Herpes Simplex Encephalitis (HSE)
HSE is a rare infection of the brain by the Herpes simplex virus-1 (HSV-
1), the causative pathogen of common orofacial cold sores. Infection
causes severe necrotizing encephalitis (particularly in the temporal
lobes, where small hemorrhages may occur). Classic encephalitic
symptoms including confusion, altered mental status, personality
changes, fever, and potentially seizures. The condition is extremely
dangerous to the fragile CNS and 70% untreated cases will be fatal; of
those treated a third will die and only 20% will recover without long
term neuro-cognitive damage. HSV-1 is a member of the
Herpesviridae and is a relatively large, double stranded DNA,
enveloped virus. It is spread primarily by direct contact with a localized
infected areas (classically cold sores) though there can still be some
Above: Severe Encephalitis cause by
shedding of viral particles in the absence of a symptomatic
HSE, particularly in left temporal lobe,
manifestation.
visualized via MRI.
Breaking the Wall: The secret tunnel
HSV gains cellular entry by envelope fusion with target membranes based on glycolipid-recetor interactions. Once
inside, HSV-1 capsid travels to the cell nucleus, where it injects its genome through a portal generated by UL6
proteins. The complete virus is assembled in the nucleus and, eventually, through a complex pathway of nuclear
budding, replicated virions are excytosed from the host cell.
 HSV-1 has the potential for latency, in which viral proteins of the lytic cycle are not produced and the virus lies
dormant, particularly in the sensory neural ganglia. It is currently speculated that from this neuro-infective
capability, through unknown mechanisms and activations, HSV-1 virus gains entry to the peripheral neural system
and migrates through the peripheral axons to infect the CNS (via retrograde axonal flow), thereby avoiding the
formidable BB barrier. It remains unclear precisely how and where this infiltration occurs, though current research
has implicated the olfactory nerve as a likely candidate.
 Causing Disease
Pathologically, HSV infected cells can balloon in size, degrading the plasma membrane and nuclear structure into
multi nucleated large cells. The virus elicits a strong immune response, engaging first the microglia, which up-
regulate their activity and expression of antigen presenting MHC proteins, and leads to increased infiltration of
granulocytes and t lymphocytes to the site of infection. HSV-1 has been demonstrated to productively infect both
neurons and astrocytes, but seems to have little productive infectious capability in microglia. Microglia however
have been show to induce apoptosis and release large quantities of neurotoxic cytokines when infected even
nonproductively. Thus damage to the CNS tissue is thought to be partly from the infectious activities of the virus,
but perhaps more critically from the wide spectrum of cytotoxic compounds and acute inflammation elicited by
the immune response. This is evidenced in the prolonged activation of microglia for up to 12 months after
treatment with antivirals and resolution. The latency and reactivation characteristics of herpes simplex in other
regions of the body is not typically observed in HSE, as the retrograde axonal migration of the virus appears
extremely rare phenomena and is not linked to prolonged infection, as only 10% of those who develop HSE report
having a history of recurrent cold sores or other HSV manifestations.
Cerebral Malaria: Plasmodium falciparum
Cerebral malaria (CM) is a serious and life-threatening complication of
malarial disease that affects more than a million lives annually.
Infection is primarily caused by the protozoan parasite Plasmodium
falciparum, which is carried and transmitted to humans by the female
Anopheles mosquito. Malaria involves a complex parasitic life cycle,
first reproducing in the liver then, emerging into the blood stream,
where the parasites preferentially infect red blood cells. Malaria is an
enormous global health challenge, infecting over 250 million people
annually though only 1 to 2% will develop a neurological
manifestation called cerebral malaria (CM), the majority of which will
be children. CM is characterized by the development of neurological
symptoms accompanying classic malaria infection. Victims may
Section of brain showing blood
become delirious, confused, altered, or dizzy and can progress to
vessels blocked with developing P.
seizures, coma, and death.
falciparum parasites (see arrows)
 Breaking the Wall: The Siege
The neuropathology of CM still not very well understood, however researchers have demonstrated that it begins with high
levels of parasitically infected erythrocytes (red blood cells) in the blood stream. Infection of red blood cells may enhance
the expression of P. falciparum erythrocyte membrane protein (PfEMP-1), which binds to ligands on endothelial cells, such
as ICAM-1 or E-selectin. As masses of infected erythrocytes adhere to the deep microvasculature serving the CNS, normal
flux is occluded and the CNS interior may become progressively stressed and hypoxic, contributing to the development of
neurological symptoms and eventually coma. It has also been implicated that a malarial toxin may induce the release of Above: Intact erythrocytes surrounding a
capillary in the cerebral cortex. Endothelial cell
cytokines by macrophages, which leads to the uncontrolled production and accumulation of toxic nitric oxide in the CNS
layer appears to have disintegrated
and, later, degradation of the BB barrier.
Causing Disease
The accumulation of infected blood cells brings a rapid host peripheral immune response, in the form of T lymphocytes and
monocytes—further crowding the already occluded capillaries. Interestingly, the CNS immune system responds as well,
probably from both environmental stress and an influx of cytokine signaling, leading to the activation of microglia. Activated
microglia contribute to even greater cytokine production from both sides, especially TNF-α, and result in the degradation of
the epithelial blood brain barrier, with some observed migration of microglia cells. As the epithelial layer weakens, micro
hemorrhaging can occur into the CNS bringing with it infected erythrocytes and elements of the immune response. Immune
activation, as well as some cytotoxic production by the parasite, damages the astrocytes and decreases regulatory
control, stressing the CNS neural environment. Severe, late stage cases can lead to the formation of ring-like liaisons on the
brain.
 
Though fatal in 30 to 40% of cases even when treated effectively with anti-malarial drugs, survivors of CM have a relatively
low risk of long term neurological impairments. Since infection does not include a large scale immune response within the
Above: Semi-thin section of capillary in brainstem. Enlarged perivascular space (*)
CNS or the recruitment of the often destructive peripheral immune cells, only about 10% of cases experience long-term
containing leukocytes in close vicinity to the vessel. Lymphocytes (arrows) and
symptoms or deficits.
monocyte (arrowhead) sequestered to the endothelial wall.
Streptococcus pneumoniae: Bacterial Meningitis
Pathogenic
Infections
of the CNS
Jesse Wackerbarth
Above Right: Major CNS complications secondary to acute bacterial
meningitis. (A) Brain edema. (B) Hydrocephalus. (C) Cerebral vasculitis with
multiple cerebral infarctions. (D) Sinus thrombosis with venous infarction
and mild cerebral hemorrhage (black arrow).
CNS Immune Privilege
The billions of Neurons that constitute the CNS, allowing us to think, move, breath, and live,
are special; unlike most other cells in the body, they cannot divide or be effectively
repaired, the neurons we have are irreplaceable. While the classic immune response is
essential and effective in most of the body, its veracity often leads to extensive localized
tissue damage from our own immune cells. For most physiological systems this is necessary
and generally reparable collateral damage, but for the CNS it can be devastating and
irreversible. The rigid skull and spinal column leaves very little room for inflammation
without dangerous consequences. Thus it is necessary that the CNS be immunologically
privileged, distinct from the peripheral immune system and more delicate in its
responses, though their interactions are numerous and complex. Immune privileged areas
are characterized partly by a greater tolerance to potential antigen, such as transplanted
tissues or foreign organisms, but also by how they mount a response when necessary; thus
the CNS is not immune-deficient, but highly immune-specialized.
Great Wall of CNS: The Blood Brain Barrier
 The CNS is separated from blood stream (and much of the generalized immune system) by
the blood-brain barrier, a system of electrically resistant tight junctions linking the epithelial
cells that line the capillaries providing the brain’s blood supply. This cellular barrier allows
gas diffusion and nutrient transfer through transport, but generally prevents the migration
of large particles, both pathogenic and immune, from the blood stream into the cerebral
spinal fluid (CSF), thereby isolating and protecting the CNS environment. The permeability
of the BB barrier is thought to be regulated by the activity of adjacent CNS cells called
astrocytes. Pathogens that infect the CNS must have some mechanism for avoiding or
overcoming these formidable barriers.
Resident Immune System
Microglia are the CNS macrophages and the workhorse of the localized immune response.
In the absence of pathogen they play a mostly neuro-supportive role, scanning for and
removing damaged tissues and plaques, but in times of infection they are activated as
specialized CNS immune soldiers. Microglia have many functions, including the classics:
non-specific antigen recognition, phagocytic and cytotoxic activity, cytokine production, as
well as antigen presentation and t cell activation in substantial infections (with expression of
MHC class I and II); great plasticity and sensitivity is necessary due to their isolated, fragile
environment—for only in cases of extreme infection are peripheral immune cells recruited
through a degraded BB barrier, often causing the most immune damage.
Above: Murine model of CNS tuberculosis. (A)
Coronary section at the level of the caudal
diencephalon, with multifocal nonsuppurative
encephalitis. (B) Cornu ammonis showing mild
perivascular lymphocytic and histiocytic
infiltration, with microgliosis and reactive
astroglia. (C) Dorsal third ventricle, choroid plexus,
and subependymal areas expanded by
lymphocytic, plasmacytic, and histiocytic
infiltration, with subependymal microgliosis and
reactive astroglia.
Streptococcus pneumoniae is a gram positive, diplococci shaped
bacteria of the phylum firmicutes. It is an extracellular pathogen
and one of the most prevalent and serious causes of bacterial
meningitis in humans, proving fatal for 30% of patients and causing
long-term neural sequelae in around 40% of survivors.
Streptococcus pneumoniae (or pneumococcus) is part of the
normal flora observed in the human upper respiratory tract, but can
opportunistically cause disease under the right conditions.
Breaking the Wall: The Trojan Horse
Pneumococcus colonizes the nasopharynx, then invades the
intravascular space. Once in the bloodstream, pneumocuccus
evades the immune system with its thick polysaccharide capsule, a
major virulence factor that cloaks the bacteria’s antigenic surfaces
and provides a strong anti-phagocytic advantage. Additionally, the
capsule provides protection from the attacks of complement and
the production of antibodies. With a high bacterial load in the
bloodstream CNS infiltration may occur. The exact site of entry into
the CSF remains unclear and highly debated. The general strategy
involves first attaching to epithelial cells at several glycoconjugates.
They then activate the host epithelial cells to increase the
expression of surface platelet-activating factor (PAF) receptor,
Above: Pneumococcus’s basic path to the
which binds to phosphorylcholine in the bacterial cell wall. When
CNS, Below: Activation of immune response.
bound, PAF receptors are coded to endocytose, in this case bringing
along the attached pneumococcus into the interior of the cell.
Though some will perish within the host cell, the bacteria (though
not an intercellular pathogen) can travel through the epithelial
cell, and emerge to infect the CNS.
Causing Disease 
Once inside the CNS, microglia respond to infection but are even
more inept in their phagocytic activity than the peripheral immune
cells. Interestingly, phase variation, in which CNS invasive
pneumococcus express higher levels of teichoic acid and cell wall
proteins relative to capsule, seems to heighten the CNS response.
Typical antigenic recognition of PAMP regions and the toxin
Pneumolysin leads to a strong immune response, consisting first in
the activation of microglia, releasing damaging inflammatory and
cytotoxic cytokines, and second, in the destructive recruitment of
peripheral immune cells. Both contribute to swelling and neural cell
destruction that leads to symptomatic disease and potentially
death; the bacteria itself, lacking the capacity for neural
intracellular invasion or serious toxic production does little real
CNS damage.
Mycobacterium tuberculosis: CNS Tuberculosis
Mycobacterium tuberculosis is an aerobic, acid-fast gram positive bacilli,
characterized by it slow growth and waxy cell wall with high lipid content
(particularly mycolic acid). This facultative intercellular pathogen is the
causative agent of tuberculosis, a primarily respiratory disease affecting
nearly a third of the world’s population, which, in around 1% of cases, can
progress to a rare, high mortality infection of the CNS. Left untreated, CNS
tuberculosis is invariably fatal. The onset of neurological symptoms
progresses similarly to most CNS infections, beginning with mild
complaints like headache, fever, or dizziness and progressing to severe
Above: Tubercles (white
neurocognitive disturbances, altered mental status and seizures typical of
spots) in the CNS can be
CNS inflammation.
clearly visualized with
MRI.
 Breaking the Wall: The Breach
Mycobacterium tuberculosis (MTB) first infects the human host through inhalation of respiratory droplets
,preferentially infecting the alveolar macrophages through a variety of phagocytosis inducing receptors. Once
inside, M. tuberculosis hijacks the phagosome and proliferates within the immune cells. Classically, pulmonary
MTB infection produces a massive inflammatory response and the charteristic formation of granulomas; as
the infection progresses low levels of MTB have the capacity to spread through the blood stream and
lymphatic system, occasionally colonizing the CNS. It has been speculated that MTB migrates through
protective epithelial cells independently, or within infected macrophages; however, recent research on animal
models indicates that MTB may not gain access to the CNS through infiltration of the blood-brain barrier, as
is typical of bacterial CNS invasions. Instead MTB can gain access to the subarachnoid space through the
rupture of adjacent parenchymal tubercle or a caseating vascular focus , thereby bypassing the barrier
defense and gaining entry to the vulnerable CNS.
 Causing Disease
Once inside the CNS, M. tuberculosis effectively and productively infects microglia cells due to their
mechanistic similarities to macrophages. The facilitate uptake via a variety of receptors, mainly the CD14
receptor when not nonopsonized. Rapid cytokine release, particularly of TNF-α, leads to inflammation and
increased permeability of the BB barrier and the rapid recruitment of destructive peripheral immune cells,
classically forming disruptive tubercular granulomas throughout different areas of the CNS infection. The
immune response against intercellular pathogens and with recruited lymphocytes is exceptionally destructive
and feeds back to an even greater inflammatory response. Depending on the area of entry MTB can cause
either encephalitis or meningitis, and can even form brain abscesses—all of these life-threatening conditions
contribute the severe neurological symptoms and the high mortality of the infection.