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MMI 415 > Neurotropism > Flashcards

Neurotropism Flashcards

1
Q

what are three major concerns regarding neurological infections?

A
  1. the development of drug resistant viruses
  2. the increasing number of immunocompromised human populations
  3. the rising number of diseases previously considered rare (e.g. Zika virus)
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2
Q

what are two unique aspects of CNS infections?

A
  1. localization of the infection dictates the clinical presentation (CNS vs PNS)
  2. brain is an immunoprivileged organ – BBB protection + innate vs adaptive immunity
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3
Q

what are the 5 classifications of zoonotic diseases?

A
  • stage 1: animal only
  • stage 2: primary infection only (e.g. rabies)
  • stage 3: limited outbreak – from animals or few human cycles
  • stage 4: long outbreak – from animals or many human cycles
  • stage 5: exlusive human agent
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4
Q

what are five determinants of emerging infections?

A
  1. susceptible populations: poverty, war, famine, immunosuppression
  2. altered human and animal contact
  3. disrupted environemnts: climate change and economic developments
  4. medical practices
  5. rapid and frequent global movement of animals and humans
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5
Q

Name and briefly describe 5 neurological infectious syndromes

A
  1. meningitis: nuchal rigidiity + cranial neuropathies
  2. encephalitis: fever, confusion/altered state –> coma, seizure, focal signs
  3. myelitis: limb weakness, back pain, sensory loss
  4. absecess: focal signs, fever, seizure
  5. radiculopathy/neuropathy: localized radicular pain, fever, weakness
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6
Q

what protects CNS cells vs PNS cells?

A
  • CNS: BBB
  • PNS: blood-nerve barrier
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7
Q

what is the difference between systemic capillaries vs CNS capillaries (BBB)?

A

systemic

  • few mito
  • fenestra

BBB

  • many mito
  • tight junctions
  • astrocytes
  • microglia
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8
Q

what is the most abundant cell in the brain?

A

astrocytes

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9
Q

what is the role of oligodendrocytes?

A

essential for CNS myelin formation

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10
Q

which cell in the brain is the key player in brain inflammation? describe its normal vs activated state

A

microglia

normal

  • immune sensors

activated

  • phagocytosis
  • chemotaxis
  • Ag presentation
  • cytotoxicity
  • morphological changes
  • proliferation
  • respiratory burst
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11
Q

which cells are permissive to HIV?

A

CD4+ T cells and macrophages

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12
Q

name three aspects of neuroHIV

A
  1. opportunistic infections
  2. ART-associated disorders
  3. primary HIV neurological symptoms (e.g. HAND)
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13
Q

does ART (antiretroviral therapy) affect HIV in the brain?

A

no – brain viral RNA, DNA, and integrated DNA were present in all HIV-infected person and realtively unaffected by ART exposure despite suppression of plasma viral loads

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14
Q

what does HAND stand for? what are some aspects of this?

A

HAND = HIV-associated neurocognitive disorder

  • memory loss
  • neuropsychiatiric dysfunction
  • immuno deficiency
  • motor abnormalities
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15
Q

what is seen in neuroimages of HAND patients?

A

brain atrophy/white matter inflammation

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16
Q

what is a potential biomarker for HAND/HIV neurovirulence?

A

MAN1B1

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17
Q

what is the hallmark of HIV disease progression and HAND?

A

chronic immune activation

18
Q

what virus causes PML?

A

JCV - a ubiquitous virus in adult populations

19
Q

how does JCV get into the brain?

A

genome undergoes rearrangment in PML

20
Q

what are the typical presentations of PML?

A
  • progressive focal neurological deficits over days to weeks to months
  • aphasia, apraxia, and cerebellar signs
  • mean survival: 6 months
  • mortality in pre-cART era: 100%
21
Q

describe the mri progression of PML

A
  • typically no enhancement or edema
  • mottled or ground glass appearance
  • spares the cortex
22
Q

describe three pathologies of PML

A
  1. sparing of coretx
  2. giant astrocytes
  3. JCV infection of astrocytes and oligodendrocytes
23
Q

what is the treatment of PML?

A
  • no proven antiviral treatment
  • restore immune function: ART for HIV pts, stop chemotherapuetic drugs in cancer/transplant patients, plasmapheresis of natalizumab in MS pts (controversial), immune enhancement drugs (e.g. checkpoint inhibitors)
24
Q

how did pembrolizumab (a checkpoint inhibitor) work in patients with PML?

A
  • five patients had clinical improvements/stabilization of PML: reduction in lesion size and decreased JCV load
  • three showed no improvement
25
Q

name 3 new approaches to treat PML

A
  • immunotherapy: checkpoint inhibitors, cell based therapy
  • antivirals: antisense oligonucleotides
26
Q

do human coronaviruses infect the brain and cause neurological disease?

A

yes

27
Q

what are 4 symptoms of long covid and what do these symptoms resemble?

A
  1. brain fog
  2. shortness of breath
  3. heart arrhythmia
  4. hypertension

resemble chronic fatigue syndrome

28
Q

what are some possible mechanisms of neurological disorders in COVID-19?

A
  • viral neuroinvasion
  • CNS endothelial damage
  • neuroinflammation
  • systemic inflammation
  • autoimmunity
29
Q

what viruses are known to cause encephalitis in humans?

A

flaviviruses (e.g. WNV, JEV, Dengue, ZIKV)

30
Q

what is the possible causitive virus of leukoencephalitis patients 1 and 2

A

HPgV-1

31
Q

describe the general characteristics of human pegivirus (HPgV)

A
  • (+)ssRNA virus
  • flaviviridae family
  • prevalence is 1-5% in human income countries and 20% in LMICs
  • antibodies against HPgV E2 protein are generated when clearing infection
  • associated with developement of lymphoma/leukemia
  • potential transmission routes: vertical and horizontal routes
32
Q

what are three neuropathologies associated with HPgV

A
  1. infiltration CD8+ T cells (e.g CTLs) evident throughout the brain in LE-1
  2. abundant CD68+ macrophages in LE-1/2
  3. disrupted APP immunoreactivity in white matter of LE-1
33
Q

what are the characterisitics of HPgV with an NS2 deletion?

A
  • found in the brain
  • replicates efficiently in astrocytes

has potential for neuroadaptation and neurovirulence

34
Q

What therapy reduces HPgV viremia in HIV/HCV co-infected patients?

A

direct acting antiviruals (DAA) therapy for HCV

35
Q

What is MS? what is it characterized by? who’s most at risk?

A
  • many scars: an inflammatory demyelinating disease of the CNS
  • characterized by progressive loss of vision, weakness, clumsiness, sensory changes or mental difficulties
  • 3:1 predominance in women
36
Q

what are the possible causes of MS?

A
  • adaptive and innate immune factors
  • genetic susceptibility (MHC domain on chr 6)
  • infections (EBV, HHV6, HERV, mycoplasma)
  • environment (vit D, tobacco, latitude dependence)
37
Q

what is the initial pathology of MS driven by?

A

myelin-reactive T cells penetrating CNS

38
Q

what is the epidemology of EBV?

A

ubiquitous virus, >90% adults in NA

39
Q

does EBV cause MS?

A
  • one study: EBV seropositivity increased risk of developing MS 32-fold
  • one study: increased EBV IgG in CSF of MS patients compared to controls
  • several PCR studies in serum and CSF generally no difference between MS and controls
  • some studies show EBV proteins and DNA at greater frequency in MS lesions than non-MS patients – results have not been replicated
40
Q

how might EBV contribute to MS?

A
  • reverse causation: preclinical immune dysregulation increases risk of EBV
  • immortalization of autoreactive B cells
  • persistant infections –> inflammation and neurodegeneration
  • molecular mimicry: EBV ags may lead to production of cross-reactive Abs and lymphocytes

MMI 415 (13 decks)

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