Neurovirology
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Neurovirology is an interdisciplinary field which represents a melding of clinical
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developme ...
,
virology Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, th ...
,
immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see the ...
, and
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
. The main focus of the field is to study
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...
capable of infecting the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for
gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
, and to eliminate detrimental populations of neural cells.Johnson, R (1995). "Neurovirology: evolution of a new discipline", ''Journal of Neurovirology'', 1(2).


Overview

The field of neurovirology was formed within the past 30 years. 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.McKendall, R and Stroop, W (1994). "Handbook of Neurovirology". Neurovirology incorporates the related fields of
virology Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, th ...
,
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developme ...
,
neurology Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
,
immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see the ...
, and
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
. 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 Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Incr ...
, 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. 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.Gosztonyi, G (2001). ''The Mechanisms of Neuronal Damage in Virus Infections of the Nervous System''. In 1881, while studying rabies, Louis Pasteur demonstrated that the central nervous system played a crucial role in the progression of the disease. 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 Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
remaining intact. White matter acute inflammatory diseases were characterized by destruction of the myelin, with neurons remaining intact. In 1938, Sbin and Olitsky discovered that the distribution of the virus within the body depended on its mechanism of entry. In 1965, ZuRhein and Chou established that destruction of myelin could result from primary virus infection, not only from autoimmune response to the virus. Most of the research of which the field of neurovirology is based upon occurred in the late 1980s and the 1900s. 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.


Major viruses studied


DNA virus family


Herpesviruses

* Herpes simplex virus type 1 (HSV-1) **Evidence may support link between virus and Alzheimer's disease, intractable focal epilepsy, and acute disseminated encephalomyelitisNath A, Berger J (2003). ''Clinical Neurovirology''. **Infection can produce
myelitis 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 re ...
and encephalitis * Herpes simplex virus type 2 (HSV-2) **Infection can produce myelitis and encephalitis * Human cytomegalovirus (CMV) **Infection is associated with
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain oft ...
**Is the most common viral cause of childhood intellectual disability **Is linked to neurological abnormalities, such as: microencephaly,
seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
, hypotomia, and sensorineural hearing loss *
Varicella-zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...
(VZV) **Is associated with neurological complications such as:
meningoencephalitis Meningoencephalitis (; from ; ; and the medical suffix ''-itis'', "inflammation"), also known as herpes meningoencephalitis, is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the menin ...
, myelitis,
cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with symptom ...
,
Reye's syndrome Reye syndrome is a rapidly worsening encephalopathy, brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While hepatotoxicity, liver toxicity typically occurs in the ...
, cranial neuropatheis, and postinfectious disseminated encephalomyelitis * Epstein-Barr virus (EBV) **Is associated with
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain oft ...
, cranial mononeuropathies, focal encephalitis, and myelitis **Is considered the leading viral candidate for causing multiple sclerosisLincoln J, Hankiewicz K (2008). "Could Epstein-Barr Virus or Canine Distemper Virus Cause Multiple Sclerosis?". ''Neurologic Clinics'' 26(699). * Human herpesvirus type 6 (HHV-6) and Human herpesvirus type 7 (HHV-7) **Have not been linked to human nervous system disease


Polyomaviruses

* JC virus (JCV) **Is associated with progressive multifocal leukoencephalopathy and demyelination


RNA virus family


Rhabdoviruses

**Rabies virus ***Gives rise to neuronal dysfunction


Paramyxoviruses

*Measles virus **Is a major cause of neurological deficits *Mumps virus **Is the leading cause of virus induced aseptic meningitis and encephalitis


Retroviruses

*Human immunodeficiency virus (
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
) **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.


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.


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.


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 Brain biopsy is the removal of a small piece of brain tissue for the diagnosis of abnormalities of the brain. It is used to diagnose tumors, infection, inflammation, and other brain disorders. By examining the tissue sample under a microscope, the ...
. Now, with the advancement of technology, less invasive means are used more frequently, such as
neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Incr ...
and the analysis of
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
(CSF).


Neuroimaging

CT scans and
MRI scans Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
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.


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. 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.


Serology

Serology Serology is the scientific study of serum and other body fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum. Such antibodies are typically formed in response to an infection (against a given mic ...
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. 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. In patients with AIDS dementia, despite antiretroviral therapy, CNS function remains diminished.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).


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.


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


See also

*
Neuroimmunology Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, home ...
*
Neurology Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
*
Virology Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, th ...


References


External links


International Society for NeuroVirology (ISNV)Pan-American Society for NeuroVirology
{{Neuroscience Clinical neuroscience Virology