%) increases mortality of flies inoculated with E. faecalis, A. tumefaciens, or S. aureus. During E. faecalis and A. tumefaciens infection, increased bacterial loads were observed, indicating that hypercapnia can decrease host resistance. Hypercapnic immune suppression is not mediated by acidosis, the olfactory CO(2) receptor Gr63a, or by nitric oxide signaling. Further, hypercapnia does not induce responses characteristic of hypoxia, oxidative stress, or heat shock. Finally, proteolysis of the Relish IkappaB-like domain is unaffected by hypercapnia, indicating that immunosuppression acts downstream of, or in parallel to, Relish proteolytic activation. Our results suggest that hypercapnic immune suppression is mediated by a conserved response pathway, and illustrate a mechanism by which hypercapnia could contribute to worse outcomes of patients with advanced lung disease, who frequently suffer from both hypercapnia and respiratory infections.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=19846771&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.0905925106
dc.subjectHypercapnia
dc.subjectPulmonary Disease, Chronic Obstructive
dc.subjectDrosophila
dc.subjectDrosophila Proteins
dc.subjectImmunity, Innate
dc.subjectNF-kappa B
dc.subjectTranscription Factors
dc.subjectImmunology and Infectious Disease
dc.titleElevated CO2 suppresses specific Drosophila innate immune responses and resistance to bacterial infection
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume106
dc.source.issue44
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/17
dc.identifier.contextkey1088914
html.description.abstract<p>Elevated CO(2) levels (hypercapnia) frequently occur in patients with obstructive pulmonary diseases and are associated with increased mortality. However, the effects of hypercapnia on non-neuronal tissues and the mechanisms that mediate these effects are largely unknown. Here, we develop Drosophila as a genetically tractable model for defining non-neuronal CO(2) responses and response pathways. We show that hypercapnia significantly impairs embryonic morphogenesis, egg laying, and egg hatching even in mutants lacking the Gr63a neuronal CO(2) sensor. Consistent with previous reports that hypercapnic acidosis can suppress mammalian NF-kappaB-regulated innate immune genes, we find that in adult flies and the phagocytic immune-responsive S2* cell line, hypercapnia suppresses induction of specific antimicrobial peptides that are regulated by Relish, a conserved Rel/NF-kappaB family member. Correspondingly, modest hypercapnia (7-13%) increases mortality of flies inoculated with E. faecalis, A. tumefaciens, or S. aureus. During E. faecalis and A. tumefaciens infection, increased bacterial loads were observed, indicating that hypercapnia can decrease host resistance. Hypercapnic immune suppression is not mediated by acidosis, the olfactory CO(2) receptor Gr63a, or by nitric oxide signaling. Further, hypercapnia does not induce responses characteristic of hypoxia, oxidative stress, or heat shock. Finally, proteolysis of the Relish IkappaB-like domain is unaffected by hypercapnia, indicating that immunosuppression acts downstream of, or in parallel to, Relish proteolytic activation. Our results suggest that hypercapnic immune suppression is mediated by a conserved response pathway, and illustrate a mechanism by which hypercapnia could contribute to worse outcomes of patients with advanced lung disease, who frequently suffer from both hypercapnia and respiratory infections.</p>
dc.identifier.submissionpathinfdis_pp/17
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages18710-5


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