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Transcript
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