Herpes Simplex Encephalitis (HSE)
Streptococcus pneumoniae is a gram positive, diplococci shaped bacteria of the phylum
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 with severe
neuroinflammation and swelling of the brain (particularly the temporal lobes, where small hemorrhages
may occur), leading to the development of 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. Modern diagnosis’s are typically made through
PCR detection of the viral genome in the CSF and treated with high dosages of Acyclovir—an antiviral
that selectively inhibits viral DNA polymerase.
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 shedding of viral particles in the absence of a symptomatic manifestation. 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. Notably, the virion host shutoff protein (VHS or UL41) inhibits host protein synthesis and
degrades host mRNA. During the lytic cycle, herpes virus protein genes, classified immediate-early, early,
and late are transcribed then translated and the complete virus is assembled in the nucleus; eventually,
through a complex pathway of nuclear budding, replicated virions are excytosed from the host cell.
 
HSV-1 also 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.
Nevertheless, once accessed, the CNS is particularly susceptible to HSV infection because the
intraneuronal spread is believed to shelter virus from host defense mechanisms.
 
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. The initial development of malaria involves a complex parasitic life cycle, in which
reproduction occurs in the liver—avoiding the attention of the immune response—and the onset of
clinical malarial disease is marked by the emergence of parasite into the blood stream, where they
Section of brain showing blood preferentially
vessels infect red blood cells and cause the characteristic fever and chills. Malaria is an
blocked with developing P. falciparum
enormous global health challenge, infecting over 250 million people annually though only 1 to 2%
parasites (see arrows) (RPH). 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 become delirious, confused, altered, or dizzy and can progress to
seizures, coma, and death.
 
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 cytokines by macrophages, which leads to
the uncontrolled production and accumulation of toxic nitric oxide in the CNS.
 
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 infect does not
include a large scale immune response within the CNS or the recruitment of the often destructive
peripheral immune cells, only about 10% of cases experience long-term symptoms or deficits.
Streptococcus pneumoniae: Bacterial Meningitis
Pathogenic
Infections of
the CNS
Major CNS complications secondary to acute bacterial meningitis.
Jesse Wackerbarth (B) Hydrocephalus. (C) Cerebral vasculitis with multiple cerebral infarctions. (D) Sinus
thrombosis with venous infarction and mild cerebral haemorrhage (black arrow).
Our central nervous system is the most important and complex system in the human
body, but also one of the most fragile. 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 and thus damage to the CNS is much more devastating than in other
areas of the body. 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. Furthermore,
encasement within 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. 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.
 
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; externally, it is protected by the covering of leptomeninges and
skull. The permeability of the BB barrier is thought to be regulated by the activity of
adjacent CNS cells called astrocytes. Similarly, the blood-CSF barrier provides a
protective layer in the choroid plexuses and the arachnoid membrane, between the
dura and the subarachnoid fluid. Thus, pathogens that infect the CNS must have some
mechanism for avoiding or overcoming these formidable barriers. While the two
immune systems were once assumed to be almost entirely separate, new research has
made it increasingly clear that their interactions are numerous and complex, though
the CNS system retains a moderate degree of autonomy.
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 and act 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; great plasticity and sensitivity is necessary due to
their isolated, fragile environment—for only in cases of extreme infection are
peripheral phagocytes recruited through a degraded BB barrier. Recent research has
indentified both the expression of MHC class I and II, as well as communication with
peripheral t lymphocytes, yet many of the mechanisms and consequences of this
interaction remain unclear.
. cell wall and other virulence hijack the phagosome and proliferate within the immune
Intact erythrocytes surrounding a capillary in the cerebral cortex. Endothelial
cell layer appears to have disintegrated (arrow)
Murine model of CNS tuberculosis. (A) Coronary section at the level of particularly
diencephalon, with multifocal nonsuppurative encephalitis. (B) Cornu ammonis
mild perivascular lymphocytic and histiocytic infiltration, with microgliosis
astroglia. (C) Dorsal third ventricle, choroid plexus, and subependymal infection.
by lymphocytic, plasmacytic, and histiocytic infiltration, with subependymal microgliosis
and reactive astroglia.
Semi-thin section of capillary in brainstem. Enlarged perivascular space (*) containing leukocytes in close
vicinity to the vessel. Lymphocytes (arrows) and monocyte (arrowhead) sequestered to the endothelial wall.
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, particularly in response to
immune suppression and with the assistance of several virulence factors. It can also be
spread through respiratory droplets or direct contact leading to colonization of the
nasopharynx as the first stage of development, initially binding to specific carbohydrate
signatures on host epithelial cells. Pnumocuccus must then invade the intravascular space,
which requires polymeric immunoglobulin receptor (pIgR) on the human cell surface and
CbpA on the pneumococcus. Hyaluronate lyase released by the bacteria also has been
(A) Brain
shown tooedema.
degrade the extracellular matrix of connective tissues and allow greater
infiltration.
Once it has gained access to 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, capsule
provides protection from the attacks of complement and the production of antibodies.
Pneumococcal surface proteins (Psp) A and C also perform sheltering functions against the
binding of c3b and the membrane attack complex. Production of the toxin Pneumolysin,
further inhibits the complement response by binding to the fc region of IGg, and generating
a false classic pathway response.
 
Pneumococcal meningitis typically requires a high bacterial load in the bloodstream prior
to CNS infiltration. 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, which binds to phosphorylcholine in the bacterial cell wall.
When 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.
 
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). It
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
neurocognitive disturbances, altered mental status and seizures typical of CNS
inflammation. Thus its rarity and lack of good diagnostic techniques, makes early
identification of CNS tuberculosis daunting problem.
Mycobacterium tuberculosis (MTB) first infects the human host through inhalation of
respiratory droplets from an individual with an active TB infection. MTB is a facultative
intercellular pathogen that preferentially infects the alveolar macrophages through a
variety of receptors inducing phagocytosis. Once inside, M. tuberculosis’s hydrophobic
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, and
occasionally colonize areas such as the CNS.
It has been speculated that MTB migrates through protective epithelial cells
independently, or within infected macrophages; however, recent research on animal
models has indicated 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.
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,
the caudal of TNF-α, leads to inflammation and increased permeability of the BB
barrier showing
and the rapid recruitment of destructive peripheral immune cells, classically
forming
disruptive tubercular granulomas throughout different areas of the CNS
and reactive
areas expanded 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