Midterm 2

Sickness Behavior

• Highly conserved physiological and behavioural changes orchestrated through interactions between the immune system and the brain in response to infection

• Behavioural changes are adaptive and promote survival during infection

• Immune system detects pathogens upon infection, and in response, the brain exerts top-down control of physiology and behaviour

• Pathogens + Innate Immune Detection + Inflammatory mediators —> Sickness state

Immune System Communication with Brain

The Brain can detect peripheral inflammation through:

1) Neural pathways: e.g. vagus nerve

2) Humoral and cellular pathways: Circulating inflammatory mediators or immune cells

Vagus Nerve

Cranial Nerve X

• Longest and most complex cranial nerve

• Part of autonomic (parasympathetic) nervous system

• Regulates involuntary functions (e.g. heart rate, digestion)

• Mediates inflammatory reflex

Vagus Nerve - “Inflammatory Reflex” Afferent

• Peripheral Infection Inflammation

• Cytokines

• Activates afferent vagus nerve fibers

• Signal sent to brain

• Nucleus tractus solitarius in the medulla

Vagus Nerve - “Inflammatory Reflex” Efferent

• Stimulation of vagus nerve EFFERENT (descending) fibers

• Acetylcholine receptor (NAChR)

• Anti-Inflammatory Suppression of peripheral cytokine production

• Cholinergic anti-inflammatory pathway (CAP)

• Nucleus tractus solitarus in the medulla

Vagus Nerve Stimulation

• Promising therapy for a diverse range of neurological conditions

• Involves surgically implanting a vagus nerve stimulation device into the human body.

• VNS stimulates both the afferent and efferent fibers of the VN.

• Exact mechanisms of actin are not fully understood.

Clinical Utility of Vagus Nerve Stimulation

• Anxiety

• Parkinson’s Disease

• Migraine and Cluster Headache

• Disturbance of Consciousness

• Alzheimer’s Disease

• Stroke (Ischemic stroke)

• Depression (approved by the FDA)

• Epilepsy (approved by the FDA)

• Autism Spectrum Disorder

Humoral and Cellular Pathways

1. Circumventricular organs (CVOs): brain regions with fenestrated capillaries

2. Endothelial signalling: cytokines act on BBB endothelial cells, which respond by producing prostaglandins and other mediators that diffuse into the brain

3. Cytokine receptors: specific transporters on BBB endothelial cells carry cytokines into the brain in regulated amounts

4. Immune cell inflex: passage of immune cells into the brain via orchestrated mechanisms

Circumventricular Organs (CVOs)

Sensory (detect peripheral signals)

• Organum vasculosum of the lamina terminalis (OVLT)

• Subfornical organ (SFO)

• Area postrema (AP)

Secretory (release brain derived hormones)

• Neurohypophysis (NH) (posterior pituitary)

• Pineal gland (PG)

• Median eminence (ME)

• Midline brain structures bordering the ventricles

• Critical gateway for brain-body communication

• Blood vessels present in these areas lack the anatomical and physiological adaptations seen in the BBB

Normal BBB neurovascular unit

• Astrocyte endfeet

• Pericyte

• Basement membrane

• Tight junction

Circumventricular organ BBB

• Loosely apposed astrocytic endfeet

• Fenestrations

• Endothelial cells

Possible Mechanisms

• Cytokines may enter the CVO tissue, activating microglia

• CVO endothelial cells produce prostaglandin E2 (lipid mediator), which binds to receptors on neurons in neighbouring brain areas

• CVO projection neurons pass a signal to more distant brain regions

The BBB is a Selective Barrier

Passes Through:

• Diffusion

  • Gases (e.g. O₂), water, small lipophilic molecules (e.g. ethanol)

• Transporter

  • Glucose

• Receptor mediated

  • Insulin

Typically/Mostly Excluded:

• Most proteins (including cytokines)

• Immune cells (under homeostasis)

• Pathogens

• Antibodies

Removed:

• Substrates of efflux pumps such as P-glycoprotein (removes many drugs)

BBB - Effects of Systemic Inflammation

• Change in signalling

• Increased leucocyte traffic

• Increased solute leakage

• Structural damage

BBB - Changes in Signalling

1. Endothelial Signalling

• Circulating cytokines bind to receptors on BBB endothelia

• The endothelium synthesizes prostaglandins (PGE2), which diffuses into the brain parenchyma

• PGE2 acts on receptors on neurons in the hypothalamus (fever) and other brain regions

2. Saturable Cytokine Transporters

• Circulating cytokines bind to saturable transporters (carriers) on BBB endothelia and are transported into the brain parenchyma

• Rates of transport are low

3. Other Transporters

• Cytokines downregulate efflux transporters like P-glycoprotein, reducing the brain’s ability to clear therapeutic drugs and their metabolites

• Cytokines transcriptionally modify expression of other transporters, such as ABCA1 which controls lipid transport

BBB - Leukocyte Trafficking

1. Resting State

• Leukocyte

2. Rolling

• Selectins

3. Activation

• Chemokines

4. Adhesion

• Integrins

5. Transendothelial migration

• Blood to brain

Summary - Back to Sickness Behaviour

• Pathogens

• Innate immune detection

• Inflammatory mediators

• Sickness state

• Neural pathway (fast)

• Humoral pathway (slow)

Non-Pathogen e.g. cancer

• Brain stem

• Hypothalamus

Mediation of Communication by Gut Brain Axis

Microbiota: collections of microorganisms that inhabit the surfaces of the body

Gastrointestinal tract (gut microbiota) represents the greatest density and abundance of microorganisms in humans

• Gut-microbiota-brain-axis: network of connections that allows bidirectional communication between gut microbiota and brain

• Critical in maintaining homeostasis of nervous, immune and GI systems

• Impacts neuronal pathways via vagus nerve

• Direct and indirect signalling to the CNS via molecules such as short-chain fatty acids

What Prevents Pathogens from Entering the Brain?

Pathogens prevented from entering brain by:

(a) BBB

(b) BCSFB (choroid plexus)

(c) BCSFB (meninges)

CNS Infection

Meningitis:

• Pathogens Infect Meningeal Layers

Encephalitis:

• Pathogens Infect Brain Parenchyma

Meningoencephalitis:

• Infection Starts in Meninges, Spreads to Brain Parenchyma

Abscess:

• Pathogens Wall Themselves Off in Brain

Meningitis

Symptoms:

• Fever, headache, neck stiffness, photophobia, seizures, can be life threatening

Viral most common

• e.g. enterovirus (coxsackievirus), herpes simplex

Bacterial severe

• Newborn babies, young children, adolescents and elderly at highest risk

• streptococcus pneumoniae (elderly)

• neisseria meningitidis (young children and adolescents)

Fungal/parasitic rare in Canada

• e.g. cryptococcal meningitis mainly in immunocompromised

• e.g. eosinophilic meningitis caused by parasitic worm infections

Encephalitis

Symptoms:

• Altered mental status, seizure, focal neurological sx

Prevalence 5 per 100,000 in Canada

• Most common in pediatric and elderly populations

Viral common (70%)

• e.g. herpes simplex virus

• e.g. transmitted by insects (West Nile virus)

Bacterial/fungal/parasitic rare

• e.g. toxoplasma encephalitis in immune compromised

Meningoencephalitis

Symptoms:

• Similar to meningitis/encephalitis

Causes:

• Viral meningitis (herpes simplex virus) - most common

• Bacterial meningitis (streptococcus pneumoniae)

Abscess

Localized area of necrosis which develops into a collection of pus surrounded by a well-defined capsule

Symptoms:

• headache, fever, and local neurological deficits

Incidence about 4 cases per million (higher in immunocompromised patients)

Bacterial causes most common - e.g. staphylococcus or streptococcus but may also stem from infections in nearby areas (ear, teeth, sinuses)

Meningitis vs Encephalitis

Meningitis pathogen infects meninges/CSF/subarachnoid space

Encephalitis pathogen infects brain parenchyma

Major Routes of Meningeal Infection

Main mechanisms:

A) Pathogens enter from blood across BCSFB (choroid plexus or blood vessels in the leptomeninges)

B) Direct invasion from adjacent tissue

A) Pathogens Cross the BCSFB

Cross endothelia (blood vessels or epithelia choroid plexus)

Mechanisms of crossing BCSFB:

A Transcellular

B Paracellular

C Trojan horse

Transcellular Entry

• May occur via:

  • receptor mediated mechanism (e.g. enteroviruses, neisseria meningitidis)

  • pinocytosis (e.g. JC virus)

• Used as a transit corridor (some viruses can replicate inside endothelial or epithelial cells)

• Pathogens have special mechanisms that they use to avoid being digested

Some Strategies to avoid detection:

• Bacteria:

  • avoid destruction in lysosomes by changing the pH

  • escape into the cytoplasm

  • capsules resist complement and phagocytosis

• Virus:

  • downregulation of MHC class I

  • inhibit interferon gamma signalling

  • mimic host RNA

Paracellular Entry

Mechanisms:

• release enzymes which break down tight junctions

• physically disrupt tight junctions

• host inflammation (e.g. cytokines increase permeability)

e.g. Bacteria - Treponema pallidum (Syphilis), virus - West Nile

Trojan Horse Entry

Mechanism:

• pathogen infects phagocytic leukocyte, which then crosses BCSFB

e.g. listeria monocytogenes (bacteria), HIV (virus), Toxoplasma Gondii (parasite), Cryptococcus neoformans (fungus)

B) Direct Invasion of Meninges

Mostly bacterial

• e.g. Streptococcus pneumoniae (bacteria)

Direct entry from adjacent infected tissues (e.g. nasal cavity)

Bypasses circulation

Major Routes of Parenchymal Infection

Main mechanisms:

A) Microorganisms enter brain from blood across BBB

B) Migration via nerves

• e.g. herpes simplex virus, rabies, prion proteins

C) Spread from CSF (meningoencephalitis) via perivascular space

A) Pathogens Cross the BBB

Main mechanisms:

A) Pathogens (viruses) enter brain from blood across BBB

• can use transcellular, paracellular, trojan horse routes

• e.g. Herpes simplex virus (HSV), West Nile virus

Viral Infection of the Brain Parenchyma

1) Viral infection of neurons increased production of interferons and activation of microglia

2) Viral replication in neurons induces production of chemokines, which drives T-cell and monocyte recruitment to the infected tissue

3) Activated microglia present antigens to T cells. This can lead to virus clearance, or pathology such as neuronal death or synaptic elimination resulting in behavioural and cognitive effects.

Immune and Viral Mediated Pathology

Post-Viral Complications

• Neurotrophic viruses affecting the CNS cause significant short- and long- term morbidity and mortality.

• Neurological, neuropsychiatric, and behavioural issues impact up to 50% of survivors

• e.g. West Nile, HSV-1

Neurotropism: The general capacity of a virus to infect and replicate within neural tissue

Key Mechanisms of Viral Immune Evasion

Key Mechanisms:

A) Disruption of interferon signalling

B) Disruption of antigen presentation

C) Viral mutations escape recognition by antibodies

D) Viral mutations increase cell to cell transmission of viruses

B) Migration Via Nerves

Olfactory nerve

• Viruses (e.g. Herpes simplex, influenza A, rabies)

• Bacteria (e.g. Neisseria meningitidis)

Vagus nerve

• Viruses (e.g. cytomegalovirus, rabies, SARS-CoV-2, HIV)

• Bacteria (e.g. Campylobacter jejuni)

• Prions

Rabies

• Viral disease that attacks the CNS of mammals, including humans

• Once clinical signs appear, rabies is usually fatal

• In Canada, rabies is mostly transmitted by bats, skunks and foxes

• While human rabies deaths are rare in North America, globally, dog rabies kills around 60,000 people each year

Mechanism:

• Virus enters following bite

• Virus replicates in muscle

• Enters nervous system at neuromuscular junction

• Travels up axons to spinal cord

• At dorsal root ganglion virus enters spinal cord and travels up towards the brain

• Viruses infect neurons (cell death is delayed)

• Virus travels back down along cranial nerves such as vagus nerve

Prions

Cellular prion protein (PrP^C)

• Protein present in neuron cell membranes

• Normally harmless, but when misfolded can cause degeneration of brain tissue

• Misfolded form can act as a template, converting normal proteins into infections prions

• Misfolded proteins can cause variant Creutzfeldt-Jakob disease in humans and BSE (mad cow disease) in cattle

Mechanism:

• Prions reach the gut and cross the intestinal epithelium

• Prions travel to secondary lymphoid organs where they accumulate and replicate

• Prions pass to nearby autonomic nerve fibers

• Prions move along nerve fibers (including the vagus nerve) to the spinal cord and brainstem, then spread through the brain

• Once in neural tissue, misfolded PrP template conversion of local PrP^C, producing spongiform pathology and neuronal loss

Virus Latency

Virus latency: the ability of a pathogenic virus to remain dormant within a host cell instead of actively replicating and destroying the cell

During this phase, proliferation of viral particles ceases, allowing the virus to completely evade the host’s immune system

The virus can reactivate later and start to replicate again when triggered by specific cues

CNS prime location for latency due to low MHC

Example - herpes simplex virus-1 (HSV-1)

Mechanism:

• Acute HSV-1 infection is initiated in peripheral cells and then spreads to nearby sensory neurons.

• HSV-1 reaches the neuronal cell body in the trigeminal ganglia via retrograde transport.

• In the neuronal nucleus, replication and viral genome transcription is silenced

• Stressors or weakened immune system can induce reactivation of the virus

• Virus leaves the neuronal nucleus and travels back to epithelial cells via anterograde trafficking

• If viral progeny reach the CNS, this can lead to herpes simplex encephalitis

Immune Compromise

immunocompromised

• Having a weakened immune system. People who are immunocompromised have a reduced ability to fight infections and other diseases. This may be caused by certain diseases or conditions, such as AIDS, cancer, diabetes, malnutrition, and certain genetic disorders. It may also be caused by certain medicines or treatments, such as anticancer drugs, radiation therapy, and stem cell or organ transplant. Also called immunosuppressed.

Immune compromise increases susceptibility to opportunistic pathogens:

• Viruses: JC virus (progressive multifocal leukoencephalopathy or PML), Cytomegalovirus (CMV), HIV (HAND)

• Fungi: Cryptococcus, Aspergillus

• Parasites: Toxoplasma gondii (cerebral toxoplasmosis)

• Bacteria: Listeria monocytogenes (meningoencephalitis)

Summary

	Meningitis	Encephalitis
Compartment	Leptomeninges, subarachnoid space, CSF	Brain parenchyma
Border Crossed	BCSFB	BBB
Main Pathogens	Bacteria (more severe) - multiply quickly Viruses (more common)	Viruses
Host Defence Challenge	Low complement and immunoglobulins	Low MHC, brain relies on interferons and T cells
Immune Response	Neutrophil (bacteria) or lymphocyte (virus)	Glial cell, lymphocyte
Damage	Mainly from immune response	From immune response and pathogen