Infections and multiple sclerosis.

Multiple sclerosis is a chronic inflammatory condition of unknown cause. Increasing evidence suggests that the disease develops as a result of interactions between the environment and the immune system in genetically susceptible individuals. It has long been recognized that infections may serve as environmental triggers for the disease, and a large number of pathogens have been proposed to be associated with multiple sclerosis. Here, we detail the historical basis linking infections to multiple sclerosis and review the epidemiology of the disease, which suggests a possible relationship with infectious agents. We also describe pathophysiologic studies in animals and other human demyelinating diseases that have demonstrated a variety of mechanisms by which infectious agents may induce chronic, relapsing central nervous system disease with myelin damage and relative preservation of axons, similar to multiple sclerosis. In addition, we discuss recent studies in individuals with multiple sclerosis indicating enhanced immune responses to infectious antigens, though not consistently demonstrating evidence for ongoing infection. Taken together, these studies suggest a role for infectious agents in the development of multiple sclerosis. Conclusive evidence, however, remains lacking.

Acute disseminated encephalomyelitis: clinical and pathogenesis features.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disorder of the central nervous system (CNS). Disease typically starts with an abrupt onset of neurologic symptoms and signs within days to weeks after a viral infection or immunization. Neuropathological examination of the CNS in ADEM reveals involvement of white matter, with infiltration of monocytoid cells and perivenous demyelination.

Emerging issues in neurovirology: new viruses, diagnostic tools, and therapeutics.

In the current era of escalating globalization with rapid transport, changing climate, and an ever growing human population with associated changes in lifestyle, poverty, and war, the emergence of new neurologic infections is accelerated. Understanding their origins using epidemiologic and molecular tools will contribute to improved control of agent spread throughout vulnerable populations. Although few interventions are effective in acute epidemics, the prompt identification of new infectious agents and the roll-out of vaccines together with new antiviral and neuroprotective drugs are promising for the management of future epidemics.

Investigations of the roles of arginine 115 and lysine 120 in the active site of 5,10-methenyltetrahydrofolate synthetase from Mycoplasma pneumoniae.

5,10-Methenyltetrahydrofolate synthetase (MTHFS) catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate coupled to the hydrolysis of ATP. A co-crystal structure of MTHFS bound to its substrates has been published (Chen et al., Proteins 56:839-843, 2005) that provides insights into the mechanism of this reaction. To further investigate this mechanism, we have replaced the arginine at position 115 and the lysine at position 120 with alanine (R115A and K120A, respectively). Circular dichroism spectra for both mutants are consistent with folded proteins. R115A shows no activity, suggesting that R115 plays a critical role in the activity of the enzyme. The K120A mutation increases the Michaelis constant (K(m)) for ATP from 76 to 1,200 microM and the K(m) for 5-formylTHF from 2.5 to 7.1 microM. The weaker binding of substrates by K120A may be due to movement of a loop consisting of residues 117 though 120, which makes several hydrogen bonds to ATP and may be held in position by K120.

Prion diseases.

Prion diseases are degenerative disorders of the nervous system caused by transmissible particles that contain a pathogenic isoform of the prion protein, a normal constituent of cell membranes. The most common human prion disease is Creutzfeldt-Jakob disease (CJD). Most cases are sporadic with unknown mode of transmission, 10-15% of cases are inherited, and a small number have been transmitted by medical procedures. The spread of human prion diseases through consumption of infected material has been implicated historically in kuru and recently in variant CJD. Animal prion diseases (scrapie of sheep, transmissible mink encephalopathy, chronic wasting disease of cervids, and bovine spongiform encephalopathy) all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed. The different modes of transmission of different prion diseases, the unpredictable species barriers, the variable distribution of infectivity in tissues, and strain variations found in some diseases all make risk assessment and predictions of future events difficult.

West Nile virus: pathogenesis and therapeutic options.

West Nile virus, a member of the family Flaviviridae, has spread throughout the United States. With more than 9000 cases and 200 deaths in 2003, West Nile virus has become the most common cause of viral encephalitis in several states. West Nile virus encephalitis is a zoonosis. The life cycle of the virus includes mainly birds as hosts and mosquitoes as vectors. Humans are accidental hosts, insufficient to support the life cycle of the virus because of low-grade, transient viremia. However, human-tohuman transmission through blood, organ transplantation, and lactation has been documented. The frequency of severe neurologic disease in the current epidemic suggests a more neurovirulent strain of virus than the one classically associated with West Nile fever. Several neurologic manifestations have been described, but the most characteristic presentation is encephalitis with weakness. Magnetic resonance imaging scans may be normal initially, but a characteristic pattern of involvement of deep gray matter nuclei can be recognized. Although results of polymerase chain reaction may be positive in the cerebrospinal fluid early in the course of the disease, diagnosis is based on serologic tests. Possible cross-reactivity with other members of the genus flavivirus mandates caution when serologic testing results are interpreted. Thus far, no therapeutic intervention has shown consistent clinical efficacy in West Nile virus disease. Several approaches, including interferon-alpha2b and immunoglobulin with high titer against West Nile virus, offer promise based on animal models and limited clinical experience. New drugs with in vitro activity are being investigated, and a vaccine is being developed.

Emerging viral infections of the nervous system.

New viral infections of the nervous system have been appearing with great regularity. Some result from the evolution of new agents and others from the entry of viruses into new hosts or environments. The emergence of neurovirulent enteroviruses causing a paralytic poliomyelitis syndrome and rhomboencephalitis represent the evolution of new human viruses. Most emerging viral infections represent movement of an agent into new geographic areas or across species barriers. The transport of neurovirulent strains of West Nile virus into the Western Hemisphere and the penetration of Nipah virus, a newly recognized paramyxovirus, across species barriers from bat to pig to man are examples that are highlighted in this review. The burgeoning human population and the speed and frequency of travel favor the evolution, preservation, and spread of new viral agents.

Diagnosis and prevention of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease.

An outbreak of bovine spongiform encephalopathy (BSE) arose in the United Kingdom as a result of prions entering and being recycled through the ruminant food chain. Humans have since developed a variant form of Creutzfeldt-Jakob disease (vCJD), also mostly in the United Kingdom, that occurs in younger individuals and causes prominent psychiatric and/or behavioral manifestations early in disease. Laboratory studies now provide strong evidence that the causative agent of BSE in cattle and vCJD in humans share a common origin. Because of a lack of information regarding the incubation period of vCJD and the number of people who may have been exposed, the future scope of this disease remains unknown. Control of the current and any future outbreaks in cattle requires strict measures to prevent contamination of the animal food chain with prions of any species. Prevention of human exposure mandates the avoidance of neural tissue in all human foods.

West Nile virus encephalitis in the United States.

West Nile virus appeared in New York City in 1999 and has subsequently spread over the eastern United States. The mode of transport across the Atlantic Ocean is unknown. During the past decade, encephalitis has been a more prominent feature of West Nile virus infection in Europe, the Middle East, and the United States, suggesting the emergence of more neurovirulent strains. The rapid spread of the virus and more serious disease caused by the virus have spurred vaccine development.