Ecology and evolution of sylvatic DENVAbstract | 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 enoFigure 1 | The transmission cycles of dengue virus. The sylvatic origins of dengue virus, and the ‘zone of emergence’, where sylvatic cycles contact human populations in rural areas of West Africa and Southeast Asia. In addition, dengue virus can persistBox 1 | Genome organization and basic biology of dengue virusBox 2 | Mechanisms of enzootic emergenceEmergence of sylvatic DENV in humans?Box 3 | The contrasting evolution and emergence of dengue virus and yellow fever virusSpillover of sylvatic DENV into human populationsFigure 2 | The geography of sylvatic dengue virus. The geographic range of known and putative mosquito vectors and non-human primate hosts for the transmission cycles of sylvatic dengue virus in Africa and Southeast Asia. Although the range of the guinea Prevention of sylvatic-DENV re-emergence ConclusionBox 4 | Dengue eradication and the ‘empty niche’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 sero-types (DENV-1 to DENV-4) within the dengue antigenic complex1. The molecular biology of DENV is summa-rized in BOX1. 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 individ-ual15–19. Other factors that may influence the progression to DHF include gender12–14 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 eco-logical 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 reser-voir 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 DENVThe origin of DENV. Humans have undoubtedly been repeatedly exposed to sylvatic DENV, and a process of *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: [email protected]:10.1038/nrmicro2595Published online 13 June 2011Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public healthNikos 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.REVIEWS532 | JULY 2011 | VOLUME 9 www.nature.com/reviews/micro© 2011 Macmillan Publishers Limited. All rights reservedNature Reviews | MicrobiologySylvatic cycle Rural areasZone of emergenceAedes furcifer (West Africa)Aedes albopictus (Southeast Asia)Aedes luteocephalus (West Africa)Aedes furcifer (West Africa)Aedes niveus spp. (Southeast Asia)Aedes aegypti subsp. aegypti (tropics)Aedes albopictus (tropics)Aedes polynesiensis (Polynesia)???TOT? TOTHuman cycleDengue antigenic complexAn antigenic subgroup within the RNA virus genus Flavivirus that
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