title: Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580.
abstract: Dengue virus (DENV) infection could lead to dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The disease outcome is controlled by both viral and host factors. Inflammation mediators from DENV-infected cells could contribute to increased vascular permeability, leading to severe DHF/DSS. Therefore, suppression of inflammation could be a potential therapeutic approach for treatment of dengue patients. In this context, p38 MAPK (mitogen-activated protein kinase) is a key enzyme that modulates the initiation of stress and inflammatory responses. Here we show that SB203580, a p38 MAPK inhibitor, suppressed the over production of DENV-induced pro-inflammatory mediators such as TNF-α, IL-8, and RANTES from human PBMCs, monocytic THP-1, and granulocyte KU812 cell lines. Oral administration of SB203580 in DENV-infected AG129 mice prevented hematocrit rise and lymphopenia, limited the development of inflammation and pathology (including intestine leakage), and significantly improved survival. These results, for the first time, have provided experimental evidence to imply that a short term inhibition of p38 MAPK may be beneficial to reduce disease symptoms in dengue patients.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
authors.forename: Andy
authors.initials: A
authors.lastname: Yip
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
authors.forename: Peck Gee
authors.initials: PG
authors.lastname: Seah
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore. Electronic address: pei_yong.shi@novartis.com.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore 138670, Singapore. Electronic address: maxime.herve@novartis.com.
authors.forename: Maxime
authors.initials: M
authors.lastname: Hervé
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D006224:Cricetinae; D009033:Culicidae; D003715:Dengue / Q000188:drug therapy* / Q000821:virology; D003716:Dengue Virus / Q000472:pathogenicity; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006400:Hematocrit; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy*; D016209:Interleukin-8 / Q000096:biosynthesis; D008231:Lymphopenia / Q000517:prevention & control; D051379:Mice; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C483024:CCL5 protein, human; C508606:CXCL8 protein, human; D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Antiviral drug discovery; Dengue therapeutics; Dengue virus; p38 MAPK