{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:30:33Z","timestamp":1792096233521,"version":"4.4.0"},"reference-count":87,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T00:00:00Z","timestamp":1448409600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever\/dengue shock syndrome (DHF\/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF\/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings<\/ns4:p>","DOI":"10.12688\/f1000research.7024.1","type":"journal-article","created":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T10:30:04Z","timestamp":1448447404000},"page":"1353","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":71,"title":["Pathogenesis of Dengue: Dawn of a New Era"],"prefix":"10.12688","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7818-348X","authenticated-orcid":false,"given":"Scott B.","family":"Halstead","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2015,11,25]]},"reference":[{"key":"ref-1","doi-asserted-by":"crossref","first-page":"179-184","DOI":"10.5694\/j.1326-5377.1916.tb117256.x","article-title":"On the Transmission of Australian Dengue by the Mosquito Stegomyia fasciata.","volume":"2","author":"J Cleland","year":"1916","journal-title":"Med J Aust."},{"key":"ref-2","first-page":"233-262","article-title":"Observations on the etiology of dengue fever.","volume":"s1\u20133","author":"A Chandler","year":"1923","journal-title":"Am J Trop Med Hyg."},{"key":"ref-3","first-page":"1-304","article-title":"Dengue: Its history, epidemiology, mechanism of transmission, etiology, clinical manifestations, immunity, and prevention.","volume":"29","author":"J Siler","year":"1926","journal-title":"The Philippine Journal of Science."},{"key":"ref-4","first-page":"1-252","article-title":"Experimental Studies of Dengue.","volume":"44","author":"J Simmons","year":"1931","journal-title":"Philipp J Sci."},{"key":"ref-5","first-page":"171-197","article-title":"On the transmission of dengue in Sumatra.","volume":"s1\u201311","author":"E Snijders","year":"1931","journal-title":"Am J Trop Med Hyg."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"640-2","DOI":"10.1126\/science.101.2634.640","article-title":"Production of immunity to dengue with virus modified by propagation in mice.","volume":"101","author":"A Sabin","year":"1945","journal-title":"Science."},{"key":"ref-7","first-page":"629-633","article-title":"On the inoculation of dengue virus into mice.","volume":"3379","author":"R Kimura","year":"1944","journal-title":"Nippon Igaku."},{"key":"ref-8","first-page":"352-64","article-title":"Clinical and serologic response of man to immunization with attenuated dengue and yellow fever viruses.","volume":"77","author":"W Dorrance","year":"1956","journal-title":"J Immunol."},{"key":"ref-9","doi-asserted-by":"crossref","first-page":"620-623","DOI":"10.4269\/ajtmh.1963.12.620","article-title":"Attenuated Living Type 1 Dengue Vaccines.","volume":"12","author":"C Wisseman","year":"1963","journal-title":"Am J Trop Med Hyg."},{"key":"ref-10","first-page":"319-328","article-title":"Philippine hemorrhagic fever.","volume":"11","author":"F Quintos","year":"1956","journal-title":"St Tomas J Med."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"1102-3","DOI":"10.1126\/science.131.3407.1102","article-title":"Viruses associated with epidemic hemorrhagic fevers of the Philippines and Thailand.","volume":"131","author":"W Hammon","year":"1960","journal-title":"Science."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"448-56","DOI":"10.1016\/S0022-3476(66)80249-4","article-title":"Shock associated with dengue infection. 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