Preface

**Encephalitises** (from Greek *enképhalos* — brain) are a group of inflammatory diseases of human and animals brain caused essentially by different pathogens. This book covers the different aspects of non-flavivirus encephalitises of different ethiology.

One of the important questions of any pathogens study are the epidemiology and the monitoring and prediction of the epidemiological situation so the first section of the book consider general problems of epidemiology such as study of zoonotic and animal vectors of encephalitis causative agents and methods and approaches for encephalitis zoonoses investigations.

The members of different virus species are known to be the causative agents of encephalitis, so the second section of the book is devoted to viral pathogens, their epidemiology, pathology and diagnostics, and the first chapter of the section describes different aspects of the virus infection and molecular mechanisms of encephalitis development.

The next chapter of the section is about HIV/SIV encephalitis whose pathogenesis still remains to be completely understood. The authors describe and discuss the association of the viruses with the alterations in the blood brain barrier and possible mechanisms of pathogenesis.

The next three chapters are connected with such herpesviruses like herpes simplex virus type 1 and equine herpesvirus 9 that also have shown to be associated with encephalitises in human and animals. Herpes simplex virus (HSV) is the most common cause of sporadic fatal encephalitis (95% cases) and the incidence of HSVassociated encephalitises is reported as 2-4/1 million/year. So the corresponding chapter is devoted to its epidemiology and clinical aspects such as pathology and diagnostics. Another example of lethal encephalitis is corresponded with equine herpesvirus 9 (EHV-9) also called as gazelle herpesvirus 1, which was isolated from enzootic encephalitis of Thomson's gazelles that died of fulminant encephalitis in a Japanese zoo. EHV-9 has been isolated from Thomson's gazelles, zebras, giraffes, polar bears and onager and also was shown to infect several experimental hosts include horse, goat, pig, cattle, hamster, mouse, rat, guinea pig, dog, cat, and marmosette. So the authors of the first chapter make the detailed discussion of the problems of its

#### XII Preface

virology and pathology, and in the second chapter the authors based on several experimental studies of EHV-9 involving various domestic animals such as dogs and cats suppose the possibility of the virus transmission to humans by contacting affected animals or zebras through certain routes. Also they describe the experimental data on EHV-9 infectivity determination in non-human primates including common marmosets and cynomolgus macaques, which have strong similarities to humans.

Preface XI

**Sergey Tkachev** 

Novosibirsk, Russia

Laboratory of Microbiology,

populations including raccoons, skunks, foxes, and bats. Rabies has the highest case fatality rate of any infectious disease and kills an estimated 55,000 people annually, primarily in developing countries within Africa and Asia. So this chapter describes the epidemiology of human rabies, examines the signs and symptoms of disease, and makes the review of the laboratory diagnostic testing and results for all reported

The next section of the book concerns the study of protozoan pathogens such as toxoplasma and amoebae. Toxoplasmic encephalitis, a life-threatening disease in HIV/AIDS infected individuals, is an inflammation of the brain caused by the reactivation of latent infection of the protozoa *Toxoplasma gondii*. In the early 1980s, at the beginning of AIDS pandemic, there were many alarming case-reports threatening the world medical community with increasing numbers of unknown causes and severe diseases presented in HIV-infected patients. Toxoplasmic encephalitis was one of the most common opportunistic infections of this immunocompromised host. So this chapter will focus on all aspects of this disease including the etiologic organism, epidemiology, clinical manifestations, diagnostic methods, management and outcome as well as prophylaxis and prevention. Amoebic encephalitis is a life-threatening disease of the central nervous system caused by free-living amoebae belonging to the genera *Acanthamoeba*, *Balamuthia* and *Naegleria*. Because they lack host-specificity, the ubiquitous amoebae can infect a wide range of species. Non-opportunistically, Acanthamoebae can induce keratitis in healthy humans, but as an opportunistic pathogen, the amoebae can cause fatal encephalitis especially in immunocompromised individuals and treatments are often ineffective. So in the next chapters the authors review and discuss the pathophysiology of *Acanthamoeba*-induced encephalitis, with a special emphasis on

human rabies cases in the United States between 1960 and 2010.

autoimmunity in mediation of the disease, and implications for therapy.

encephalitis and can be real problem for millions of people infected with it.

colleagues who gave me a lot of support during the work on this book.

The last section of the book is devoted to multicellular pathogen as human Filaria Loa Loa - a filarial worm restricted to the West Africa, from Guinea in the North through Benin up to Ouganda in the East with Gabon, Cameroun Nigeria in the West toward Angola in the South with the hyper endemic area in Cameroun , Gabon, Nigeria, Congo Brazzaville and Congo Kinshasa (DRC). This pathogen can cause the

So the authors and editors of the second part of the book hope that this work might increase the interest in this field of research and the readers will find it useful for their investigations and clinical usage. Also I'd like to thank my family, parents and

Institute of Chemical Biology and Fundamental Medicine SB RAS,

The next chapter describes the measles virus, its clinical aspects and pathogenicity and antiviral therapeutic approaches to encephalitis caused by virus infection of the central nervous system. Despite the availability of an efficient live attenuated vaccine, measles virus still remains an important global pathogen infecting over 25 million individuals and causing over 250.000 deaths per year, being one of the main causes of child death worldwide. During acute measles, the virus produces a transient clinical significant immunosuppression that can contribute to some complications that infrequently may cause central nervous system lethal complications.

The next chapter is devoted to coronaviruses as encephalitis-inducing infectious agents. Coronaviruses are known to be the ubiquitous respiratory and enteric pathogens but they also represent one family of viruses that bear neurotropic and neuroinvasive properties in various hosts including humans, pigs, and rodents. In this work the authors discuss the mechanisms and consequences of virus interactions with the nervous system which are essential for better understanding of potentially pathological relevant consequences and design intervention strategies that are highly relevant to encephalitis. Also, collecting of new data is necessary to the understanding of how a ubiquitous respiratory virus, the human coronavirus, given the proper susceptibility conditions and proper virus evolution and infection conditions, could trigger the neuropathology that is characteristic of at least some forms of encephalitis.

The next chapter is about alphaviruses. The *Alphavirus* genus in the family *Togaviridae*  contains three viruses capable of causing human encephalitis: Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV). No specific therapy or vaccine is currently available against these viruses. In this chapter the development and progression of alphavirus encephalitis in both human populations and murine models of alphavirus infection, the host response that characterizes the development of central nervous system disease after alphaviral infection and data on immune factors that influence successful resolution of infection were summarized. Also this chapter briefly describes the basic viral dissemination and spread in natural cycles, both enzootic and epizootic, followed by a more in-depth overview of the primary encephalitic alphavirus.

The last chapter of the book section contains information about the rabies virus highly neurotropic zoonotic viruses belonging to the Lyssavirus genus in the Rhabdoviridae family, causing an acute progressive encephalitis. Rabies virus is distributed globally and found on all continents except Australia and Antarctica. In the United States, multiple virus variants circulate in wild mammalian reservoir populations including raccoons, skunks, foxes, and bats. Rabies has the highest case fatality rate of any infectious disease and kills an estimated 55,000 people annually, primarily in developing countries within Africa and Asia. So this chapter describes the epidemiology of human rabies, examines the signs and symptoms of disease, and makes the review of the laboratory diagnostic testing and results for all reported human rabies cases in the United States between 1960 and 2010.

X Preface

virology and pathology, and in the second chapter the authors based on several experimental studies of EHV-9 involving various domestic animals such as dogs and cats suppose the possibility of the virus transmission to humans by contacting affected animals or zebras through certain routes. Also they describe the experimental data on EHV-9 infectivity determination in non-human primates including common marmosets and cynomolgus macaques, which have strong similarities to humans.

The next chapter describes the measles virus, its clinical aspects and pathogenicity and antiviral therapeutic approaches to encephalitis caused by virus infection of the central nervous system. Despite the availability of an efficient live attenuated vaccine, measles virus still remains an important global pathogen infecting over 25 million individuals and causing over 250.000 deaths per year, being one of the main causes of child death worldwide. During acute measles, the virus produces a transient clinical significant immunosuppression that can contribute to some complications that infrequently may

The next chapter is devoted to coronaviruses as encephalitis-inducing infectious agents. Coronaviruses are known to be the ubiquitous respiratory and enteric pathogens but they also represent one family of viruses that bear neurotropic and neuroinvasive properties in various hosts including humans, pigs, and rodents. In this work the authors discuss the mechanisms and consequences of virus interactions with the nervous system which are essential for better understanding of potentially pathological relevant consequences and design intervention strategies that are highly relevant to encephalitis. Also, collecting of new data is necessary to the understanding of how a ubiquitous respiratory virus, the human coronavirus, given the proper susceptibility conditions and proper virus evolution and infection conditions, could trigger the neuropathology that is characteristic of at least some forms of encephalitis.

The next chapter is about alphaviruses. The *Alphavirus* genus in the family *Togaviridae*  contains three viruses capable of causing human encephalitis: Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV). No specific therapy or vaccine is currently available against these viruses. In this chapter the development and progression of alphavirus encephalitis in both human populations and murine models of alphavirus infection, the host response that characterizes the development of central nervous system disease after alphaviral infection and data on immune factors that influence successful resolution of infection were summarized. Also this chapter briefly describes the basic viral dissemination and spread in natural cycles, both enzootic and epizootic, followed

The last chapter of the book section contains information about the rabies virus highly neurotropic zoonotic viruses belonging to the Lyssavirus genus in the Rhabdoviridae family, causing an acute progressive encephalitis. Rabies virus is distributed globally and found on all continents except Australia and Antarctica. In the United States, multiple virus variants circulate in wild mammalian reservoir

by a more in-depth overview of the primary encephalitic alphavirus.

cause central nervous system lethal complications.

The next section of the book concerns the study of protozoan pathogens such as toxoplasma and amoebae. Toxoplasmic encephalitis, a life-threatening disease in HIV/AIDS infected individuals, is an inflammation of the brain caused by the reactivation of latent infection of the protozoa *Toxoplasma gondii*. In the early 1980s, at the beginning of AIDS pandemic, there were many alarming case-reports threatening the world medical community with increasing numbers of unknown causes and severe diseases presented in HIV-infected patients. Toxoplasmic encephalitis was one of the most common opportunistic infections of this immunocompromised host. So this chapter will focus on all aspects of this disease including the etiologic organism, epidemiology, clinical manifestations, diagnostic methods, management and outcome as well as prophylaxis and prevention. Amoebic encephalitis is a life-threatening disease of the central nervous system caused by free-living amoebae belonging to the genera *Acanthamoeba*, *Balamuthia* and *Naegleria*. Because they lack host-specificity, the ubiquitous amoebae can infect a wide range of species. Non-opportunistically, Acanthamoebae can induce keratitis in healthy humans, but as an opportunistic pathogen, the amoebae can cause fatal encephalitis especially in immunocompromised individuals and treatments are often ineffective. So in the next chapters the authors review and discuss the pathophysiology of *Acanthamoeba*-induced encephalitis, with a special emphasis on autoimmunity in mediation of the disease, and implications for therapy.

The last section of the book is devoted to multicellular pathogen as human Filaria Loa Loa - a filarial worm restricted to the West Africa, from Guinea in the North through Benin up to Ouganda in the East with Gabon, Cameroun Nigeria in the West toward Angola in the South with the hyper endemic area in Cameroun , Gabon, Nigeria, Congo Brazzaville and Congo Kinshasa (DRC). This pathogen can cause the encephalitis and can be real problem for millions of people infected with it.

So the authors and editors of the second part of the book hope that this work might increase the interest in this field of research and the readers will find it useful for their investigations and clinical usage. Also I'd like to thank my family, parents and colleagues who gave me a lot of support during the work on this book.

> **Sergey Tkachev**  Laboratory of Microbiology, Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia

**Part 1** 

**General Problems of Epidemiology** 
