12. Viruses that cause Stupor, Delirium, and Coma

Which herpes simplex virus is the more common cause of encephalitis: HSV-1 or HSV-2?

HSV-1

What is the morphology of HSV?

Enveloped, icosahedral, DNA virus

What is the pathology of HSV encephalitis?

Has a predilection for the anterior and medial temporal lobes and the inferior frontal lobes

What are the acute symptoms of arthropod-borne viral encephalitis?

altered mental status

What is the morphology of the alphaviruses and flaviviruses?

(+) RNA, enveloped, icosahedral capsid

Which classification of viruses are neurotropic?

Alphaviruses

Flaviviruses target which cells? What is the result of this?

monocyte-macrophage lineage → pass BBB using Trojan horse method

What is the host of Eastern Equine Encephalitis virus? How is it transmitted?

Birds; Culiseta melanura mosquito

How is the Powassan virus transmitted?

bite of infected tick

How is Powassan virus diagnosed?

Serum or CSF fluid to detect Powassan-specific IgM and neutralizing antibodies

How is West Nile virus transmitted?

Culex mosquitoes

Which virus has a genomic architecture of three segments of single stranded RNA?

La Crosse virus → oval, enveloped

How is La Crosse virus transmitted?

Aedes triseriatus

Severe neuroinvasive disease caused by La Crosse virus affects which population?

children → seizures, partial paralysis

What is the function of the P and L proteins of Rhabdoviridae?

make up the RNA dependent RNA polymerase

What is the function of the G protein of Rhabdoviridae?

only viral protein of its surface; binds to the host cell receptors like nAchR or neural cell adhesion molecule

What is the function of the N protein of Rhabdoviridae?

protects RNA from RNAse and keeps RNA in a structure suitable for transcription

How does Rhabdovirus replicate?

1. Attachment and Entry: The first step in the replication cycle is the attachment of G protein to NCAM or nAchR. Once attached, the virus enters the host cell through endocytosis via clathrin coated pits with p75.

2. Uncoating and Release of Viral RNA: The viral envelope fuses with the endosomal membrane, releasing the viral RNA into the cytoplasm of the host cell.

3. Transcription and Replication: Transcription produce mRNAs for the viral proteins, while replication generates new copies of the viral genome. This occurs in Negri bodies.

4. Translation and Protein Synthesis: The viral mRNAs are translated by the host cell's ribosomes to produce viral proteins, including the RNA-dependent RNA polymerase, which is essential for viral replication.

5. Assembly: New viral genomes and proteins are assembled into progeny virions in the cytoplasm of the infected cell. The viral nucleocapsid is formed, and the viral envelope proteins are inserted into the host cell membrane.

6. Budding and Release: The assembled virions bud from the host cell membrane, acquiring their envelope. This process allows the virus to exit the host cell without causing immediate cell death, enabling the infection to spread to other cells.

7. Spread and Infection of New Cells: The released virions can then infect neighboring cells, continuing the cycle of infection and replication.

How does Rhabdovirus spread within the nervous system?

• enters muscle by binding nAchR

• PNS to CNS via microtubule dependent retrograde axonal transport (axon to soma)

• p75NTR receptor allows for more rapid transport of Rhabdovirus to CNS

• Spreads to salivary glands or skin of head (highly innervated areas) via anterograde transport and sheds

How is rabies transmitted?

saliva

How does the invasion of the CNS by Rabies lead to neuronal dysfunction?

induces apoptosis (no interference with host protein synthesis or cytopathic effects)

What is the difference between furious/encephalitic and paralytic rabies? Which one is more lethal and why?

1. Furious/Encephalitic Rabies: This form of rabies is characterized by hyperactivity, agitation, hydrophobia, aerophobia, and sometimes hallucinations or delirium. Patients with furious rabies may exhibit erratic behavior, agitation, and may become violent or disoriented.

2. Paralytic Rabies: Also known as dumb rabies, this form of the disease is characterized by muscle weakness, paralysis, and a lack of coordination. Paralytic rabies progresses more slowly than furious rabies and can take weeks or even months to cause death.

Furious rabies tends to progress more rapidly and is often more easily recognized, leading to earlier diagnosis and intervention. Furious rabies is also associated with greater amount of virus and lower immune response. Paralytic rabies, on the other hand, may be less easily recognized initially, as its early symptoms can be mistaken for other illnesses.

What is the incubation period for Rabies?

eclipse phase → virus cannot be easily detected

What are the three phases of symptoms associated with rabies virus?

1. Prodromal phase

2. Acute neurologic phase - sympathetic overactivity, hydrophobia

3. Coma - respiratory paralysis

What can help provide immunity against rabies?

• presence of rabies-specific virus neutralizing antibodies (VNAs)

• Post-exposure prophylaxis: passive (give pre-formed Abs) and active (stimulate immune system to make Abs) immunization, wound cleaning

Which innate signaling cascades does Rabies block?

Rig I, IRF3, IFN, and JAK-STAT

How is postmortem diagnosis of rabies done?

• presence of antibody in serum of CSF in unvaccinated individual diagnostic

• skin biopsy from nuchal area containing hair follicles

• saliva has highest rate of positivity

What is the DFA test?

Direct Fluorescent Antibody (DFA) Test: This is the most common and reliable test for diagnosing rabies postmortem. It involves examining brain tissue (specifically the hippocampus, brainstem, cerebellum) for the presence of the rabies virus antigen using fluorescent antibodies. The DFA test is highly specific and can provide a definitive diagnosis of rabies.

What is the hallmark diagnostic finding of rabies?

Negri bodies in the CNS

What is the current vaccine for rabies?

HDCV - human diploid cell vaccine; killed-virus prepared vaccine

What are the passive antibodies of rabies? Are they given to those who were previous vaccinated or to those who have never been vaccinated and are exposed to rabies?

hRIG and ERIG → given to all previously unvaccinated cases

What is the disease caused by JC polyomavirus?

fatal demyelinating disease called progressive multifocal leukoencephalopathy in immunocompromised individuals

How is JC virus transmitted?

inhalation and/or oral infection of tonsils → viremia to kidney

asymptomatic in the immuno-competent

What are the symptoms of progressive multifocal leukoencephalopathy caused by JC virus?

Causes productive infection of oligodendrocytes leading to lesions in white matter of the brain

• difficulty speaking

• poor coordination

• paralysis and death

What is the morphology of JC virus?

nonenveloped, dsDNA genome

What is the function of the early and late genes of JC virus?

• Early - produces Large and small T proteins for viral replication, cell cycle regulation, and cell transformation

• Late - produces structural proteins: VP1, VP2, VP3, agno

How does JC virus attach to cell receptors?

JCV binds to Sialic acid then 5HT2a serotonin receptor via VP1

How does JC virus cross the blood brain barrier?

replicates in endothelial cells of capillaries

JC has an abortive infection in _(which cell) and a productive infection in _(which cell)

What does this mean?

astrocytes; oligodendrocytes

An abortive infection occurs when a virus enters a host cell but is unable to complete its replication cycle or produce infectious progeny virions. A productive infection occurs when a virus enters a host cell, completes its replication cycle, and produces infectious progeny virions.

Productive infection in oligodendrocytes leads to demyelination in the brain and cell death