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dc.contributor.authorHirako, Isabella C.
dc.contributor.authorGallego-Marin, Carolina
dc.contributor.authorAtaide, Marco A. Oswalso Cruz Founda
dc.contributor.authorAndrade, Warrison A.
dc.contributor.authorGravina, Humberto
dc.contributor.authorRocha, Bruno C.
dc.contributor.authorde Oliveira, Rosane B.
dc.contributor.authorPereira, Dhelio B.
dc.contributor.authorVinetz, Joseph
dc.contributor.authorDiamond, Betty
dc.contributor.authorRam, Sanjay
dc.contributor.authorGolenbock, Douglas T.
dc.contributor.authorGazzinelli, Ricardo T.
dc.date2022-08-11T08:09:44.000
dc.date.accessioned2022-08-23T16:41:21Z
dc.date.available2022-08-23T16:41:21Z
dc.date.issued2015-11-17
dc.date.submitted2016-01-15
dc.identifier.citationMBio. 2015 Nov 17;6(6). pii: e01605-15. doi: 10.1128/mBio.01605-15. <a href="http://dx.doi.org/10.1128/mBio.01605-15">Link to article on publisher's site</a>
dc.identifier.issn2150-7511 (Electronic)
dc.identifier.doi10.1128/mBio.01605-15
dc.identifier.pmid26578679
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39865
dc.description.abstractHigh levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-alpha and IL-1beta in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases. IMPORTANCE: Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26578679&dopt=Abstract">Link to Article in PubMed</a>
dc.rights<p>Copyright © 2015 Hirako et al. This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license</a>, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/
dc.subjectImmunology of Infectious Disease
dc.subjectImmunopathology
dc.subjectParasitic Diseases
dc.subjectParasitology
dc.subjectPathogenic Microbiology
dc.titleDNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients
dc.typeJournal Article
dc.source.journaltitlemBio
dc.source.volume6
dc.source.issue6
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3669&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2665
dc.identifier.contextkey8015315
refterms.dateFOA2022-08-23T16:41:21Z
html.description.abstract<p>High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-alpha and IL-1beta in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases.</p> <p>IMPORTANCE: Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease.</p>
dc.identifier.submissionpathoapubs/2665
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pagese01605-15


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<p>Copyright © 2015 Hirako et al. This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license</a>, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>
Except where otherwise noted, this item's license is described as <p>Copyright © 2015 Hirako et al. This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license</a>, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>