REVIEWS Fever from the forest prospects for the continued emergence of sylvatic dengue virus and its impact on public health Nikos Vasilakis Jane Cardosa Kathryn A Hanley Edward C Holmes and Scott C Weaver Abstract The four dengue virus DENV serotypes that circulate among humans emerged independently from ancestral sylvatic progenitors that were present in non human primates following the establishment of human populations that were large and dense enough to support continuous inter human transmission by mosquitoes This ancestral sylvatic DENV transmission cycle still exists and is maintained in non human primates and Aedes mosquitoes in the forests of Southeast Asia and West Africa Here we provide an overview of the ecology and molecular evolution of sylvatic DENV and its potential for adaptation to human transmission We also emphasize how the study of sylvatic DENV will improve our ability to understand predict and ideally avert further DENV emergence Department of Pathology Center for Biodefense and Emerging Infectious Disease Institute for Human Infection and Immunity and Center for Tropical Diseases University of Texas Medical Branch Galveston Texas 77555 USA Institute of Health and Community Medicine Universiti Sarawak Malaysia UNIMAS 94300 Kota Samarahan Sarawak Malaysia Department of Biology New Mexico State University Las Cruces New Mexico 88003 USA Center for Infectious Disease Dynamics Department of Biology Mueller Laboratory The Pennsylvania State University University Park Pennsylvania 16802 USA Fogarty International Center National Institutes of Health Bethesda Maryland 20892 USA Correspondence to N V e mail nivasila utmb edu doi 10 1038 nrmicro2595 Published online 13 June 2011 Dengue virus DENV is a positive sense single stranded RNA virus of the genus Flavivirus family Flaviviridae that uses mosquitoes of the genus Aedes as vectors for transmission among primates FIG 1 DENV occurs as four antigenically distinct but genetically related serotypes DENV 1 to DENV 4 within the dengue antigenic complex1 The molecular biology of DENV is summarized in BOX 1 In recent decades DENV transmission among humans has intensified and the virus currently infects 100 million people each year worldwide being found in over 100 countries2 Most DENV infections are subclinical or result in classical dengue fever which is characterized by fever muscle and joint pain and rash However approximately 0 5 of infections result in the most severe manifestation of the disease dengue haemorrhagic fever DHF which can be fatal in as many as 5 of cases Infection with a given serotype results in lifelong homologous immunity to that serotype but increases the risk of haemorrhagic fever upon infection by a heterologous serotype3 The principal risk factors for developing DHF include the strain of infecting virus4 7 prior infection with a heterologous serotype8 11 and the age12 14 and genetic background of the individual15 19 Other factors that may influence the progression to DHF include gender 12 14 and nutrition20 21 Each of the four DENV serotypes is maintained in two ecologically and evolutionary distinct transmission cycles a sylvatic cycle and a human cycle The sylvatic cycle involves non human primates and arboreal Aedes mosquitoes and has been documented in transmission foci in West Africa and peninsular Malaysia The human cycle involves the domestic Aedes aegypti subsp aegypti22 and peridomestic Aedes albopictus mosquitoes and can be found in a diverse range of environments throughout the tropics and subtropics In the human cycle humans are the only known reservoir hosts and amplification hosts a unique host usage pattern among arthropod borne viruses arboviruses 23 This Review examines the ecological and evolutionary processes that could have led to the establishment of the four existing serotypes of human DENV as well as the current disease burden and the future risks that are posed by the continued spillover of sylvatic DENV into human populations Although the importance of sylvatic DENV mediated disease in humans has largely been discounted we argue that this is premature in light of the paucity of information concerning sylvatic DENV infection in humans More generally it has become increasingly clear that of all the viruses with the potential to shift from an animal reservoir into humans the most likely to shift are those like sylvatic DENV that are carried by our closest relatives the non human primates24 41 Ecology and evolution of sylvatic DENV The origin of DENV Humans have undoubtedly been repeatedly exposed to sylvatic DENV and a process of 532 JULY 2011 VOLUME 9 www nature com reviews micro 2011 Macmillan Publishers Limited All rights reserved REVIEWS Dengue antigenic complex An antigenic subgroup within the RNA virus genus Flavivirus that includes all four dengue virus serotypes and is based on the antigenic cross reactivities cross neutralization of monoclonal and polyclonal antibodies Aedes luteocephalus West Africa Aedes furcifer West Africa Aedes niveus spp Southeast Asia TOT Aedes aegypti subsp aegypti tropics Aedes albopictus tropics Aedes polynesiensis Polynesia Aedes furcifer West Africa Aedes albopictus Southeast Asia TOT Dengue fever An acute mosquito borne disease of the tropics characterized by sudden onset and followed by a benign self resolving course of transient fever headache lymphadenopathy rash and severe joint and muscle pain It is the most common disease manifestation in persons infected with dengue virus although the majority of infections lack symptoms an outcome called inapparent infection Dengue haemorrhagic fever A syndrome that is caused by infection with dengue virus and characterized by abdominal pain haemorrhage and circulatory collapse This syndrome is also referred to as severe dengue disease Sylvatic Pertaining to a form of a disease or virus that occurs in wild animals in the case of dengue virus in non human primates in the forest Peridomestic Of a vector or location in and around human habitats Amplification hosts Host in which an infectious agent replicates to high enough concentrations for transmission to additional hosts For dengue virus humans and non human primates are the only known amplification hosts Arboviruses Arthropod borne viruses In the case of arboviruses that infect humans mosquitoes are the most common vectors Spillover Cross species virus transmission into small localized groups of people or other animals with no sustained
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