**2. Encephalitis and clinical manifestations**

The clinical hallmark of acute viral encephalitis includes classically fever, headache, and altered level of consciousness. Other associated clinical observations are disorientation, behavioral and speech disturbances and seizures. These clinical signs distinguish a patient with encephalitis from one with viral meningitis, who can have headache, nuchal rigidity, and fever (Whitley and Gnann, 2002). Clinical findings reflect disease progression and the specific areas of CNS involvement, which is determined by the tropism of different viruses for different cell types expressing different viral receptors. Neurons are most likely to be targeted by several viruses such as polioviruses which preferentially infect motor neurons and rabies which selectively infects neurons of the limbic system (Griffin, 2010). Oligodendrocytes, the myelin-forming cells can also be infected (e.g. HHV6, SFV) and leading to direct or indirect demyelination (Fazakerley et al., 2006; Mock et al., 1999). Other

with the presence of IgM anti-CHIKV in the CSF, encephalitis, Guillain-Barre, encephalomyeloradiculitis and rare deaths (Economopoulou et al., 2009; Lemant et al., 2008). In recent histopathological studies, CHIKV infection in adults was associated with bilateral frontoparietal white matter lesions with restricted diffusion, which is described as an early sign of viral encephalitis (Ganesan et al., 2008). Focal perivascular lymphocytic infiltrates were also present in area of active demyelination and some degree of microglial activation was also noted in the gray matter which may contribute to bystander neuronal loss (Ganesan et al., 2008). Although data are still scarce, the number of cases with CNS involvement appears to support the neurotropic/neuroinfectious activity of CHIKV. This unique CNS infection illustrated by subventricular white matter lesions and intraparenchymal haemorrhages have been confirmed experimentally. CHIKV diseases can be reproduced in several animal models and the virus was shown to infect mouse/macaque brains and to replicate in cultures of glial and neuronal cells (Gardner et al., 2010; Labadie et al., 2010; Solignat et al., 2009; Wang et al., 2008; Ziegler et al., 2008). The incidence of neuroinfection is dramatically increased following either the injection of high viral titers, the route of injection (intranasal > intraperitoneal), in young animals (less than two week-old) or in mice failing to mount a robust interferon response (i.e. IFNAR knockout animals). Thus, experimental infections where mice were inoculated subcutaneously showed rapid and robust replication (106-107 PFU/ml) of CHIKV in the brain particularly of newborn mice. Interestingly, infected mice showed signs of illness suggestive of human clinical pathology such as loss of balance, difficulty of walking, dragging of the hind limbs, skin lesions but with rare mortality. CHIKV neuroinfection is particularly severe in IFNAR -/ mice and targets the leptomeninges, the choroid plexus and ependymal cells lining the subventricular zone (SVZ) also known as one of the neural stem cell niche in adult brains. The nature of the receptor(s) mediating cell attachment and infection remains to be characterized but the role of apoptotic blebs carrying the virus from cell to cell has recently been established as in a Trojan-horse paradigm (see below). On the one hand, the local innate immune response is the key to the control of viral infection but could also, on the other, contribute to neuronal loss through the uncontrolled release of cytotoxic inflammatory cytokines, complement proteins or proapoptotic molecules (TNF-, FasL, granzymes) (Hauwel et al., 2005). We will review herein the pathological mechanisms as well as the innate immune mechanisms engaged during encephalitis and with special

The clinical hallmark of acute viral encephalitis includes classically fever, headache, and altered level of consciousness. Other associated clinical observations are disorientation, behavioral and speech disturbances and seizures. These clinical signs distinguish a patient with encephalitis from one with viral meningitis, who can have headache, nuchal rigidity, and fever (Whitley and Gnann, 2002). Clinical findings reflect disease progression and the specific areas of CNS involvement, which is determined by the tropism of different viruses for different cell types expressing different viral receptors. Neurons are most likely to be targeted by several viruses such as polioviruses which preferentially infect motor neurons and rabies which selectively infects neurons of the limbic system (Griffin, 2010). Oligodendrocytes, the myelin-forming cells can also be infected (e.g. HHV6, SFV) and leading to direct or indirect demyelination (Fazakerley et al., 2006; Mock et al., 1999). Other

emphasis on chikungunya.

**2. Encephalitis and clinical manifestations** 

cells within the CNS can also be the site of viral replication and for instance with mumps virus which can infect epithelial cells of the choroid plexus. The involvement of ependymal cells of the SVZ can result in hydranencephaly following infection for instance by adenoviruses or coxsackie viruses.

Viruses vary greatly in their capacity to induce encephalitis. For some viruses (e.g. mumps), neuroinfection is a common but a relatively benign part of the syndrome.

For others (flaviviruses such as JEV or WNV), although the infection is highly asymptomatic, CNS infection when it occurs is the most prominent clinical feature. A third group of viruses are those which commonly cause infection, but only rarely cause encephalitis (herpes simplex virus, HSV or CHIKV). In this group, newborns and elderly patients are at risk because they either have a poor or inappropriate immune response against the infectious challenge (Hoarau et al., 2010).

A paramyxovirus isolated from a Malaysian patient with encephalitis showed *in vitro*  characteristics similar to Hendra virus (HeV), a new morbillivirus previously isolated from horses and human in 1995. Subsequent virological studies have shown that the Malaysian pathogen, now named Nipah virus (NiV), is closely related to, but distinct from HeV and that the two belong to a new genus within the family paramyxoviridae capable of causing major outbreaks of encephalitis. Patients present with fever, headache, dizziness, vomiting, and altered mental state.

Finally, there are viruses for which human infection inevitably and exclusively results in CNS disease (e.g. rabies). In addition to acute pathology, other viruses (e.g. measles) can cause syndromes of post-infectious encephalopathy with the capacity of the virus to hide into tissue sanctuaries. The capacity of these viruses to reactivate the viral cycle is poorly understood and may be the results of immune escape mechanisms.
