Infections and Immunology of the CNS Flashcards
Define and differentiate the difference between:
Neurotropic, neuroinvasive and neurovirulent
as they relate to viral infections of the CNS
Neurotrophic
- Capable of replicating in nerve cells
Neuroinvasive
- Capable of entering or infecting the CNS
Neurovirulent
- Capable of causing disease within the CNS
Define the following terms:
Meningitis, Encephalitis, Myelitis, Encephalomyelitis, Primary viral encephalitis and secondary viral encephalitis
Meningitis
- Infection of the meninges
Encephalitis
- Inflammation of brain tissue itself
Myelitis
- Infection of the spinal cord itself
Encephalomyelitis
- Infection of both the brain and spinal cord
Primary viral encephalitis
- Direct viral infection of the brain/spinal cord
Secondary encephalitis
- Results from complications of a current viral infection where the virus spreads to the brain - usually via the blood
Outline the common causitive agents of viral meningits
Viral meningitis
- more common than bacterial meningitis but less severe
- presentation is headache, fever, neck stiffness, with or without vomiting and/or photophobia
- main cause is enteroviruses (common viruses that enter the body through the mouth)
- other viral causes - mumps, varicella zoster, influenza, HIV, and herpes simplex type 2 (genital herpes).
Outline the common causitive agents of viral encephalitis
_Viral Encephalitis _
- one of the most serious viral diseases
- presentation like meningitis, then personality and behavioral changes, seizures, partial paralysis, hallucinations, and altered levels of consciousness, ultimately coma and death.
- mostly caused by herpes simplex virus types 1 and 2, rabiesvirus, arboviruses (insect-borne viruses) or enteroviruses
- mumps virus meningitis can also involve the brain parenchyma but is generally mild
Outline the common causitive agents of **post-infectious encephalomyelitis **
Postinfectious encephalomyelitis:
- Can occur a few days after infections such as measles, chickenpox, rubella or mumps
- No virus present but inflammation and demyelination are evident
- Possibly autoimmune in nature
Outline the common causitive agents of Guillain-Barre Syndrome
Guillain-Barre syndrome
- Is an acute inflammatory demyelinating disease following infection with several viruses such as EBV, CMV, HIV
- Results in partial or total paralysis but most people (75%) fully recover within weeks
- An outbreak followed vaccination with inactivated influenza vaccine in 1976 (but not since) so does not require active infection
Outline the common causative agents of Reye’s syndrom, Chronic demyelinating disease and AIDS encephalopathy
_Reye’s syndrome _
- Post-infection with influenza or chickenpox in children
- 25% case-fatality rate
- Cerebral edema but not inflammation
- Epidemiological association with administration of aspirin during initial fever
_Chronic demyelinating diseases _
- Very rare
- Exemplified by sub-acute sclerosing panencephalitis (SSPE), a late sequel to measles infection
_AIDS Encephalopathy (AIDS dementia complex): _
- Once HIV infection leads to immunodeficiency the neurovirulence of HIV becomes manifest
- 50% of patients develop progressive dementia
What ways can viral agent gain access to the brain?
Viruses can enter the CNS via the:
- Peripheral Nervous System
- Bloodstream
- Olfactory Bulb
Why would viruses target the peripheral nervous as a way of entering the CNS?
The peripheral nervous system is comprised of nerve fibres and ganglia that are continuous with the CNS and aren’t subjected to the defense of the meninges.
Some viruses exploit this entry point and travel via axon fibres of the PNS into the CNS.
Viruses are protected from cytotoxic T-cells (CD8+) as nerve cells do not possess class I MHC molecules to sample and display intracellular proteins
Whole virions or uncoated nucleocapsids are able to be carried passively along axons or dendrites
- Replication of viruses occurs in the cell body where protein synthesis machinery is present
- Progeny are transported to the axon terminals where they are released an cross the synaptic junctions to the next neuron
Examples include rabies virus, yellow fever virus and herpes simplex virus (types 1 and 2)
Although the blood brain barrier provides some protection, what viruses are capable of infecting the CNS directly from the blood?
Other viruses enter CNS directly via the bloodstream as for other tissues - particularly occurs at the choroid plexus
Examples include poliovirus, mumps virus, measles virus, coxsackievirus; also HIV in monocytes
What type of viruses are capable of infecting the CNS via the olfactory bulb?
coronovirus and herpes simplex virus
Generally, what can viruses do once they get into the CNS/brain?
Viruses that directly kill neurons cause inflammatory disease
- extensive loss of neurons results in permanent sequelae: mental retardation, epilepsy, paralysis, deafness or blindness etc
- Inflammation breaks down the blood brain barrier allowing lymphocytes, antibodies and immune effector to conduct an inflammatory immune response.
Other viruses replicate in non-neuronal cells, such as oligodendricytes, causing demyelination of CNS axons.
Discuss the rabiesvirus and rabies
Rabies and the rabiesvirus
Viral properties
- High neuroinvasiveness and high neurovirulence
- Bullet shaped
- Negative stranded RNA virus
- Helical capsid and envelop
Replication Cycle
- replication in nerve cells is an obligatory part of the life cycle of the virus
- replication in cell body leads to rabies glycoprotein to be displayed on the host cell surface - undergoes budding to obtain envelope proteins.
- does not hide from immune system
- intentionally causes severe cell death due to antibody complement activation
Rabies Epidemiology
- 55,000 people die every year of rabies worldwide
- Australia doesn’t have classical rabies but does have related lyssavirus transmitted by bats; New Zealand only place in the world that is rabies free
Rabies Pathophysiology
The virus is present in the saliva of rabid animals and is transmitted during a biting event that penetrates the skin and infects the PNS.
Replication in muscles + peripheral nerves for 10-60 days before infecting the CNS (important because this is one of the few diseases you can vaccinate against once you have already been infected)
CNS infection days 50-70 resulting in neuronal dysfunction, clinical rabies and/or death.
- Interestingly, the virus has evolved to target brain areas that increase aggression, decrease thirst and become terrified of drinking water so the salivary virus isnt diluted and is more likely to be transmitted to next animal.
Virus moves and replicates in salivary glands in preparation for transmission to next host.
What viruses are classified as alpha herpesviruses?
Alpha herpesviruses include:
- Herpes Simplex virus (types 1 & 2)
- Varicella-zoster virus
Growth in nerve cells is an obligatory part of their life cycle
The demonstrate low neuroinvasiveness but high neurovirulence
These viruses have a linear dsDNA genome, icosahedral virion and envelope
Illustrate the general life cycle of the alphaherpes viruses
Describe the pathogenesis of the herpes simplex virus type 1
The virus enters the body through contact with infected saliva.
Primary infection typically involves the mouth and/or throat leading to cold sores or gingivostomatitis (particularly in young children); while in other patients signs of infection may not be apparent.
Discuss the latency of HSV infections
It is known that 20% of people harbour latent HSV infection in their ganglia
The HSV genome is maintained as an episome coated with histones and there is no structural gene expression. There are 2kb latency activated mRNA transcripts (LATs) of unknown function produced.
Immune mechanisms (particularly CD8+ T cells) are responsible for keeping virions in a latent phase.
- when people are older, stressed or immunocompromised reactivation can occur and cause disease.
Illustrate the pathogenesis of varicella zoster virus (VZV)
VZV is the cause of chicken pox and shingles
During chicken pox the viral spread is haemotogenous; the virus subsequently enters the nerves from a resulting vesicular rash of the skin.
Latent VZV can occur as result of 10-20% of primary cases.
Reactivation of the VZV leads to VZV virus migrating back to the skin causing painful shingles blisters that follow the dermatome of the latent gangilia
Discuss the viral characteristics of poliovirus
Poliovirus is a member of the enterovirus genus
It is a cytocidal virus, killing the cells in which it reproduces. Has a low neuroinvasiveness and high neurovirulence
Growth in nerve cells is NOT an obligatory part of the poliovirus life cycle
It is a positive stranded RNA virus with an icosahedral capsid and no envelope
Illustrate the pathogenesis of poliovirus
Simply put:
- Poliovirus is ingested via contaminated food or water
- Moves out of intestinal system via M-cells and replicates in regional lymph nodes
- It migrates to the blood circulatory system causing viremia
- Crosses the BBB to anterior horn cells of the spinal cord which have specific receptors that take the virus up
- Replication in anterior horn cells leads to the death of the cells
- These cells contain important motor neurons and their death leads to paralysis
- Poliovirus migrates back to GIT and is excreted in faeces
What are the consequences of contracting polio from the poliovirus?
- If the virus invades the central nervous system (CNS), may cause total paralysis within hours.
- 50% of cases occur before the age of three years old
- Rarely, virus enters nerve cells from the blood
- Virus is cytolytic and kills motor neurons
- Less than 1% of infections lead to irreversible paralysis
- The lower limbs are affected more often than the upper limbs, leading to acute flaccid paralysis.
- More extensive paralysis involving the trunk, thorax and abdomen, can result in quadriplegia.
- Among those paralyzed, the mortality rate is 5 to 10% once respiratory muscles become immobilized
In the most severe of cases, polio attacks motor neurons of the brainstem which reduces breathing capacity, increased swallowing difficulty and impedes speech articulation
- Iron lungs were required to maintain life in these patients
- Polio is now erradicated in the western world due to successful vaccination programmes
By what method do enteroviruses enter and disseminate in the body?
Enteroviruses, which includes coxsackie virus (A + B) and echoviruses, are spread by fecal-oral route.
They migrate into the bloodstream after passing through the GIT mucosal associated lymphatic tissues (MALT) and distribute to their target organs.
Enterovirus Meningtits
Often occurs as a result of these viruses - most commonly during a summer/autumn epidemic
Meningitis may be the sole presentation in some patients - while others may have rashes or myositis
Discuss the diversity of antigen receptors generated by the human immune system
The human lymphocyte pool consists of a large number of cells that express antigen receptors of random specificity
- provides a large repitoire of antigen receptors -> don’t need to know what will exactly infect us because we are prepared for almost all.
During the development process some of these randomly constructed **receptors may recognise self-antigens **or harmless enviromental antigens. In which case, these immune cells would cause damage to self when stimulated.
TOLERANCE SERVES TO PROTECT US FROM SELF REACTIVE LYMPHOCYTES
Generally, what types of tolerance exist?
Central tolerance occurs within the primary lymphoid organs: thymus for T cells and bone marrow for B cells.
- Deletion and anergy of autoreactive lymphocytes are the main mechanisms of tolerance here
- B-cell tolerance is less efficient than T cell tolerance
- but autoantibodies are generally short lasting and self limiting thus not as severe as self-reactive T-cells.
Peripheral tolerance is induced when mature lymphocytes recognize self antigens and die by apoptosis, or become incapable of activation by re-exposure to that antigen.
- Peripheral tolerance is important for maintaining unresponsiveness to self antigens that are expressed in peripheral tissues and not in the generative lymphoid organs and for tolerance to self antigens that are expressed only in adult life, after many mature lymphocytes specific for these antigens may have already been generated.
- Peripheral mechanisms may also serve as a backup for the central mechanisms, which do not eliminate all self-reactive lymphocytes.
- Largely maintained by regulatory T cells (Treg) that actively suppress self antigen-specific lymphocytes. Treg suppression occurs in secondary lymphoid organs and in nonlymphoid tissues.
How do autoimmune diseases begin?
Autoimmune diseases normally begin in the presence of inflammation following damage to injured cells.
Commonly follows infections where dendritic APC’s can provide co-stimulation of self-reactive T-cells
Discuss how autoreactive lymphocytes can be activate by molecular mimicry
Antigens from pathogens may be similar in shape to autoantigens; meaning that pathogen antigens are capable of cross reacting with self reactive lymphocytes (T or B cells)
For example: Streptococcus m-proteins are capable of promoting a cross reactive response to self-reactive B-cell that produce Ig that bind antigens of heart muscle.
How do you diagnose meningitis according to the diagnostic testing
Note: there is lack of sensitivity and specificity with the parameters of CSF fluid
There can be cross over between bacterial and viral criteria
Note: emergency antibiotic treatment on suspicion of bacterial meningitis will alter the CSF analysis
What antibiotics should be administered to treat bacterial meningitis?
