S U M M A RYFlaviviruses, including Dengue, West Nile, Japanese encephalitis, and Tick-borne encephalitis virus, are major emerging human pathogens, affecting millions of individuals worldwide. Many clinically important flaviviruses elicit CNS diseases in infected hosts, including traditional "hemorrhagic" viruses, such as Dengue. This review focuses on the epidemiology, symptomatology, neuropathology, and, specifically, neuropathogenesis of flavivirus-induced human CNS disease. A detailed insight into specific factors priming towards neuroinvasive disease is of clear clinical significance, as well as importance to the development of antiviral therapies and identification of key mechanisms involved in the (re)emergence of specific flaviviruses, including potentially novel or previously unrecognized ones, as neuroinvasive pathogens. Copyright © 2011 John Wiley & Sons, Ltd.
INTRODUCTIONBecause of rapid changes in climate and demography, vector-transmitted arboviral diseases pose an increasing threat to global health and welfare [1,2]. Among the most severe arboviral infections known to affect human race are those caused by members of the Flavivirus genus of the Flaviviridae. The genus comprises over 70 different members and includes major human pathogens such as Yellow Fever virus (YFV), Dengue virus (DENV), Japanese encephalitis virus (JEV), Tick-borne encephalitis virus (TBEV), and West Nile virus (WNV) [3][4][5].Flaviviruses are single-stranded, positive-sense RNA viruses, whose genome encodes three structural and seven NS proteins [6]. All flaviviruses circulate in transmission cycles consisting of vertebrate hosts and insect vectors, in which humans mostly act as deadend hosts [7]. Natural cases of human infection almost invariably follow the bite of an infected tick or mosquito, although incidental cases related to other transmission mechanisms, including the use of infected blood products and organ transplants or, in case of TBEV, oral transfer through consumption of unpasteurized milk (products) have, infrequently, been reported as well [4,5]. A spectrum of distinct clinical syndromes is known to complicate flavivirus infections in humans, ranging from relatively mild fever and arthalgia to severe hemorrhagic and encephalitic manifestations [5]. In contrast to the systemic syndromes, the development of encephalitic pathology relies upon the ability of the virus to gain entry to the CNS, a process known as viral neuroinvasiveness, and to infect neural cells, a phenomenon known as neurovirulence [8]. Interestingly, both abilities seem to be widely dispersed among various members of the Flavivirus genus (Figure 1, red). Neuroinvasive infections frequently occur upon infection with emerging viruses such as JEV, WNV, and TBEV, which have a global distribution range ( Figure 2) and affect hundreds of thousands of individuals worldwide, annually [5,9]. Recently, however, they have also increasingly been reported in the setting of *Corresponding author: Dr. Jolanda M. Smit, Department of Medical Microbiology, Mol...