Neurovirology

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Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for gene therapy, and to eliminate detrimental populations of neural cells. [1]

Contents

Overview

The field of neurovirology was formed within the past 30 years. [1] It was founded upon the discovery that a large number of viruses are capable of invading and establishing latent infections in nervous tissue. Such viruses have been shown to produce slow, chronic, or progressive nervous system diseases. [2] : v  Neurovirology incorporates the related fields of virology, neuroscience, neurology, immunology, and molecular biology. The main focus of the field is to study the molecular and biological basis of virus induced diseases of the nervous system. In addition to this, the field studies the use of these viruses as tracers of neuroanatomical pathways and as vectors for gene therapy.

The field relies upon neuroimaging, isolation of the virus from brain tissue or CSF, serological testing of serum and CSF, and microscopic examination of tissue to diagnose nervous system infections.

History

Neurovirology only became an official field within the past 30 years. [1] However, the true origin of neurovirology can be accredited to the discovery that some viruses may have an affinity for nervous system tissue. This discovery was made in the late 1880s with research involving rabies. [3] : 1 

In 1881, while studying rabies, Louis Pasteur demonstrated that the central nervous system played a crucial role in the progression of the disease. [4] Following this discovery, in 1890, Schaffer demonstrated histological evidence that the rabies virus spread via neural networks.

In 1929 Heinrich Pette established the first classification criteria for inflammatory diseases of the nervous system. This classification separated the diseases into two groups: gray matter acute and white matter acute inflammatory diseases. Gray matter acute inflammatory diseases were characterized by damage to neurons with myelin remaining intact. White matter acute inflammatory diseases were characterized by destruction of the myelin, with neurons remaining intact. [3] : 4 

In 1938, Sbin and Olitsky discovered that the distribution of the virus within the body depended on its mechanism of entry. [3] : 6 

In 1965, ZuRhein and Chou established that destruction of myelin could result from primary virus infection, not only from autoimmune response to the virus. [3] : 8 

Most of the research of which the field of neurovirology is based upon occurred in the late 1980s and the 1900s. [3] : 10 

Beginning in 1999 the International Society of Neurovirology has recognized and awarded individuals who have contributed significantly to the field with the Pioneer in NeuroVirology Award. [5]

Major viruses studied

DNA virus family

Herpesviruses

Polyomaviruses

  • JC virus (JCV)
    • Is associated with progressive multifocal leukoencephalopathy and demyelination [2] : 343 

RNA virus family

Rhabdoviruses

    • Rabies virus
      • Gives rise to neuronal dysfunction [9]

Paramyxoviruses

  • Measles virus
    • Is a major cause of neurological deficits [6] : 401 
  • Mumps virus
    • Is the leading cause of virus induced aseptic meningitis and encephalitis [6] : 1431 

Retroviruses

  • Human immunodeficiency virus (HIV)
    • Is associated with cognitive dysfunction

Viral entry into the nervous system

Viruses have evolved mechanisms enabling them to easily infiltrate the nervous system. Two main methods of viral entry have been identified: transneuronal spread and hematogenous spread.

Transneuronal spread

The mechanism behind transneuronal spread is not entirely known yet, but it involves the virus escaping the immune system by traveling up the axons of the nerves. [10]

Hematogenous spread

There are two main ways that a virus is thought to enter the brain via hematogenous spread. The first is by infecting an immune cell, which then carries the virus to the nervous tissue. Viral examples of this include the JC virus which infects B cells and HIV which infects CD4 T cells and macrophages to infiltrate the brain. The second is by crossing the blood capillaries as a free virus or in leukocytes. [6] : 23 

Advantages of infecting the nervous system

Neurons lack molecules necessary to present viral peptides on the surface to killer cells, which means they provide a safe house for viruses to replicate. Once viruses get in neurons they can persist for the hosts lifetime and can influence the factors that disturb the function of neurons and the homeostasis of the nervous system, leading to nervous system diseases. [6] : 26 

Tools used for diagnosing neuroviral infections

There are several diagnostic tools which have become invaluable to diagnosing viral infections of the nervous system. In the past, more invasive methods of obtaining samples for diagnosis were needed such as the use of brain biopsy. Now, with the advancement of technology, less invasive means are used more frequently, such as neuroimaging and the analysis of cerebrospinal fluid (CSF).

Neuroimaging

CT scans and MRI scans are useful in visualizing inflammation and lesions caused by viral infection of the CNS. MRI is used to visualize deep white matter and temporal lobe lesions, which are not well defined by a CT scan. [11]

Lumbar puncture and CSF analysis

This method is valuable in diagnosing viral infections of the CNS. CSF analysis typically involves determining the patients total white cell count, glucose level, and protein level in the CSF. Viral infection of the CNS tends to increase the total white cell count, while increasing the level of protein. The levels of glucose tend to be decreased by viral infection, due to an increased glucose consumption.

CSF nucleic acid amplification using polymerase chain reaction (PCR)

PCR is frequently used to for rapid identification of specific DNA viruses from the CSF, while Reverse transcriptase PCR is commonly used to identify RNA viruses in the CSF. [12] The accuracy of this diagnostic tool is limited by the amount of the virus present in the CSF. Viral replication tends to peak early and then decline to undetectable levels in CNS infection. Within the first 5 days of symptom onset, before the decline of viral replication, PCR assays have a higher incidence of detecting CNS infection. [13]

Serology

Serology is useful in diagnosing viral infections of the CNS when PCR analysis returns negative results.

Brain biopsy

In recent years, due to the development of less invasive diagnosis techniques, brain biopsies are no longer frequently used for diagnosing viral infections of the nervous system. [6] : 35  However, some viral infections of the CNS cannot be diagnosed without histological and electron microscopic evidence. In these cases, brain biopsies are only performed when the patient has a serious neurological illness and is in need of immediate therapy, an alternative procedure will not lead to a specific diagnosis, and the information gained by the brain biopsy will outweigh the risks.

Research and therapy

Use of antivirals to treat CNS infection

The use of antiviral treatment with both Multiple Sclerosis and AIDS dementia has proven ineffective as a treatment. In patients with Multiple Sclerosis, antiviral treatment of EBV with Acyclovir showed no significant difference from the placebo. [8] In patients with AIDS dementia, despite antiretroviral therapy, CNS function remains diminished. [14]

Use of viruses for gene therapy

HSV-1 is a promising gene therapy agent, which could be used for gene delivery to neurons. This therapy may be used to treat metabolic brain diseases, neurodegenerative disorders, or to help enhance repair of brain tissue in neurological diseases. [6] : 121 

Future of field

New viruses and viral infections of the nervous system will continue to emerge and the field of neurovirology must constantly expand to meet these growing needs. [6] : v  While the interest in researching viruses that infect the nervous system has increased dramatically over the past 40 years, there are three key components vital for the continued advancement of the field:

  1. Training: New researchers and clinicians need to be trained about the significance of viral infection in the progression of neurological diseases.
  2. Technology: New technology needs to be refined and developed which will aid in the progression of research.
  3. Development of Therapy: Insight gained by research should be applied to the therapy of neurological diseases.

See also

Related Research Articles

Transverse myelitis Medical condition of the spinal cord

Transverse myelitis (TM) is a rare neurological condition in which the spinal cord is inflamed. Transverse implies that the inflammation extends horizontally across the spinal cord. Partial transverse myelitis and partial myelitis are terms sometimes used to specify inflammation that only affects part of the width of the spinal cord. TM is characterized by weakness and numbness of the limbs, deficits in sensation and motor skills, dysfunctional urethral and anal sphincter activities, and dysfunction of the autonomic nervous system that can lead to episodes of high blood pressure. Signs and symptoms vary according to the affected level of the spinal cord. The underlying cause of TM is unknown. The spinal cord inflammation seen in TM has been associated with various infections, immune system disorders, or damage to nerve fibres, by loss of myelin. As opposed to leukomyelitis which affects only the white matter, it affects the entire cross-section of the spinal cord. Decreased electrical conductivity in the nervous system can result.

Viral meningitis Medical condition

Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges. Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.

Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged resulting in symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; however, any inflammatory attack on the spinal cord is often referred to as transverse myelitis.

Japanese encephalitis Infection of the brain caused by the Japanese encephalitis virus

Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). While most infections result in little or no symptoms, occasional inflammation of the brain occurs. In these cases, symptoms may include headache, vomiting, fever, confusion and seizures. This occurs about 5 to 15 days after infection.

<i>Tick-borne encephalitis virus</i> Species of virus

Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Flavivirus.

Aseptic meningitis Medical condition

Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, mycobacteria, spirochetes, fungi, medications, and cancer malignancies. The testing for both meningitis and aseptic meningitis is mostly the same. A cerebrospinal fluid sample is taken by lumbar puncture and is tested for leukocyte levels to determine if there is an infection and goes on to further testing to see what the actual cause is. The symptoms are the same for both meningitis and aseptic meningitis but the severity of the symptoms and the treatment can depend on the certain cause.

Oropouche fever Medical condition

Oropouche fever is a tropical viral infection transmitted by biting midges and mosquitoes from the blood of sloths to humans. This disease is named after the region where it was first discovered and isolated at the Trinidad Regional Virus Laboratory in 1955 by the Oropouche River in Trinidad and Tobago. Oropouche fever is caused by a specific arbovirus, the Oropouche virus (OROV), of the Bunyaviridae family.

Viral encephalitis is inflammation of the brain parenchyma, called encephalitis, by a virus. The different forms of viral encephalitis are called viral encephalitides. It is the most common type of encephalitis and often occurs with viral meningitis. Encephalitic viruses first cause infection and replicate outside of the central nervous system (CNS), most reaching the CNS through the circulatory system and a minority from nerve endings toward the CNS. Once in the brain, the virus and the host's inflammatory response disrupt neural function, leading to illness and complications, many of which frequently are neurological in nature, such as impaired motor skills and altered behavior.

HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe. HAND may include neurological disorders of various severity. HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia. These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. The essential features of HIV-associated dementia (HAD) are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.

Granulomatous meningoencephalitis (GME) is an inflammatory disease of the central nervous system (CNS) of dogs and, rarely, cats. It is a form of meningoencephalitis. GME is likely second only to encephalitis caused by canine distemper virus as the most common cause of inflammatory disease of the canine CNS. The disease is more common in female dogs of young and middle age. It has a rapid onset. The lesions of GME exist mainly in the white matter of the cerebrum, brainstem, cerebellum, and spinal cord. The cause is only known to be noninfectious and is considered at this time to be idiopathic. Because lesions resemble those seen in allergic meningoencephalitis, GME is thought to have an immune-mediated cause, but it is also thought that the disease may be based on an abnormal response to an infectious agent. One study searched for viral DNA from canine herpesvirus, canine adenovirus, and canine parvovirus in brain tissue from dogs with GME, necrotizing meningoencephalitis, and necrotizing leukoencephalitis, but failed to find any.

Primary central nervous system lymphoma Medical condition

Primary central nervous system lymphoma (PCNSL), also termed primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS), is a primary intracranial tumor appearing mostly in patients with severe immunodeficiency. It is a subtype and one of the most aggressive of the diffuse large B-cell lymphomas. PCNSLs represent around 20% of all cases of lymphomas in HIV infections.. Primary CNS lymphoma is highly associated with Epstein-Barr virus (EBV) infection in immunodeficient patients, and does not have a predilection for any particular age group. Mean CD4+ count at time of diagnosis is ~50/uL. In immunocompromised patients, prognosis is usually poor. In immunocompetent patients, there is rarely an association with EBV infection or other DNA viruses. In the immunocompetent population, PCNSLs typically appear in older patients in their 50s and 60s. Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. The cause for the increase in incidence of this disease in the immunocompetent population is unknown.

A neurotropic virus is a virus that is capable of infecting nerve tissue.

Rabies Deadly viral disease, transmitted through animals

Rabies is a viral disease that causes inflammation of the brain in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, violent movements, uncontrolled excitement, fear of water, an inability to move parts of the body, confusion, and loss of consciousness. Once symptoms appear, the result is virtually always death, regardless of treatment. The time period between contracting the disease and the start of symptoms is usually one to three months but can vary from less than one week to more than one year. The time depends on the distance the virus must travel along peripheral nerves to reach the central nervous system.

The Central Nervous System controls most of the functions of the body and mind. It comprises the brain, spinal cord and the nerve fibers that branch off to all parts of the body. The Central Nervous System viral diseases are caused by viruses that attack the CNS. Existing and emerging viral CNS infections are major sources of human morbidity and mortality. Virus infections usually begin in the peripheral tissues, and can invade the mammalian system by spreading into the peripheral nervous system and more rarely the CNS. CNS is protected by effective immune responses and multi-layer barriers, but some viruses enter with high-efficiency through the bloodstream and some by directly infecting the nerves that innervate the tissues. Most viruses that enter can be opportunistic and accidental pathogens, but some like herpes viruses and rabies virus have evolved in time to enter the nervous system efficiently, by exploiting the neuronal cell biology. While acute viral diseases come on quickly, chronic viral conditions have long incubation periods inside the body. Their symptoms develop slowly and follow a progressive, fatal course.

Retrograde tracing

Retrograde tracing is a research method used in neuroscience to trace neural connections from their point of termination to their source. Retrograde tracing techniques allow for detailed assessment of neuronal connections between a target population of neurons and their inputs throughout the nervous system. These techniques allow the "mapping" of connections between neurons in a particular structure and the target neurons in the brain. The opposite technique is anterograde tracing, which is used to trace neural connections from their source to their point of termination. Both the anterograde and retrograde tracing techniques are based on the visualization of axonal transport.

The International Society for NeuroVirology (ISNV) was founded to promote research into disease-causing viruses that infect the human brain and nervous system. The ISNV membership includes scientists and clinicians from around the world who work in the fields of basic, translational, and clinical neurovirology.

Polioencephalitis is a viral infection of the brain, causing inflammation within the grey matter of the brain stem. The virus has an affinity for neuronal cell bodies and has been found to affect mostly the midbrain, pons, medulla and cerebellum of most infected patients. The infection can reach up through the thalamus and hypothalamus and possibly reach the cerebral hemispheres. The infection is caused by the poliomyelitis virus which is a single-stranded, positive sense RNA virus surrounded by a non-enveloped capsid. Humans are the only known natural hosts of this virus. The disease has been eliminated from the U.S. since the mid-twentieth century, but is still found in certain areas of the world such as Africa.

Robyn S. Klein American neuroimmunologist

Robyn S. Klein is an American neuroimmunologist as well as the Vice Provost and Associate Dean for Graduate Education at Washington University in St. Louis Missouri. Klein is also a professor in the Departments of Medicine, Anatomy & Neurobiology, and Pathology & Immunology. Her research explores the pathogenesis of neuroinflammation in the central nervous system by probing how immune signalling molecules regulate blood brain barrier permeability. Klein is also a fervent advocate for gender equity in STEM, publishing mechanisms to improve gender equity in speakers at conferences, participating nationally on gender equity discussion panels, and through service as the president of the Academic Women’s Network at the Washington University School of Medicine.

Georgette D. Kanmogne is a Cameroonian American geneticist and molecular virologist and a Full Professor and Vice Chair for Resource Allocation and Faculty Development within the Department of Pharmacology and Experimental Neurosciences at the University of Nebraska Medical Center in Omaha, Nebraska. Kanmogne's research program focuses on exploring the pathogenesis of neuroAIDS by deciphering the mechanisms underlying blood brain barrier dysfunction and viral entry into the central nervous system. Her research also addresses the lack of HIV therapies that cross the blood brain barrier (BBB) and has played a critical role in the development of nanoparticles encapsulating HIV-drugs that can cross the BBB to prevent viral-mediated neuron death in the brain. Kanmogne collaborates with clinical and basic researchers across America, Cameroon, and West Africa, spanning disciplines from hematology to psychiatry, to explore how viral genetic diversity is correlated with the neurological impact of HIV.

References

  1. 1 2 3 Johnson, R (1995). "Neurovirology: evolution of a new discipline", Journal of Neurovirology, 1(2).
  2. 1 2 3 4 McKendall, R and Stroop, W (1994). "Handbook of Neurovirology".
  3. 1 2 3 4 5 Gosztonyi, G (2001). The Mechanisms of Neuronal Damage in Virus Infections of the Nervous System.
  4. ↑ G. M. Baer, T. R. Shanthaveerappa, G. H. Bourne (1965). "Studies on the Pathogenesis of Fixed Rabies Virus in Rats", Bull. Org. mond. Sante, 33(783).
  5. ↑ "International Society for NeuroVirology".
  6. 1 2 3 4 5 6 7 8 Nath A, Berger J (2003). Clinical Neurovirology.
  7. ↑ Mueller N, Gilden D, Cohrs R, (2008). "Varicella Zoster Virus Infection: Clinical Features, Molecular Pathogenesis of Disease, and Latency". Neurologic Clinics. 26(675).
  8. 1 2 Lincoln J, Hankiewicz K (2008). "Could Epstein-Barr Virus or Canine Distemper Virus Cause Multiple Sclerosis?". Neurologic Clinics 26(699).
  9. ↑ Jackson A. (2008) "Rabies". Neurologic Clinics. 26(717).
  10. ↑ Wright E, Brew B, Wesselingh S (2008). "Pathogenesis and Diagnosis of Viral Infections of the Nervous System". Neurologic Clinics. 26 (617).
  11. ↑ Wright, E et al (2008). Pathogenesis and Diagnosis of Viral Infections of the Nervous System. 26(617).
  12. ↑ Irani, D (2008). "Aseptic Meningitis and Viral Myelitis", Neurologic Clinics, 26(635).
  13. ↑ Davies NW, Brown LJ, Irish D, et al. (2005). "Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections". Journal of Neurology, Neurosurgery, and Psychiatry. 76 (82).
  14. ↑ Ferris M, Mactutus C, Booze R (2008). "Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS". Neuroscience and Biobehavioral Reviews 32(883).
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