**3. Mechanism of central nervous system (CNS) infection by arboviruses**

Despite many years of intensive efforts and investigations on the pathways leading to infec‐ tions of the CNS by arboviral families after the bite of an arthropod carrying an infectious agent, the exact mechanism remains to be further delineated. There are multiple routes that can be considered, depending on the characteristics of the virus. Some advocate the mecha‐ nism of direct viral spread from the periphery to the CNS [39], particularly for arboviruses involved in brain infections. It is thought that these viruses are amplified in dermal tissues and then in lymph nodes via migration of dendritic (Langerhans) cells before invading the CNS [40, 41]. However, the mechanism allowing for these viruses to perform the last step, to enter and invade the CNS, is less clear. The MVE, SLE, and JE viruses were speculated to enter the CNS via the olfactory pathway [42], while transcytosis across cerebral capillary en‐ dothelial cells was reported in JE [43]. In addition, virion-budding on the parenchymal cells after replication at the blood-brain barrier may also occur [44]. In experimental models, many infections by encephalitic arboviruses are diffusely spread throughout the brain [45, 46]. Furthermore, the absence of viral antigens in the choroid plexus or ependyma indicate that these viruses were not actively targeted to and replicated in this tissue but rather en‐ tered the CNS via a hematogenous route [47] (Figure 2), especially in patients with severe viremia [48].

**Figure 2.** Hypothetic routes for arboviruses to infect the brain tissue hematogenously. (A) Infection of endothelial cells before the virion enters the brain tissue. (B) Virions enter the brain tissue through disrupted BBB. (C) Infected white

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In a study on JE, extensive infection of neurons resulting in cellular defects was shown in the cerebrum and cerebellum [49]. The cerebral and cerebellar capillary endothelial cells are responsible for maintaining the integrity of the blood-brain barrier (BBB) [50]. In both ani‐ mals and humans, the BBB generally prevents viral invasion into the CNS [51], unless it has been disrupted, resulting in increased permeability and inflammatory cell infiltration [52, 53]. Disruptions in the BBB actually allows for peripheral blood mononuclear cells (PBMCs)

blood cells enter the brain tissue by passing through the disrupted BBB.

to migrate from the circulation into brain tissues [54, 55].

spread all over North America and caused more than 20,000 humans to be ill and 770 deaths (http://www.cdc.gov/ncidod/dvbid/westnile/surv and control.htm). Neuroinvasive disease due to WN virus infection can occur, 2946 and 2866 cases were reported in 2002 and 2003,

The SLE virus is a close relative to WN virus, and actually is a member of the Japanese ence‐ phalitis serocomplex [35]. Predominantly, SLE virus is naturally maintained in a transmis‐ sion cycle between ornithophilic mosquitoes and birds, but occasionally these arthropods feed on mammalian blood, causing encephalitis in humans [36]. Nearly 5000 human infec‐ tions were reported between 1964 and 2005, making it the major cause of epidemic encepha‐ litis in association with flaviviral infections before the introduction of WN virus into the

*Buynaviridae.* In this family, viruses involving symptoms of encephalitis include Rift Valley fever (RVF), LAC, CE, and Jamestown Canyon [37]; all are mosquito-borne. RVF virus most‐ ly occurs in Africa and the Middle East, while the other three, which are classified in the California serogroup, are restrictedly distributed in North America [37]. Of these, the LAC virus causes the most human disease, with dozens to hundreds of hospitalized cases report‐ ed each year in the United States [38]; unlike EEE, California serogroup including LAC is not dependent on avian hosts for natural transmission. Rodents usually serve as its major

**3. Mechanism of central nervous system (CNS) infection by arboviruses**

Despite many years of intensive efforts and investigations on the pathways leading to infec‐ tions of the CNS by arboviral families after the bite of an arthropod carrying an infectious agent, the exact mechanism remains to be further delineated. There are multiple routes that can be considered, depending on the characteristics of the virus. Some advocate the mecha‐ nism of direct viral spread from the periphery to the CNS [39], particularly for arboviruses involved in brain infections. It is thought that these viruses are amplified in dermal tissues and then in lymph nodes via migration of dendritic (Langerhans) cells before invading the CNS [40, 41]. However, the mechanism allowing for these viruses to perform the last step, to enter and invade the CNS, is less clear. The MVE, SLE, and JE viruses were speculated to enter the CNS via the olfactory pathway [42], while transcytosis across cerebral capillary en‐ dothelial cells was reported in JE [43]. In addition, virion-budding on the parenchymal cells after replication at the blood-brain barrier may also occur [44]. In experimental models, many infections by encephalitic arboviruses are diffusely spread throughout the brain [45, 46]. Furthermore, the absence of viral antigens in the choroid plexus or ependyma indicate that these viruses were not actively targeted to and replicated in this tissue but rather en‐ tered the CNS via a hematogenous route [47] (Figure 2), especially in patients with severe

United States (http://www.cdc.gov/ncidod/dvbid/arbor/pdf/SLEDOC07132006.pdf).

respectively [34].

76 Encephalitis

vertebrate host [37].

viremia [48].

**Figure 2.** Hypothetic routes for arboviruses to infect the brain tissue hematogenously. (A) Infection of endothelial cells before the virion enters the brain tissue. (B) Virions enter the brain tissue through disrupted BBB. (C) Infected white blood cells enter the brain tissue by passing through the disrupted BBB.

In a study on JE, extensive infection of neurons resulting in cellular defects was shown in the cerebrum and cerebellum [49]. The cerebral and cerebellar capillary endothelial cells are responsible for maintaining the integrity of the blood-brain barrier (BBB) [50]. In both ani‐ mals and humans, the BBB generally prevents viral invasion into the CNS [51], unless it has been disrupted, resulting in increased permeability and inflammatory cell infiltration [52, 53]. Disruptions in the BBB actually allows for peripheral blood mononuclear cells (PBMCs) to migrate from the circulation into brain tissues [54, 55].

Under normal circumstances, lymphocytes constantly enter the CNS, but in small numbers [56]. However their presence in the CNS may increase in response to viral infections [57]. In fact, infected PBMCs can be isolated in brains from mice inoculated with JE virus as early as 3 days post-infection [58]. Moreover, leukocytes were observed moving between endothelial cells of capillaries at sites in the BBB where tight junctions had been dissociated [49]. This suggests that at least some inflammatory leukocytes that had become infected in the periph‐ ery move along in the blood current and migrate to the CNS tissues [58, 59]. Furthermore, infection and resultant apoptosis of astrocytes, which serve as a protective component of the BBB and can defend against penetrated virions or virus-infected leukocytes, are frequently seen in the brain. This probably results in severe impairment of the BBB, facilitating the pas‐ sage of more virus-infected PBMCs, using a "Trojan horse" strategy.

rus in the blood may be a sign that humans are an accidental or dead-end host to most arbo‐ viruses. Identifying the cellular sources responsible for viremia will likely help us uncover the underlying mechanisms leading to arboviral encephalitis and aid in the development of vaccines and anti-viral drugs. Because of this, finding the permissive cell lineages account‐ ing for circulating virus in infected patients has been the central focus for several decades. In

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**Figure 3.** The possible route of the virus in vertebrates from peripheral tissues to the brain. Arboviral infections start with the bite of insects carrying an infectious virus. The exact location where the virus is deposited remains poorly un‐ derstood. There are multiple ways a virus may spread and circulate before reaching to the brain. Please refer to the

spite of these efforts, the answer remains elusive.

text for more details.
