CNSImmunology

Question 1

What are examples of viral infection of CNS

Answer 1

Herpes Simplex Virus
JC virus
Rabies
HIV

Question 2

Humoural vs T-cell response

Answer 2

-Humoral response: antibodies bind to virus particles in the blood
and at mucosal surfaces blocking the spread of infection.
-T cell response: T cells recognize and kill infected cells

Question 3

How can virus get into the CNS?

Answer 3

1. hematogenous spread via blood by infecting an immune cell

2. transneuronal spread via travelling within neurons

Question 4

What causes encephalitis?

Answer 4

Herpes simplex virus (HSV1 & 2)

Question 5

What are the symptoms for encephalitis?

Answer 5

abrupt onset of fever, confusion, behavioral changes, olfactory hallucinations, and/or gustatory hallucinations may also occur

Question 6

Herpes simplex

Answer 6

Spread: transneuronal spread
HSV1 transmitted by saliva; initial infection is stomatitis and later to trigeminal ganglion and to whole body
Potential genetic cause: TLR3 suppress replication; patients lack in TLR3 meaning virus replication is not suppressed

Question 7

HIV

Answer 7

• It occurs shortly after the person is first infected with HIV
• May cause headache, neck stiffness, drowsiness, confusion and/or seizures.
• High recovery rate

Question 8

entry of HIV-1 into the brain

Answer 8

1) “Trojan Horse hypothesis” : via migration of infected monocytes which differentiate intoperivascular macrophage.
2) The passage of infected CD4+ T cells into the brain.
3) the direct entrance of the virus via tight junctions across the membrane
4) entrance of HIV-1 by transcytosis phenomenon

Question 9

Symptoms of rabies

Answer 9

odd behaviors, delirium精神錯乱, combativeness, loss of muscle function, muscle spasms, drooling,
convulsions, pain

Question 10

The cycle of rabies infection

Answer 10

RV binds to nerve or muscle cells at the site of the inoculation via nicotinic acetylcholine receptors. Here can remain up to several months.
• RV can replicate in muscle cells at the site of the bite with no obvious symptoms.
• RV moves along the nerve axons to the CNS through retrograde axonal transport and transsynaptic spread.
• RV spreads from the postsynaptic site to the presynaptic site via receptor-mediated endocytosis.
• Brain Infection leads to encephalitis and neural degeneration. During this period, the virus can spread from the CNS via neurons, to the skin, eye and the salivary glands

Question 11

Immune evasion by RV

Answer 11

• RV inhibits alterations in BBB during infection.
• RV virus kill protective migrating T cells
• RV enter into the CNS without triggering apoptosis of the infected neurons and preserving the integrity of neurites.
RV evade immune clearance and cause a lethal infection
despite eliciting strong anti-viral immune responses in the periphery.

Question 12

BBB and Rabies

Answer 12

If BBB is forcefully broken, using EAE induction, clearance of RV occurs. Breaking BBB increase the anti-viral response allowing the mice to survive rabies

Question 13

PML

Answer 13

Progressive Multifocal Leukoencephalopathy
aka JC virus

50-70% of the population has been infected
Infection may initiate in the tonsils/ GI tract and persist in the other organs (kidney, tonsils)

Often see as consequence of immunosuppressive treatment (e.g. Natalizumab for MS)

Cleaning blood is the treatment

Question 14

Why is natalizumab risky?

Answer 14

It is a non depleting blocker (does not kill any cell but block adhesion so cell cannot leave the bloodstream)
-Check for JC virus before using to patients with MS

Immunosuppressive treatment can do more damage than good as 1/3 patients die, 1/3 have disability

Question 15

Meningitis

Answer 15

Meningitis is inflammation of the meninges that surround
the brain and spinal cord, usually caused by an infection
with bacteria or viruses
Can be viral or bacterial

Question 16

Viral meningitis

Answer 16

• aseptic無菌の meningitis
• Most cases of meningitis are caused by a viral
infection.
• Viral meningitis is often less severe than bacterial
meningitis and usually resolves without specific
treatment.
• But it can be severe or fatal depending on the virus
causing the infection, the person’s age, or whether a
person has a weakened immune system

Question 17

Etiology of Viral meningitis

Answer 17

Most viral meningitis cases especially during the summer
months, are caused by enteroviruses: Coxsackie and echovirus,
Enterovirus 71, Poliovirus, Rhinovirus
• Other viral infections that can lead to meningitis include
– Mumps
– Herpes virus, including Epstein-Barr virus, herpes simplex viruses,
and varicella-zoster virus
– Measles
– Influenza
– Viruses spread through mosquitoes and other insects (arboviruses)
– In rare cases, LCMV (lymphocytic choriomeningitis virus), which is spread by rodents

Question 18

Treatment /prevention of Viral meningitis

Answer 18

There are no vaccines for the most common
causes of viral meningitis.
Best way to prevent viral meningitis is to prevent
the spread of viral infections

Question 19

Bacterial Meningitis

Answer 19

• Acute bacterial meningitis usually occurs when bacteria
enter the bloodstream and migrate to the brain and
spinal cord.
• It can also occur when bacteria directly invade the
meninges, as a result of an ear or sinus infection, or a
skull fracture, or rarely, after some surgeries.
• Bacterial meningitis is a very severe disease but less prevalent

Question 20

etiology of Bacterial Meningitis

Answer 20

• Haemophilus influenzae type b (Hib) was the leading
cause of bacterial meningitis before the 1990s.
• New vaccines given to children as part of their routine
immunizations have reduced the occurrence of
invasive disease due to H. influenzae.
• Streptococcus pneumoniae and Neisseria meningitidis (the worst) are now the leading causes of bacterial meningitis

Question 21

Meningitis Common symptoms

Answer 21

High fever, headache, and stiff neck are common in anyone over the age of 2 years. Other symptoms: nausea, vomiting, discomfort looking into bright lights,
confusion, and sleepiness
-Hard to detect symptoms in newborns
-As the disease progresses, patients of any age may have seizures

Question 22

How can we diagnose for meningitis

Answer 22

by examining a sample of spinal fluid obtained by a lumbar puncture (spinal tap).

Question 23

Treatment for meningitis

Answer 23

start as early as possible. Appropriate antibiotic
treatment of most common types of bacterial meningitis should reduce the risk of dying from meningitis to below 15%
Meningitis caused by Neisseria meningitidis (also called
meningococcal meningitis) is contagious

Question 24

Immune response in acute meningitis

Answer 24

• 30%, mortality despite effective antibiotic treatment
• Clinical complications (formation of brain edema, increased intracranial pressure, and alterations of the cerebral blood flow), contribute to the unfavorable outcome.
• These alterations seems mediated by host immune responses and leukocyte function
• Experimental data in meningitis caused by S. pneumoniae suggest that bacterial toxins mediate approximately 50% of the neuronal cell loss while the remaining neuronal damage is driven by host immune responses
• However a deficient immune response may lead to
death.
(• Neisseria meningitidis is the most common cause of bacterial meningitis.)
• There are vaccines available for group A, B and C
• B meningococci now account for the majority of
meningitis cases in Germany (~700-800 cases)

Question 25

Symptom differences

Answer 25

Meningitis: headache, neck stiffness
Encephalitis: confusion, epileptic seizures

Question 26

How is immune response system in in acute

meningitis work?

Answer 26

• The complement system attacks all foreign structures circulating in the blood.
• Complement factor H is a member of the regulators of complement activation. CFH binds to glycosaminoglycans on the surface of host cells, preventing any immune response.
• Neisseria bacteria express a protein (factor H binding protein) that also binds factor H, mimicking body cells and preventing any attack from the innate immune system.
• This binding structures mimicks the glycosaminoglycans that occur naturally on host endothelial cells (Schneider et al. Nature 2009)

Question 27

Complement pathways

Answer 27

Classical pathway: induction by Ab binding
Lectin pathway: induction by microbial surface
Alternative pathway: induction by microbial surface

All leads to activating Complement 3 which then leads to inflammation, cell lysis and or cell clearance

Question 28

Take home messages

Answer 28

Viruses and bacteria have developed specific
mechanisms to infect and/or evade immune
surveillance in the CNS
• Meningitis: headache, neck stiffness
• Encephalitis: confusion, epileptic seizures
• Vaccinations prevent the majority of serious brain
infections
• Immune suppression increases the risk of brain
infections