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Viral infections of the CNS 2 Chronic infections Ikuo Tsunoda, MD, PhD MPID 5 (Micro #289 Pathogenesis of Infectious Diseases II) March 16, 2016 [email protected] LSUHSC-S Medical Library E-Book http://lib-sh.lsuhsc.edu/ebooks/ebooks.php • Virology – Knipe.Fields' virology 6th edition (2013) – Collier.Human virology: a text for students of medicine, dentistry, and microbiology 4th edition (2011) – King.Virus taxonomy: ninth report of the International Committee on Taxonomy of Viruses (2011) Textbook Human virology-4th edition (2011) Oxford University Press Part 3 - Special syndromes 30 Viral diseases of the central nervous system 1 Acute infections (Group 1) 2 Acute postexposure syndromes (Group 2) 3 Chronic infections (Group 3) 4 Laboratory diagnosis Reminders / Further eading Virus diseases of the CNS: general classification Virus usually demonstrable in CNS Yes No Acute Group 1 Group 2 Chronic Group 3 •Group 1: Acute virus infections •Meningitis, poliomyelitis, encephalitis •Group 2: Postinfection and postimmunization encephalomyelitis •ADEM •Guillain-Barré syndrome in the peripheral nervous system •Group 3: Chronic infections Tissue injury in virus infection • Direct virus infection damages tissues: Viral pathology • Acute, group 1 • Chronic, group 3 • Anti-viral immune responses damage tissues; Immunopathology • Acute, group 2 • Chronic, group 3 Group 3 Chronic CNS virus infections © L. Collier and J. Oxford, 2006 Table 30.4 Virus diseases of the central nervous system. Group 3: chronic infections (all rare) Viruses Predominant neurological lesions Subacute sclerosing panencephalitis (SSPE) Measles, rubella Neuronal degeneration, demyelination, microglial proliferation Progressive multifocal leucoencephalopathy (PML) Multiple foci of demyelination in Papovaviruses (JC, brain; hyperplasia of Infection of very rarely SV40) oligodendroglia and Bizarre-looking astrocytes Syndrome Creutzfeldt-Jakob disease (CJD), scrapie, kuru, and other spongiform encephalopathies Prions Spongiform degeneration and atrophy of brain and anterior horn cells; astrocytosis Human Virology – 4th Ed. (2011) ADEM, demyelination; MIBE; inclusion body and viral antigen ADEM, acute disseminated encephalomyelitis MIBE; measles inclusion body encephalitis Acute Subacute Chronic SSPE, subacute sclerosing panencephalitis •Occurs years or decades after an initial measles infection •0.4 to 9.7 per million patients with measles •Mutations in the M protein •Clonal expansion of the mutated virus within the brain •M protein is not produced, no budding •Cell fusion by the F and H proteins is maintained, allowing the virus to spread within the brain by local cell fusion; gliosis [´´ + osis, condition]: virus evades the immune system, anti-virus antibodies proliferation of astrocytes= scar in other than M protein the CNS. Brain atrophy, gliosis and mononuclear cell infiltration, and rarefied and gliotic white matter A pediatric patient with progressively developing degenerative neurologic disease/disorder has an elevated CSF antibody titer to measles virus. You should suspect which of the following? (A) Acute Lyme disease (B) Fifth disease (C) Possible hepatitis B infection (D) Possible subacute sclerosing panencephalitis (SSPE) (E) Susceptibility to chicken pox Answer (D) Progressive rubella panencephalitis • Very rare encephalitis presents several years after the initial, usually congenital, rubella infection • Ages between 8 and 20 with insidious dementia and ataxia, slowly progressive • Rubella virus isolated from brain in only one case • High antiviral antibody • Anti-viral T cells react against myelin antigen by molecular mimicry between viral and host epitopes? • Inflammation, neuronal loss, demyelination, gliosis • Cerebellum atrophy Cuffing: A perivascular accumulation of various leukocytes seen in infectious, inflammatory, or autoimmune diseases. Perivascular infiltrate (cuffing) Molecular mimicry • • • • Molecular mimicry occurs when a microorganism and its host share an immunological epitope (Fujinami and Oldstone, 1985) Infection with a virus having molecular mimicry with a self epitope could lead to an autoimmune response Cross-reacting antibodies and T cells can react with conformational as well as linear epitopes Antibody against Campylobacter cross react with gangliosides leads to an axonal form of Guillain-Barré syndrome Progressive multifocal leukoencephalopathy (PML) • JC virus, the genus Polyomavirus – Early report of PML due to SV40 infection probably reflected confusion of SV40 with JC virus, SV40 causes PML in monkey • 35 - 80% of healthy adults have JC virus antibodies • Incidence has risen during the AIDS epidemic; 90% associated with HIV infection, 2% AIDS patients died had PML • Paralysis, mental deterioration, visual loss; multifocal • Immunocompromised hosts: AIDS, immunosuppression therapy (e.g. for autoimmune diseases or for organ transplantation), anti-VLA-4 antibody treatment • Progressive fatal, death in 3-6 months. Pharmacotherapies that reverse immunosuppression are effective • Demyelination with only scanty lymphocytes • Infected oligodendrocytes with enlarged nuclei • Bizarre-looking astrocytes (astrocyte infection is rare) Oligodendrocytes with enlarged nuclei Multiple lesions in the white matter Bizarre-looking astrocytes Viral antigens in oligodendrocytes Demyelination Bizzare astrocytes Oligodendrocytes Anti-VLA-4 antibody treatment and PML in patients with multiple sclerosis (MS) • Natalizumab is an antibody against the α chain of α4β1integrin (adhesion molecule VLA-4, very late antigen) • Interaction between VLA-4 on T cells and VCAM-1 (vascular cell adhesion molecule-1) on endothelium is important for CNS T cell entry • VLA-4 antibody treatment is effective in MS • 1 in 1000 patients treated with natalizumab develop PML • Natalizumab blocks virus-specific T cell entry into the CNS? Monoclonal antibody nomenclature • -mab: monoclonal antibody • Sub-stems indicate species -zu-: humanized -o-: mouse -u-: human -xi-: chimeric • Sub-stems indicate disease/target -li-: immunomodulatory -tu-: tumor WHO Drug Information, 23, 195, 2009 A 58-year-old man receiving immunosuppressive therapy after undergoing a kidney transplant begins to suffer from multifocal neurologic symptoms, including memory loss, difficulty speaking, coordination problems, and loss of some use of his right arm. PCR analysis of a CSF sample is performed using viral sequences from simian virus 40 (SV40). The results indicate the presence of a related virus. Which virus is the MOST likely the cause of this man's condition? (A) Echovirus 11 (B) Human T-lymphotropic virus type 1 (C) Measles virus (D) Western equine encephalitis virus (E) JC virus Answer (E) Human immunodeficiency virus (HIV) infection • Neurologic dysfunction develops in 60% of AIDS patients • Neurologic manifestations may be due to direct effects of the virus, opportunistic infections, or primary CNS lymphoma – Patients on highly active antiretroviral therapy (HAART) are much less likely develop opportunistic CNS infections – Cryptococcal meningitis, toxoplasma encephalitis, CMV, VZV, and JC viruses • Aseptic meningitis is a common manifestation of primary infection • AIDS dementia complex Chronic CNS infections • Vacuolar myelopathy AIDS dementia complex (ADC) HIV-associated dementia complex • Subcortical dementia; Forgetfulness, inability to concentrate, apathy, mild confusion, irritability, ataxia, leg weakness, and tremor – Degeneration in the subcortical structures; excessive delay in the performance of intellectual tasks • Most survive less than 1 year • Pathological findings; HIV encephalitis (not all ADC) – Perivascular inflammation, microglial nodule – multinucleated giant cells; monocyte / macrophage lineage cell fusion – Virus infection in mononucleated and multinucleated macrophages “cortical” signs: aphasia, apraxia, visual field deficits HIV encephalitis (c) Perivascular mononuclear cell infiltrate and multinucleated giant cell (f) HIV-infected mononucleated and multinucleated macrophages Vacuolar myelopathy • 5 to 30% of AIDS patients • Leg weakness, spastic paralysis, sensory ataxia, incontinence • Vacuolation of spinal cord white matter in the posterior and lateral funiculi • Macrophages, myelin breakdown, axonal degeneration Normal spinal cord HTLV-I associated myelopathy (HAM) Tropical spastic paraparesis (TSP) • Caused by the human retrovirus, human T-cell lymphotropic virus type I (HTLV-I) • HTLV-1 is endemic in southern Japan, the Caribbean, Africa, and South America – A cause of adult T-cell leukemia (ATL) • 0.25% infected people develop HAM/TSP • Infect CD4+ T cells • Transmission through breast milk, sexual intercourse, blood transfusion, contaminated needle • Slowly progressive spastic weakness of the lower limbs, sensory disturbances, sphincter disturbances • Perivascular inflammation and microglial nodules • Immune-mediated disease? HAM / TSP (a) Lateral and anteior fuiculus myelin loss (d) T cell infiltration Normal spinal cord Group 2 Postinfectious demyelinating diseases Neuroimmunology • Brain as an ‘immunologically privileged’ site • Lack of conventional lymphatic system – (Drain into the deep cervical lymph node) • Presence of the blood-brain barrier – Activated T cells can enter the CNS – Circulating antibody cannot enter the CNS • Lack of constitutive expression of major histocompatibility complex (MHC) MHC expression and antigen presentation in the CNS • CD4+ and CD8+ T cells recognize antigen presented by MHC class II and I, respectively • Neurons do not express MHC class I or II – Neurons cannot be targets of T cell attack • Astrocytes do not express class I or II, but both class I and II antigens can be induced by interferon (IFN)-γ. Antigen presentation? • Oligodendrocytes do not express MHC, but only class I can be induced by IFN-γ • Activated, not resting, microglia express both class I and II Brain has been proposed as an “immunologically privileged” site.” Which of the following statements is NOT true? (A) Neurons can be targets of T cell attack when MHC molecules on neurons are induced by interferon-γ (B) Activated T cells can enter the central nervous system (CNS) (C) The CNS lacks the conventional lymphatic system. (D) Circulating antibody cannot enter the CNS because of the presence of the blood-brain barrier. (E) All major neuronal cells in the brain do not express major histocompatibility complex (MHC) class I or II, unless they are activated. Answer (A) Guillain-Barré syndrome • Harrison's Online Featuring the complete contents of Harrison's Principles of Internal Medicine, 18e Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Josep Loscalzo, Eds. • LSUHSC-S medical Library E-book http://www.accessmedicine.com/content.aspx?aID=2907354&searchStr=guillainbarre+syndrome Guillain-Barré syndrome (GBS) • Acute inflammatory demyelinating or axonal neuropathy in the peripheral nervous system (PNS) • In the US and Canada, 1 case per million per month or 3500 cases per year • Rapidly evolving motor paralysis • The legs are usually more affected than the arms • 30% require ventilatory assistance at some time during the illness • 70% of cases of GBS occur 1 - 3 weeks after an acute infectious process, usually respiratory or gastrointestinal • Campylobacter jejuni, human herpes virus, Cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae • Influenza vaccine – controversial • Old-type rabies vaccine • Anti-microbial immune responses that misdirect to host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism? S Schwann cell = myelin forming cell in the PNS Postulated immunopathogenesis of GBS associated with C. jejuni infection. B cells recognize glycoconjugates on C. jejuni (Cj) (triangles) that cross-react with ganglioside present on Schwann cell surface and subjacent peripheral nerve myelin. Some B cells, activated via a T cell–independent mechanism, secrete primarily IgM (not shown). Other B cells (upper left side) are activated via a partially T cell–dependent route and secrete primarily IgG; T cell help is provided by CD4 cells activated locally by fragments of Cj proteins that are presented on the surface of antigen-presenting cells (APC). A critical event in the development of GBS is the escape of activated B cells from Peyer's patches into regional lymph nodes. Activated T cells probably also function to assist in opening of the blood-nerve barrier, facilitating penetration of pathogenic autoantibodies. The earliest changes in myelin (right) consist of edema between myelin lamellae and vesicular disruption (shown as circular blebs) of the outermost myelin layers. These effects are associated with activation of the C5b-C9 membrane attack complex and probably mediated by calcium entry; it is possible that the macrophage cytokine tumor necrosis factor (TNF) also participates in myelin damage. B, B cell; MHC II, class II major histocompatibility complex molecule; TCR, T cell receptor; A, axon; S, Schwann cell. • Experimental autoimmune neuritis (EAN) is an autoimmne disease that can be induced by the inoculation with PNS antigens and adjuvant • EAN, post vaccine polyneuritis, and GBS are similar Wallerian degeneration = Axonal degeneration PNS: Peripheral nervous system C) This important information was somehow deleted from 2013-2014 statement “Barré” not “Barre” 36,000 people die by flu per year in the US (20092010 CDC statement) http://www.cdc.gov/flu/abou t/disease/us_flurelated_deaths.htm This information was included in 2009-2013 (but not in 2013-2014, 2015) CDC statement CIDP; chronic inflammatory demyelinating polyradiculoneuropathy There is a theory that influenza vaccines induce Guillain-Barré syndrome. Which of the following statements is NOT true? (A) In 1976, an influenza vaccine was associated with Guillain-Barré syndrome (GBS). Since then, flu vaccine has not been clearly linked to GBS. (B) On average, 226,000 people are hospitalized every year because of influenza and 36,000 die-mostly elderly. (C) The relative risk of developing GBS is considerably higher after the natural flu than after vaccination. (D) Anyone who has a history of GBS and is in higher risk groups, including the elderly and those with other serious illness, should not consider getting vaccinated. (E) A risk of GBS from current flu vaccines is much lower than the risk of severe influenza, which can be prevented by vaccination. Answer (D) Acute disseminated encephalomyelitis (ADEM) • ADEM has a monophasic course and is associated with antecedent immunization (postvaccinal encephalomyelitis) or infection (postinfectious encephalomyelitis) • Perivenular inflammation and demyelination • Fever, headache, paralysis, seizure, and lethargy progressing to coma may develop. • Postvaccinal encephalomyelitis; smallpox and certain rabies vaccines • Postinfectious encephalomyelitis; measles virus is the most common antecedent (1 in 1000 cases) • Cross-reactive immune response to the infectious agent or vaccine that triggers an inflammatory demyelinating response? Neuroimaging demonstrates multifocal signal abnormalities in subcortical white matter Perivascular demyelination (left) and axonal injury (right, beading) in ADEM Rabies post-vaccinal encephalitis and “human EAE” Neuroparalytic accidents complicating rabies vaccination Vaccines were prepared using formalin or phenol treated infected neural tissue from a variety of animal species Transverse myelitis and encephalitis of about 1 in 1600 to 1 in 200 Resemblance to experimental autoimmune encephalomyelitis (EAE) in animals Repeated injections of CNS tissues as “fresh cell therapy” induced a fetal coma with CNS lesions suggestive of ADEM Rabies post-vaccinal encephalomyelitis Human EAE. Injections of calf neural tissue as a treatment of Parkinson’s disease Perivenous lesions Myelin debris in macrophage Possible viral cause of multiple sclerosis (MS) • Apparent epidemics in the Faroe Islands, Denmark – No MS before 1943 – Prevalence in 1977, 34 per 100,000 – 1941 to 1949, British occupation; British military introduced MS? – 16 patients between 1943 to 1949 – Additional 16 patients between 1950 and 1973 – No cases between 1973 and 1981 Viruses and anti-viral antibodies in MS CSF: cerebrospinal fluid Viral models for MS Viral pathology Immunopathology Demyelinating antibody, DTH Determinant (epitope spreading) from viral to myelin antigen Target by anti-viral immunity: virus infected cells Innocent-bystander: myelin, oligodendrocyte Viral models for multiple sclerosis (MS) have been used to study the pathogenesis of MS. Which of the following viruses is NOT used for viral models for MS? (A) Mouse hepatitis virus (MHV) (B) Theiler’s murine encephalomyelitis virus (TMEV) (C) Semliki Forest virus (D) Canine distemper virus (E) West Nile virus Answer (E) Questions • Name at least four diseases caused by chronic CNS virus infections (2 point) – Answer: SSPE, PML, HIV encephalitis, HAM/TSP • Explain “Brain as an immunological privileged site,” using keywords, MHC, blood-brain barrier (3 points) • One of your friends consults you whether she should have a flu shot this year, since she believes that Microbiology-Immunology graduate students can give her advice. She had a history of GuillainBarré syndrome caused by Campylobacter jejuni, about 10 years ago. In the past 5 years, she had several flu shots without adverse effects. Advise her using keywords molecular mimicry, and monophasic (5 points) Table 30.5. Methods for detecting markers of viral infection within the central nervous system Marker Specimen Test Specific antibody generated within the CNS Serum/CSF Antibody - protein ratios Characteristic inclusion bodies Brain biopsy Light microscopy Replicating virus Brain biopsy, CSF Virus isolation PCR Viral antigen Brain biopsy Immunofluorescence Viral nucleic acid Brain biopsy Nucleic acid hybridization, PCR Histological changes Brain biopsy Cytology, protein, sugar (not specific) CSF Light microscopy (not specific) Microscopy, biochemical tests © L. Collier and J. Oxford, 2011