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Questions and Answers
Which site is NOT associated with latency for HSV-1 infection?
What is a consequence of the immune response during HSV encephalitis?
Which of the following is primarily associated with the mechanism of viral entry in HSV-1 infection?
In what percentage of HSV encephalitis cases are anti-NMDAR antibodies observed?
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What potential mechanism is suggested for the production of anti-NMDAR antibodies in the context of HSV encephalitis?
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What type of cell infection does HSV-1 typically initiate after entering the host cell?
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Which of the following best describes the nature of HSV-1 meningoencephalitis?
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What is the primary characteristic of relapses in HSV encephalitis cases?
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Which type of immune cells are typically the first to respond in the case of CNS invasion during viral encephalitis?
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What is a common consequence of activation of Toll-like Receptors (TLRs) in microglial and astrocyte cells?
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Which cytokine is noted for its pro-inflammatory effects and is produced in response to microbial detection?
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Which of the following best describes the nature of brain lesions resulting from a primary infection?
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What is the role of matrix metalloproteinases (MMPs) in the context of CNS inflammation?
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Which chemokine is primarily involved in attracting migratory cells during inflammation in the CNS?
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In the context of bacterial encephalitis, what is one of the main triggers for the inflammatory response?
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Which complication is frequently associated with the clinical manifestations of encephalitis?
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Which viral infection is associated with the inflammation of the meninges and is known to cause meningoencephalitis?
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What defines the neurotropic mechanism of poliovirus in the central nervous system?
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Which type of encephalitis is characterized by demyelination and often involves astrocytes and oligodendrocytes infected by VZV?
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Which organism is commonly known to cause tuberculous meningoencephalitis?
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How does the entry of rabies virus typically occur in humans?
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Which immunocompromised condition is linked to an increased risk of multifocal encephalitis caused by VZV?
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What is a common pathological feature observed in severe cases of cerebral malaria caused by Plasmodium falciparum?
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Which cell type is primarily targeted during the CNS invasion by HIV in early contamination?
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What is the primary consequence of the immune response to the presence of Mycobacterium tuberculosis in the CNS?
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Which feature distinguishes enterovirus infections in the CNS from other viral infections?
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Which pathology is commonly associated with the autoimmune response from anti-NMDAR antibodies?
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Which of the following viruses relies primarily on neuronal cell receptors CD155 for its neurotropic effects?
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What is the role of endothelial cells in the context of VZV infection and vasculopathy?
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What mechanism allows Coxsackie virus to affect the central nervous system?
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Study Notes
HSV-1
- HSV-1 enters the body through reactivation of latent infection in the trigeminal ganglion or other areas of the central nervous system (CNS), direct neuroinvasion through olfactory sensory cells, or hematogenous spread during viremia.
- HSV-1 infection involves viral glycoproteins (gB, gC, gD, gH, GL) interacting with neuronal surface molecules (heparan sulfate, HVEM, nectin 1 & 2).
- HSV-1 is a DNA virus that invades the nucleus, replicates, and produces proteins.
- HSV-1 encephalitis causes panencephalitis (multiple cell type infection) leading to host cell lysis, viral spread, and an intense inflammatory response characterized by edema, necrosis, and detersion.
HSV Encephalitis and Auto-immunity
- Anti-NMDAR antibodies are present in the blood, cerebrospinal fluid (CSF), or both during the acute-subacute phase of HSV encephalitis in 30% of cases, but not during enterovirus (EV) or varicella zoster virus (VZV) encephalitis.
- Relapses of HSV encephalitis are often linked to the presence of anti-NMDAR antibodies, especially in children.
- The occurrence of anti-NMDAR antibodies could account for half of the cases of HSV encephalitis relapses.
- The mechanism of antibody production might involve molecular mimicry, antibody production secondary to neuronal lysis and antigen release, or recognition of pathogen-associated molecular patterns (PAMPs) by Toll-like receptors (TLRs) on microglial cells and astrocytes.
- Activation of TLRs leads to the production of nitric oxide (NO), interferon alpha and beta (IFN α and β), major histocompatibility complex (MHC) expression on microglia, perivascular macrophages and astrocytes, and cytokine and chemokine production by microglia and astrocytes.
Cytokines and Chemokines in HSV Encephalitis
- Cytokines, such as IL-1, IL-6, and TNF-alpha, are proinflammatory signals that target cells like cerebrovascular endothelial cells (CVE).
- Chemokines, like CCL2 (MCP-1), CCL3 (MIP-beta), CCL5 (RANTES), and CXCL10 (IP10), target migratory cells including mononuclear phagocytes and T lymphocytes.
- CVE cells produce intercellular adhesion molecules (ICAMs), vascular cell adhesion molecules (VCAMs), and matrix metalloproteinases (MMPs) which contribute to the entry of systemic immune cells through increased blood-brain barrier (BBB) permeability.
The Adaptive Immune System in HSV Encephalitis
- The adaptive immune system invades the CNS in response to cytokines and chemokines stimulation.
- Immune cell infiltration occurs in the following order: NK cells, antigen-specific CD8+ and CD4+ T cells, B cells, and monocytes and macrophages.
- Immune cell infiltration leads to meningeal and parenchymatous inflammation, aiming to clear the foreign microorganism.
Brain Lesions in HSV Encephalitis
- Primary lesions caused by infection vary based on the microorganism’s tropism and the extent of the inflammatory response.
- Destructive phagedenic processes can lead to abscess formation.
- Neuronal, oligodendrocyte, and astrocyte dysfunction or destruction occur.
- Gliosis, ependymal necrosis, infiltration of inflammatory cells, infectious granulomas, and vasculitis contribute to brain lesions.
Secondary Insults Leading to Brain Lesions in HSV Encephalitis
- Brain edema and compression of healthy structures can lead to herniation and microvasculature impairment.
- Hydrocephalus, infarction due to arterial or venous damage, and hypoxic anoxic damage are additional insults contributing to brain lesions.
Clinical Manifestations of Encephalitis
- CNS lesions give rise to common clinical manifestations of encephalitis, including headache, seizures, focal deficits (motor, sensory, cognitive), and decreased consciousness.
VZV Meningoencephalitis Pathophysiology
- VZV meningoencephalitis results from primary infection or reactivation of the virus.
- The pathophysiology involves meningeal inflammation, brain swelling, and parenchymal VZV infection.
- VZV encephalitis is characterized by focal vasculitis of various vessel sizes, involving endothelial and smooth muscle cells in the vessel walls.
- Immunosuppression, prevalent in the elderly, individuals with lymphoma or cancer, those taking immunosuppressant drugs, and AIDS patients, plays a critical role in worsening VZV infections.
VZV Vasculopathies
- VZV vasculopathies can lead to localized complications like zoster ophthalmicus and contralateral hemiplegia, particularly in individuals with multifocal infections, often associated with AIDS.
Demyelinating Meningoencephalitis
- VZV reactivation can lead to demyelinating meningoencephalitis upon infection of astrocytes, oligodendrocytes, ependymal cells, and endothelial cells.
- Ventriculitis, a condition characterized by inflammation of the ventricles of the brain, can also occur with VZV reactivation.
Enterovirus Polioencephalitis
- Enterovirus polioencephalitis, caused by RNA viruses like Enterovirus 70, 71, Poliovirus 1, 2, 3, Coxsackie A4, A7, and B3, and Echovirus 2, 9, 30, is characterized by gray matter (GM) involvement and sparing of white matter (WM).
- Inflammation, microglial nodules, and neuronophagia are typical pathological features of polioencephalitis caused by Enterovirus and Coxsackie viruses.
Routes of CNS Invasion in Enterovirus Polioencephalitis
- Enterovirus can enter the CNS via various pathways after fecal-oral transmission.
- These pathways include BBB crossing during viremia, Trojan horse mechanism (BBB crossing by EV-infected immune cells), and neuronal centripetal spreading from damaged muscle nerve terminals.
Specific CNS Neurotropism of Enteroviruses
- Poliovirus specifically binds to CD155 receptors on all neurons, including ganglionic sensory cells, astrocytes, and oligodendrocytes, targeting the pyramidal tract and spinal cord anterior horn.
- Enterovirus 71 binds to SCARB2 receptors on neurons and astrocytes, affecting basal ganglia, pyramidal systems, reticular formation.
- Coxsackie viruses bind to CAR receptors on neuronal progenitor cells and neurons, affecting the choroid plexus, neurogenic regions, hippocampus, and cortex.
Humoral Immunity Defect in Echovirus Encephalitis
- A defect in humoral immunity is associated with the development of Echovirus encephalitis.
Japanese Encephalitis (JE)
- Japanese encephalitis is an example of arbovirus encephalitis, transmitted through mosquito bites.
- JE involves hematogenous invasion and infection of meningeal, neuronal, and endothelial cells.
- JE causes polioencephalitis, affecting the brain and cerebellar cortex, basal ganglia, substantia nigra, thalamus, hippocampus, pons, medulla oblongata, and spinal cord anterior horn.
HIV Invasion of the CNS
- HIV can enter the CNS during the early stages of infection, leading to primary encephalitis and a resting virus state.
- During the full-blown AIDS stage, HIV invades the CNS through infected mononuclear phagocytes (Trojan horse mechanism) and direct invasion.
- Microglial cells and astrocytes are the primary targets of HIV infection within the CNS.
Neuropathology of HIV in the CNS
- Different forms of neuropathology associated with HIV infection include leukoencephalitis, polio-dystrophy due to host and viral toxic factors, and IRIS (immune reconstitution inflammatory syndrome) characterized by massive CD8 infiltration.
Rabies Infection
- Rabies infection typically occurs through a skin or muscle wound, most commonly from a dog bite.
- Rabies exhibits neurotropism, characterized by slow replication in muscle fibers.
- The virus enters the nervous system through the nicotinic receptor of the motor endplate.
- It travels retrogradely through axons to the spinal cord and subsequently spreads through cell-to-cell and transsynaptic pathways.
- The virus eventually infects brain neurons, leading to a caudal-rostral polioencephalitis.
- The virus disseminates centrifugally from the brain to innervated organs, such as skin, salivary glands, myocardium, and others.
Rabies Clinical Manifestations
- The clinical manifestations of rabies can be characterized as furious rabies or paralytic rabies.
Mycobacterium Tuberculosis CNS Infection
- Mycobacterium tuberculosis can infect the CNS through low-level bacteremia, invading the endothelial cells of microvessels.
- This leads to the formation of caseating vascular foci (Rich focus) located in the meninges or brain parenchyma.
- Release of MT and subsequent dissemination can result in meningitis, encephalitis, tuberculoma, and abscesses.
Tuberculous Meningoencephalitis
- Tuberculous meningoencephalitis features a dense gelatinous inflammatory exudate, most pronounced in the basal cisterns, due to the CSF flow pattern.
- The exudate also occurs around the spinal cord, surrounding nerves and arteries, leading to vasculitis.
- The meningeal exudate is composed of macrophages, lymphocytes, plasma cells, and fibrin, impeding CSF flow.
Listeria Monocytogenes CNS Infection
- Listeria monocytogenes can infect the CNS by hematogenous spread from the gut, leading to meningitis.
- It can also spread neurally, causing rhombencephalitis.
- Hematological dissemination of the bacteria can cause CNS infection through cranial nerves, with subsequent cell-to-cell and axonal spreading.
- The bacteria can enter the nervous system through the oral mucosa, travel through the trigeminal nerve, and reach the brainstem.
- Immunosuppression plays a role in the initial phase of Listeria monocytogenes infection in the CNS.
Cerebral Malaria
- Cerebral malaria, induced by Plasmodium falciparum infection, leads to global CNS dysfunction.
- Sequestration of parasitized red blood cells in the brain microvasculature causes significant engorgement of small vessels.
- Deposition of antigen-antibody (Ag-Ab) complexes, endothelial damage, and platelet aggregation contribute to edema, capillary necrosis, and perivascular hemorrhages.
- Necrotic blood vessels surrounded by hemorrhages form the characteristic Dürck granuloma.
- The cell-mediated immune response leads to severe parenchymal and meningeal inflammation in cerebral malaria.
Fungal CNS Infection
- Fungal CNS infection occurs through inhalation, skin wounds, or gut translocation.
- Invasion of the brain usually happens through hematogenous routes or directly from infected sinuses, air, or bone.
- Fungal CNS infection is often associated with immunosuppression.
- Common fungal species causing CNS infections include Cryptococcus neoformans, Candida sp., Histoplasma capsulatum, Blastomyces dermatidis, and Aspergillus sp.
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Description
Test your knowledge on HSV-1, including its transmission, infection mechanisms, and the impact of HSV encephalitis. Explore the role of anti-NMDAR antibodies and their relation to immunity during infection. This quiz covers crucial aspects of viral infections and neurological implications.
