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 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.

Streptococcus pneumoniae: Bacterial MeningitisStreptococcus 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, 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. Hyaluronatelyase released by the bacteria also has been Major CNS complications secondary to acute bacterial meningitis. (A) Braindegrade the extracellular matrix of connective tissues and allow greater shown to oedema. (B) Hydrocephalus. (C) Cerebral vasculitis with multiple cerebral infarctions. (D) infiltration.Sinus thrombosis with venous infarction and mild cerebral haemorrhage (black arrow).

Pathogenic Infections of the CNSJesse Wackerbarth

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 immunedeficient, 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.

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 plateletactivating 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.

Cerebral Malaria: Plasmodium falciparumCerebral 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 preferentially infect red blood cells and cause the characteristic fever and chills. Malaria is an Section of brain showing blood vessels 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 Eselectin. 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- , 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.

Mycobacterium tuberculosis: CNS TuberculosisMycobacterium 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 cell wall and other virulence hijack the phagosome and proliferate 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, 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.

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. .

Intact erythrocytes surrounding a capillary in the cerebral cortex. Endothelial cell layer appears to have disintegrated (arrow)

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 Murine model of CNS tuberculosis. (A) Coronary section at the level of the caudal of TNF- , leads to inflammation and increased permeability of the BB barrier and the diencephalon, with multifocal nonsuppurative encephalitis. (B) Cornuammonisrapid recruitment of destructive peripheral immune cells, classically forming showing mild perivascular lymphocytic and histiocytic infiltration, with microgliosis disruptive tubercular granulomas throughout different areas of the CNS infection. The and reactive astroglia. (C) Dorsal third ventricle, choroid plexus, and subependymal immune response against intercellular pathogens and with recruited lymphocytes is areas expanded by lymphocytic, plasmacytic, and histiocytic infiltration, with exceptionally destructive and feeds back to an even greater inflammatory response. subependymalmicrogliosis and reactive astroglia. Depending on the area of entry MTB can cause either encephalitis or meningitis, and can Semi-thin section of capillary in brainstem. Enlarged perivascular space (*) containing leukocytes in close even form brain abscesses all of these life-threatening conditions contribute the severe vicinity to the vessel. Lymphocytes (arrows) and monocyte (arrowhead) sequestered to the endothelial wall. neurological symptoms and the high mortality of the infection.