The concept that molecules can signal neurons and axons and convince them to behave in new, even innovative ways is exciting. Trophic factors are molecules, usually proteins, that act on specific cell receptors to induce changes in protein synthesis, outgrowth, or survival. In the nervous system, nerve growth factor (NGF) leads the classic family of growth factors known as “neurotrophins.” A working definition of a neurotrophin is “an endogenous soluble protein regulating survival, growth, morphologic plasticity or synthesis of proteins for differentiated function of neurons” [256]. NGF was discovered in 1951 by Rita Levi-Montalcini and subsequently characterized by Stanley Cohen, culminating in the award of the Nobel Prize in Physiology or Medicine in 1986 to both investigators [388,389]. Using sarcoma tumor in the mouse model, Levi-Montalcini and Viktor Hamburger established that NGF was a soluble factor from mouse sarcoma tumor that was capable of inducing hyperplasia in sympathetic ganglia [389,390](Figure 9.1). The original articles describing these discoveries are recommended and make for fascinating reading [390]:

Nerve regrowth has a context, a microenvironment replete with molecular, physical, and other determinants of success. Some are roadblocks, others are partners. The growth factors considered in Chapter 9 are only part of the story of how nerves fare during regeneration. In this chapter, we consider a number of other salient features of the regenerative milieu that influence regeneration. These range from adhesion and basement membrane molecules, to novel signaling systems to interactions within altered environments as occur during aging, diabetes mellitus, or entry into the spinal cord.

Adhesion molecules

Cell adhesion molecules (CAMs) represent the interface between axons, SCs, and the basement membrane. They provide the essential extracellular “clutch” domains that allow differential movement of membranes and molecules along one another. During nerve regeneration, adhesion molecules permit axon growth with basement membranes, along guiding SC processes, or with other fasciculating axons guided by pioneer axons. In turn, the linkages of CAMs to the intracellular cytoskeleton influence cell mobility. To accomplish their task, CAMs can interact with each other (homophilic) or other molecules (heterophilic). These interactions vary in adhesive strength depending on the location and intensity of their expression, distribution on a given cell, and electrical charge.

Three major families of CAMs are recognized. The immunoglobulin (IgCAMs) family contains extracellular β sheets that resemble the variable or constant domains of immunoglobulins (Igs). This family is further subdivided into three types, depending on the type of Ig domains and the presence of fibronectin-like or other extracellular domains.

Peripheral nerve injuries are common, disabling and difficult to treat. These injuries arise because nerve trunk anatomical pathways expose them to a variety of injury types, including both blunt and penetrating lesions. The injury type, in turn, has a major bearing on how nerves respond. There are unique and challenging attributes of nerve trauma biology that set the stage for subsequent regenerative activity. These attributes are examined in this chapter.

Overall considerations

The type of injury experienced by a peripheral nerve determines how regeneration might proceed. Several classifications exist and are given here. The simplest classification is provided by Seddon, who grouped injuries into neurapraxia, axonotmesis, and neurotmesis lesions.

Neurapraxia is a lesion that occurs most often from blunt nerve trauma and involves focal demyelination over several internodes at the injury site. By definition, there is no associated axonal injury. Since neurapraxic lesions are identified by the loss of function associated with them, they require that enough internodes be disrupted to block conduction, or function. For example, a common type of neurapraxic lesion is the “Saturday night palsy” of the radial nerve in the arm that develops from prolonged compression of the inner arm by a chair or the head of a partner (and is often associated with alcohol intoxication!). Compression, however, need not be prolonged, since it is highly likely that the mechanical distortion of the nerve is responsible for demyelination. Ochoa and colleagues, in experimental work, described how myelinated axons “intussuscept” from undue mechanical stress [521].

Information representation in neuronal populations: what is the “machine language” of the brain?

Research in the area of neuroscience and brain functions has made extraordinary progress in the last 50 years, in particular with the advent of novel methods that enables us to look at the properties of neuroanatomy and neurophysiology in much finer detail, and even at the activity of living brains during the performance of tasks. However, the question of how information is actually represented and encoded by neurons is still one of the “final frontiers” of neuroscience, and surprisingly little progress has been made here. How information is encoded in the brain has captivated medics, scientists, and philosophers for centuries. Scholars such as Leonardo da Vinci or René Descartes had already an astonishingly detailed knowledge of the anatomy of the brain, and had made suggestions that it is the brain that processes information and even harbors the seat of the personality or of the soul. However, whenever suggestions are brought forward how information might be processed and represented in the brain, these often turn out to be simplistic and idealistic. These rarely add up to more than a kind of “homunculus” that somehow receives information that is received via the eyes or the ears. This model only transfers the problem of information representation from the brain to the homunculus.

One problem with the research of information encoding is that it is completely counter-intuitive.

Introduction

Auditory cortex function beyond bottom–up feature detection

Until the 1980s the auditory cortex was mainly conceptualized as the neuronal structure implementing the top hierarchy level of bottom–up processing of physical characteristics (features) of auditory stimuli. In that respect, plastic changes in anatomical and functional principles were only considered relevant for developmental processes towards an otherwise stable adult brain. Presently, this view has been replaced by a conceptualization of auditory cortex as a structure holding a strategic position in the interaction between bottom–up and top–down processing (for review see Irvine, 2007; Scheich et al., 2007), in particular auditory learning (for review see Weinberger, 2004; Irvine and Wright, 2005; Ohl and Scheich, 2005).

In this chapter we review experimental evidence from gerbil and macaque auditory cortex that has led to this change of view about auditory cortex function. It will be argued that a fundamental understanding of the role of auditory cortex in learning has required to move beyond the study of simple classical conditioning and feature detection learning, for which auditory cortex does not seem to be a generally necessary structure (see below). Specifically, it will be elaborated that the abstraction from trained particular stimuli, as it is epitomized in the phenomenon of category learning (concept formation), is a complex but fundamental learning phenomenon for which auditory cortex is a relevant structure harboring the necessary functional organization.

Decoding simultaneously recorded spike trains

Pioneering studies of motor cortex by Georgopoulos and colleagues (e.g. Georgopoulos et al., 1982) established that “population vectors,” constructed from weighted averages of the responses of single neurons, can accurately predict behavioral variables, such as movement direction. This approach has been used to study population coding in a number of cortical systems and has led to the view that cortical neurons act as independent processors of information (e.g. Gochin et al., 1994). However, some recent work has challenged this interpretation of neural population activity. For example, Schneidman et al. (2003) proposed interpreting neural ensemble activity by comparing ensemble information with information represented by the single neurons that comprise the ensemble. In a synergistic coding scheme, ensembles encode more than the sum of the component neurons. The advantage of synergy is that there can be a massive gain in information from the activity of multiple neurons. In a redundant coding scheme, the removal of individual neurons has little effect on encoding and thus the ensembles can be less noisy and less prone to errors. In Narayanan et al. (2005), we adapted the information-theoretical framework proposed by Schneidman et al. (2003) to measures of decoding of the performance of a delayed response task with activity from the rodent motor cortex. The predictive relationship between neural firing rates and a categorical measure of behavior, e.g. correct vs. error performance of a reaction time task, was quantified using statistical classifiers.

Viral oncolysis

“Viral oncolysis” refers to the ability of some viruses directly to kill cancer cells by infecting them, replicating intracellularly, and then lysing the cells as infectious viral progeny are released and subsequently infect surrounding cancer cells. Ideal anticancer agents specifically target neoplastic cells, effectively kill them, and are nontoxic both systemically and to surrounding tissues. Molecular engineering techniques have permitted design of viral “vectors” that retain the ability to replicate yet are nonpathogenic. Viral oncolysis differs from what is typically thought of as “gene therapy” in that efficacy depends not on the efficient transfer of a gene of interest into a cancer cell but rather on the ability of the virus itself to kill the cell. For instance, “replication-defective” or nonreplicating viruses have been used in preclinical models and cancer clinical trials to transfer genes that correct cancer-associated genetic defects such as p53 mutations or encode for prodrug-activating enzymes, such as for HSV-thymidine kinase (HSV-tk) or cytosine deaminase [1]. Other delivered genes include those that inhibit angiogenesis or stimulate antitumor immunity. Nonreplicating viruses can be further modified to enhance tropism for their intended cancer targets and to more specifically and efficiently transfer genes. On the other hand, viral oncolysis depends fully on the ability of the virus to replicate in tumor tissue. Safe, targeted viral oncolysis is made possible by the ability to engineer DNA viruses in the laboratory for tumor selectivity (HSV and adenovirus) or by use of wild-type or spontaneously arising attenuated RNA viruses with intrinsic tumor selectivity (reovirus, Newcastle disease virus, poliovirus, measles, and vesicular stomatitis virus).

Introduction

Most cases of viral encephalitis are acute, although a few viruses can cause chronic progressive encephalitis. Rarely, systemic virus infection may trigger post-infectious encephalomyelitis. Viral encephalitis typically reflects viral invasion of the brain parenchyma. Encephalitis patients usually have alterations in their state of consciousness. Some viruses produce “diffuse” encephalitis in which the predominant features are impaired consciousness, signs of generalized central nervous system (CNS) dysfunction such as generalized seizures, and a cerebral spinal fluid (CSF) pleocytosis. Conversely, other viruses produce “focal encephalitis,” in which altered consciousness and CSF abnormalities are accompanied by prominent focal abnormalities on neuroimaging tests or clinical examination including hemiparesis, aphasia, hemisensory loss, ataxia, focal as well as generalized seizures, and, less often, involuntary movements, visual field defects, and cranial nerve deficits. Personality changes, language, and memory disturbances and psychotic features are frequent. Viral encephalitis must be distinguished from nonviral conditions that can present a similar clinical picture, including Lyme disease, tuberculosis, syphilis, Listeria, Mycoplasma, fungal and parasitic infections, brain abscess, subdural hematoma or abscess, brain tumors, CNS vasculitis, and toxic/metabolic encephalopathies.

Viral encephalitis may be epidemic or sporadic (see also Chapter 17). Causes of epidemic viral encephalitis include the togaviruses, enteroviruses (see Chapter 17), mumps and lymphocytic choriomeningitis (LCM) virus (see Chapter 1). The toga-viruses are RNA viruses transmitted by mosquitoes or ticks (arthropod-born) (see Chapters 6, 7, and 20), with a peak incidence in the Northern Hemisphere in the warm summer months.

Introduction: TLRs and viruses

Toll-like receptors and their specificity

Toll-like receptors (TLRs) are pattern recognition proteins found both on cell surfaces as well as within intracellular compartments. Originally defined on the basis of their homology to the Drosophila protein Toll, which is important in the fruit fly defense against fungal infections [1], mammalian TLRs were first demonstrated to be critical in determining whether animals develop shock after challenge with bacterial lipopolysaccharide (LPS). The interaction between E.coli LPS and TLR4 leads to a series of events resulting in the production of cytokines and inflammatory mediators that affect vascular permeability and that ultimately cause a decrease in blood pressure and death of the animal. Subsequent studies have revealed a role for TLRs in the immune responses not only to bacteria but also to fungi, parasites, and viruses.

TLRs are a family of proteins with a structure including an N-terminal pattern recognition domain composed of leucine-rich repeats which form a molecular scaffold and a cytosolic C-terminal Toll-interleukin-1 receptor (TIR) domain that interacts with a series of adapter proteins. Engagement of TLR adapters ultimately leads to intracellular signaling events that induce the production of chemokines and cytokines (Figure 15.1). The human genome encodes 10 different TLR proteins, all of which are homologous to the interleukin-1 receptor (IL-1R) protein in their TIR domain. While TLRs are pattern recognition proteins (recognizing viruses and bacteria predominantly through their leucine-rich repeat regions), they initiate the production of cytokines and chemokines that directly (through activation of other cells) or indirectly (through stimulating migration of immune cells) result in the initial host response to infection.

Introduction

It is now well-recognized that more than 75% of emerging diseases over the past 2 decades have been zoonoses. Many of these zoonotic viruses have caused neurological disease, especially those emerging during this period in the South-East Asian and Western Pacific regions [1, 2]. Most of the diseases emerging from wildlife have been from bats and rodents. Bats are only second to rodents in terms of mammalian species richness [3] and constitute about 20% of all mammalian species. Thus, with their wide distribution and abundance, it is not surprising that there is growing awareness that bats are the reservoir hosts for a number of these emerging viruses [4, 5, 6, 7] and suspected of being associated with many others on serological grounds. Not only have they been shown to be the reservoir hosts for rabies and related lyssaviruses but also for other human pathogens, or potential pathogens, such as SARS-coronavirus-like viruses [8, 9, 10], Ebola virus [11, 12], Menangle virus [13], and Hendra and Nipah viruses [14, 15, 16]. This brief review looks at the biological features that make bats good reservoir hosts, and the more important neurological viruses associated with bats that are, or have the potential to be, transmitted to humans.

Bats as reservoir hosts: Implications for virus transmission

The order chiroptera, their diversity, evolution, abundance, and social behavior

The mammalian Order Chiroptera is divided into two suborders, the Megachiroptera, or Old World fruit- and nectar-feeding bats, including flying foxes, and the Microchiroptera, or echolocating bats [17].

Viruses that infect the central nervous system may cause acute, chronic, or latent infections. In some cases, the diseases manifested are attributable to viral damage of neurons or supporting parenchymal tissues; in other cases, to immune attack on virally infected cells. They can be spread by excretion, by respiratory droplets or fomites, or, alternatively, by bites of insects or animals. These viruses range from those such as polio (Chapter 1) or rabies (Chapter 3), whose history in man is as old as the earliest records, to those that emerge from animal reservoirs to human hosts for the first time, such as SARS, Hendra, and Nipah viruses (see Chapter 21).

In this section of Neurotropic virus infections, viruses with an RNA genome are described, starting with the simplest, picornaviruses (Chapter 1), to the most complex, alphaviruses (Chapter 6) and flaviviruses (Chapter 7). RNA viruses require an enzyme not found in host cells: RNA-dependent RNA polymerases to generate both sense (mRNA) and antisense RNA copies. Because of the lack of the host cell proofreading capacity for genome copying, errors are frequently introduced. Some of these errors are neutral, others may be deleterious (and are selected against) or, alternatively, potentially beneficial in evading host immune responses ranging from innate immune recognition to host adaptive immune recognition by Th1 or CD8 cells of epitopes expressed by host MHC or MHC I molecules, respectively, or of antibody recognition of native proteins expressed by virions or infected host cells.

Introduction/classification

Mouse hepatitis virus (MHV) is a member of the Coronaviridae family in the order Nidovirales. Coronaviruses are classified into one of three antigenic groups, with MHV classified as a member of group 2 [1]. Members of the Coronaviridae family infect a wide range of species including humans, cows, pigs, chickens, dogs, cats, bats, and mice. In addition to causing clinically relevant disease in humans ranging from mild upper respiratory infection (e.g., HCoV [human coronavirus]-OC43 and HCoV-229E responsible for a large fraction of common colds) to severe acute respiratory syndrome (SARS) [2, 3], coronavirus infections in cows, chickens, and pigs exact a significant annual economic toll on the livestock industry.

MHV is a natural pathogen of mice that generally is restricted to replication within the gastrointestinal tract [4, 5]. However, there exist several laboratory strains of MHV that have adapted to replicate efficiently in the central nervous system (CNS) of mice and other rodents. Depending on the strain of MHV, virulence and pathology ranges from mild encephalitis with subsequent clearance of the virus and the development of demyelination to rapidly fatal encephalitis. Thus, the neurotropic strains of MHV have proved to be useful systems in which to study processes of virus- and immune-mediated demyelination, virus clearance and/or persistence in the CNS, and mechanisms of virus evasion from the immune system.

Neurotropism and neuroinvasiveness have also has been described for two other members of the Coronaviridae family, HCoV-OC43 and SARS-coronavirus (CoV) (Table 4.1).

Introduction

Although vaccinations against the measles virus have nearly eliminated subacute sclerosing panencephalitis (SSPE) and other measles virus-induced neurologic disorders in countries with compulsory immunization programs, SSPE remains a rare, fatal neurodegenerative disorder in many regions of the world. This chapter summarizes current information regarding the epidemiology, virology, clinical manifestations, diagnosis, and management of SSPE.

Epidemiology

Measles

Due to the relatedness (sequence homology) of measles virus with rinderpest virus [1], whose natural hosts are cattle, goats, sheep, antelopes, and other cloven-hoofed animals, some hypothesize that the measles virus originated from the rinderpest virus or a common predecessor. As humans first domesticated such animals in the Fertile Crescent of the Middle East, they would have been in close contact with rinderpest virus [2]. Many morbilliviruses – of which measles and rinderpest viruses are members – can cross species. Recent examples of this phenomenon are the Nipah and Hendra viruses; their natural host is the fruit bat, but both viruses can also infect pigs and humans [3, 4].

Although incursions of the measles virus or a measles-like virus into human populations likely occurred with regularity in ancient times, measles did not emerge as a human disease entity until urban areas of several hundred thousand came into existence about 2500 years ago [5]. Measles virus entered human populations quickly; the virus genome stabilized, and measles virus adapted to replicating efficiently in human cells and transmitting among humans [6]. Measles was appreciated as a disease distinct from smallpox around the tenth century [7].

Introduction

Alphaviruses are members of the Togaviridae family of icosahedral, enveloped, single-strand, message-sense RNA viruses. The mosquito-borne alpha-viruses are important causes of encephalomyelitis in the Americas and are on the category B list of agents of biodefense concern. Eastern equine encephalitis (EEE), western equine encephalitis (WEE), and Venezuelan equine encephalitis (VEE) viruses are the neurotropic alphaviruses of greatest importance as causes of human encephalomyelitis and were initially recognized for their ability to cause disease in horses. Semliki Forest virus (SFV) and Sindbis virus (SINV) do not usually cause encephalitis in humans, but are studied frequently in mice as model systems for alphavirus encephalomyelitis.

EEE virus (EEEV) was first isolated in 1933 from the brains of horses during an epizootic of equine encephalitis in Virginia and New Jersey [1] and was demonstrated to cause human encephalitis in 1938 [2]. In the summer of 1930 a similar equine epizootic occurred in the San Joaquin Valley of California and WEEV was isolated from the brains of affected horses [3], followed in 1938 by recovery of the same virus from the brain of a child with fatal encephalitis [4]. A related WEEV complex virus, Highlands J virus (HJV), was isolated in the eastern part of the United States in 1952 [5, 6]. In 1936, an outbreak of equine encephalitis spread from Colombia into Venezuela, the virus isolated from the brains of affected horses was antigenically distinct from EEEV and WEEV and became the third encephalitic alphavirus identified in the Americas [7, 8].

Discovery and classification of arenaviruses

The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) was one of the first human pathogenic viruses isolated. In 1933, Armstrong and Lillie obtained a filterable infectious agent from a brain of a patient who died during a St. Louis encephalitis epidemic [1]. In the mid-1930s, Rivers and Scott isolated a virus from cerebrospinal fluid (CSF) of a patient with aseptic meningitis [2], which was later shown to have the same serologic properties as the virus isolated by Armstrong and Lillie and a pathogen causing chronic infections in mouse colonies [3]. By the 1960s, several other viruses had been discovered that shared common morphology with a characteristic sandy (Latin, arenosus) appearance of ribosomes seen in thin sections of virions in electron microscopic images, serology, and biochemical features. These findings led to the establishment of the new virus family Arenaviridae in 1970 [4].

The Arenaviridae are a large group of viruses, which is currently subdivided into two major subgroups, the Old World (OW) arenaviruses and the New World (NW) arenaviruses [5, 6, 7]. The OW lineage contains LCMV endemic in Europe, the Americas, and likely present also in other geographic regions, and the African viruses Lassa (LASV), Mopeia (MOPV), Mobala (MOBV), and Ippy (IPPY). LCMV infections in humans are common, in some cases severe, and are of considerable concern in human pediatric medicine [8, 9, 10]. Fatal LCMV infection has also been recently documented in several transplant patients [11].

Introduction

The exogenous human retrovirus human T-lymphotropic virus type 1 (HTLV-1) results in a highly dynamic persistent infection that has a significant clinical impact in endemic areas. HTLV-1 usually causes an asymptomatic infection, but in a small proportion of individuals disease may develop: adult T-cell leukemia or a range of inflammatory diseases. Of these inflammatory diseases HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the most studied. HAM/TSP is a chronic inflammatory disease of the central nervous system. It is rarely fatal, but can be severely debilitating. HTLV-1 is not a classical neurotropic virus and does not directly infect the cells of the central nervous system (CNS). Instead, HTLV-1 is found primarily within infiltrating, infected CD4+ T lymphocytes. CD4+ T-cell infiltration into the CNS is currently believed to be the pivotal event for the pathogenesis of HAM/TSP. Here we describe the immune control of HTLV-1 infection in the periphery and discuss its relationship with inflammation in the CNS. We explore the current hypothesis of HAM/TSP pathogenesis, identify crucial factors, and suggest a new hypothesis focused on why the majority of HTLV-1-infected individuals do not develop neuroinflammatory disease.

HTLV-1

HTLV-1 was the first exogenous replication competent human retrovirus to be identified over 20 years ago by Poiesz et al. [1]. HTLV-1 virions were isolated from a cell line established from a cutaneous T-cell lymphoma. HTLV-1 has since been associated with two different types of disease: lymphoma/leukemia and chronic inflammatory diseases [2, 3, 4, 5].