**7. Acknowledgements**

Work from authors's laboratory was funded by grants from Comunidad de Madrid, Ministerio de Ciencia e Innovación, Fondo de Investigaciones Sanitarias, Fundación MAPFRE Medicina, Fundación Española de Esclerosis Multiple to M.L.Celma and R. Fernandez-Muñoz. We thank Purnell Choppin, Erling Norrby, George Klein, Fabian Wild, Albert Osterhaus, Martin Billeter and Roberto Cattaneo for valuable materials and Concepción Muela and Ricardo Vázquez for skilful art work.

#### **8. References**

178 Non-Flavivirus Encephalitis

The comparison of the MV genomic sequence corresponding to Madrid SSPE cases SMa79, SMa84, and SMa94 with those of MV genotypes circulating in Madrid during the last 5 decades provided the first confirmation that the MV causing SSPE corresponds to the virus producing the measles acute infection and not to a possible re-infection years later at onset of the encephalitis. This was the first example of a human persistent infection by an RNA

2. Concerning the question of where the virus could persist and replicate during the long latent period, we have observed that at least in the final stages of SSPE, MV is also present in abdominal and thoracic lymph nodes. The comparison of MV genomic RNA from brain and

3. In two SSPE cases, those presenting an average and long disease course, but not in the short disease course case, biased hypermutation U to C was observed in the matrix M gene at a high level (38% U to C) and low level (10%U to C) respectively. The mutation map across the entire genome was the same from distant parts of each brain, supporting the indication of clonal origin of MV brain invasion proposed by V. ter Meulen, M. Billeter and collaborators. After the first decription of biased U to C hypermutation phenomena by M.Billeter and collaborators in one brain from a MIBE case, our results were the first description of biased hypermutation in SSPE brain. Our results indicate that biased hypermutation U to C are found at autopsia in brain of SSPE patients after years of disease, and it is not proportional to the length of the disease. Biased hypermutation U to C is present in MV localized in lymph nodes at similar or higher level than in the respective brain, suggesting that biased hypermutation may take place also in infected lymphoid cells. In the three cases the transcription of M, F and H genes were down-regulated, and M protein ability

lymph nodes for each patient showed both viruses belong to the same genotype.

to bind to MV nucleocapsids was impaired by deletion or biased hypermutation.

4. The length of MV genome found in the brain of SSPE remains constant, 15894 after years to decades of persitent infection, and no evidence of significant proportion of nucleocapsid subgenomic RNAs was found in the brains of the SSPE cases studied. Copy-back subgenomic RNAs were found in MV nucleocapsids only in one of the three brains, indicating that the presence of MV defective interfering particles is not an universal feature

5. Currently, no efficient treatment for SSPE o MIBE patients is available. New approaches to therapy of these lethal encephalitis are underway in several laboratories, and possibly the future treatments will combine several therapies to control MV infection by specific antiviral designed drugs and molecules that would counteract virus escape to host immune response. Today, the only effective way to prevent MV encephalitis is the implementation of measles

Work from authors's laboratory was funded by grants from Comunidad de Madrid, Ministerio de Ciencia e Innovación, Fondo de Investigaciones Sanitarias, Fundación MAPFRE Medicina, Fundación Española de Esclerosis Multiple to M.L.Celma and R. Fernandez-Muñoz. We thank Purnell Choppin, Erling Norrby, George Klein, Fabian Wild, Albert Osterhaus, Martin Billeter and Roberto Cattaneo for valuable materials and

Concepción Muela and Ricardo Vázquez for skilful art work.

**6. Conclusions** 

virus.

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**7. Acknowledgements** 


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**9** 

*Canada* 

**Coronaviruses as Encephalitis** 

Pierre J. Talbot, Marc Desforges, Elodie Brison and Hélène Jacomy

Encephalitis usually refers to brain inflammation of various possible causes, including viral infections. Overall, viruses represent the most common cause of encephalitis in humans. The U.S. Center for Disease Control and Prevention (CDC) estimates an annual incidence of usually between 150 and 3000 new cases per year of Arboviral encephalitis in the United States (http://www.cdc.gov/). Although several thousand cases of encephalitis of various viral origins are reported each year, the CDC suspects that many more cases may go unreported. Indeed, encephalitis can follow or accompany common viral illnesses, such as infectious respiratory diseases, and sometimes signs and symptoms of the latter may mask concurrent encephalitis. Most commonly, clinically relevant viral encephalitis affects children, young adults, or elderly patients. The involvement of other determinants, such as the nature of the specific viral agent, the host immune status, and various genetic and

The pathophysiology of viral encephalitis varies according to the virus family involved. Encephalitis occurs in two forms: primary encephalitis involving direct viral infection of the central nervous system (CNS; brain and spinal cord) and secondary encephalitis involving a viral infection which first occurs elsewhere in the body and then travels to the brain. Viruses may enter the CNS through two distinct routes: hematogenous dissemination or neuronal retrograde dissemination. The hematogenous spread, which is the most common path, involves the presence of a given virus in the blood (viremia), where it can either remain free for a period of time or infect leukocytes that will become some sort of viral reservoir. This latter situation, called the Trojan horse, is the route taken by human immunodeficiency virus (HIV) to disseminate to the CNS in humans. Arboviruses also use the hematogenous route to gain access to the CNS, where they can induce a zoonotic encephalitis, with the virus surviving in infection cycles involving bites by arthropods and various vertebrates, especially birds and rodents. After an insect bite, the virus can be transmitted in the blood of

Another form of viral spread towards the CNS is through retrograde neuronal dissemination, where a given virus infects neurons in the periphery and uses the transport

Neuroinvasive viruses can damage the CNS as a result of misdirected host immune responses (virus-induced neuroimmunopathology) and/or viral replication, which will

**1. Introduction** 

environmental factors, is also of importance.

a susceptible animal after local replication in the skin.

machinery within those cells in order to gain access to the CNS.

**- Inducing Infectious Agents** 

*INRS-Institut Armand-Frappier, Laval (Québec)* 

*Laboratory of Neuroimmunovirology,* 

