Dengue

Cell. Mol. Life Sci. (2010) 67:2773–2786 DOI 10.1007/s00018-010-0357-z

Cellular and Molecular Life Sciences

REVIEW

Dengue virus life cycle: viral and host factors modulating infectivity
Izabela A. Rodenhuis-Zybert • Jan Wilschut Jolanda M. Smit
•

Received: 4 January 2010 / Revised: 8 March 2010 / Accepted: 16 March 2010 / Published online: 6 April 2010 Ó Springer Basel AG 2010Abstract Dengue virus (DENV 1-4) represents a major emerging arthropod-borne pathogen. All four DENV serotypes are prevalent in the (sub) tropical regions of the world and infect 50–100 million individuals annually. Whereas the majority of DENV infections proceed asymptomatically or result in self-limited dengue fever, an increasing number of patients present more severe manifestations, such asdengue hemorrhagic fever and dengue shock syndrome. In this review we will give an overview of the infectious life cycle of DENV and will discuss the viral and host factors that are important in controlling DENV infection. Keywords Dengue Á Flavivirus Á Life cycle Á Immune response Á Pathogenesis Á Host factors Á Virulence Á Antibody-dependent enhancement

Introduction Dengue is the most commonarthropod-borne viral infection in the world [1, 2]. The disease is endemic in more than 100 countries throughout Africa, the Americas, the Eastern Mediterranean, South-East Asia, and the Western Pacific. There are four distinct serotypes of dengue virus (DENV) and each of these serotypes can cause disease symptoms ranging from self-limited febrile illness called

dengue fever (DF) to denguehemorrhagic fever (DHF) and dengue shock syndrome (DSS) [2–4]. Infection with one serotype confers protective immunity against that serotype but not against other serotypes. In fact, several retrospective and prospective studies have revealed that secondary infection with a heterologous serotype is a risk factor for developing DHF/DSS [4–8]. Also, infants born to dengueimmune mothers are at risk todevelop more severe dengue during a primary infection [9, 10]. This suggests that antibodies play an important role in controlling the outcome of an infection. It is believed that antibodies specifically direct the virus particles to cells carrying Fc-receptors (FcR), such as monocytes, macrophages, and dendritic cells, which—as the natural targets for the virus—are permissive for DENV infection. Thisleads to enhanced infection of these cells and thus, to high viral loads, resulting in extensive T cell activation early in the infection process. As a consequence, high amounts of cytokines and chemical mediators are released, which may lead to endothelial cell damage and subsequent plasma leakage. Other factors that are implicated in disease pathogenesis include viral virulence, the ethnicbackground and age of the individual, and specific epidemiological conditions [11–15]. In this review we will give a general overview of the infectious life cycle of DENV, and describe the viral and host factors that may influence disease outcome.

I. A. Rodenhuis-Zybert Á J. Wilschut Á J. M. Smit (&) Molecular Virology Section, Department of Medical Microbiology, University Medical Center Groningen,University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands e-mail: jolanda.smit@med.umcg.nl

Dengue virus life cycle Virion structure DENV is an enveloped positive-strand RNA virus belonging to the Flaviviridae family [16, 17]. Mature

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virions contain three structural proteins, the capsid protein C, membrane protein M, and the envelopeprotein E. Multiple copies of the C protein (11 kDa) encapsulate the RNA genome to form the viral nucleocapsid [18–20]. The nucleocapsid is surrounded by a host-cell-derived lipid bilayer, in which 180 copies of M and E are anchored. The M protein is a small (approx. 8 kDa) proteolytic fragment of its precursor form prM (approx. 21 kDa). The E protein is 53 kDa and has three distinct structural...