Neurotropism Flashcards
what are three major concerns regarding neurological infections?
- the development of drug resistant viruses
- the increasing number of immunocompromised human populations
- the rising number of diseases previously considered rare (e.g. Zika virus)
what are two unique aspects of CNS infections?
- localization of the infection dictates the clinical presentation (CNS vs PNS)
- brain is an immunoprivileged organ – BBB protection + innate vs adaptive immunity
what are the 5 classifications of zoonotic diseases?
- 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
what are five determinants of emerging infections?
- susceptible populations: poverty, war, famine, immunosuppression
- altered human and animal contact
- disrupted environemnts: climate change and economic developments
- medical practices
- rapid and frequent global movement of animals and humans
Name and briefly describe 5 neurological infectious syndromes
- meningitis: nuchal rigidiity + cranial neuropathies
- encephalitis: fever, confusion/altered state –> coma, seizure, focal signs
- myelitis: limb weakness, back pain, sensory loss
- absecess: focal signs, fever, seizure
- radiculopathy/neuropathy: localized radicular pain, fever, weakness
what protects CNS cells vs PNS cells?
- CNS: BBB
- PNS: blood-nerve barrier
what is the difference between systemic capillaries vs CNS capillaries (BBB)?
systemic
- few mito
- fenestra
BBB
- many mito
- tight junctions
- astrocytes
- microglia
what is the most abundant cell in the brain?
astrocytes
what is the role of oligodendrocytes?
essential for CNS myelin formation
which cell in the brain is the key player in brain inflammation? describe its normal vs activated state
microglia
normal
- immune sensors
activated
- phagocytosis
- chemotaxis
- Ag presentation
- cytotoxicity
- morphological changes
- proliferation
- respiratory burst
which cells are permissive to HIV?
CD4+ T cells and macrophages
name three aspects of neuroHIV
- opportunistic infections
- ART-associated disorders
- primary HIV neurological symptoms (e.g. HAND)
does ART (antiretroviral therapy) affect HIV in the brain?
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
what does HAND stand for? what are some aspects of this?
HAND = HIV-associated neurocognitive disorder
- memory loss
- neuropsychiatiric dysfunction
- immuno deficiency
- motor abnormalities
what is seen in neuroimages of HAND patients?
brain atrophy/white matter inflammation
what is a potential biomarker for HAND/HIV neurovirulence?
MAN1B1
what is the hallmark of HIV disease progression and HAND?
chronic immune activation
what virus causes PML?
JCV - a ubiquitous virus in adult populations
how does JCV get into the brain?
genome undergoes rearrangment in PML
what are the typical presentations of PML?
- 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%
describe the mri progression of PML
- typically no enhancement or edema
- mottled or ground glass appearance
- spares the cortex
describe three pathologies of PML
- sparing of coretx
- giant astrocytes
- JCV infection of astrocytes and oligodendrocytes
what is the treatment of PML?
- 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)
how did pembrolizumab (a checkpoint inhibitor) work in patients with PML?
- five patients had clinical improvements/stabilization of PML: reduction in lesion size and decreased JCV load
- three showed no improvement
name 3 new approaches to treat PML
- immunotherapy: checkpoint inhibitors, cell based therapy
- antivirals: antisense oligonucleotides
do human coronaviruses infect the brain and cause neurological disease?
yes
what are 4 symptoms of long covid and what do these symptoms resemble?
- brain fog
- shortness of breath
- heart arrhythmia
- hypertension
resemble chronic fatigue syndrome
what are some possible mechanisms of neurological disorders in COVID-19?
- viral neuroinvasion
- CNS endothelial damage
- neuroinflammation
- systemic inflammation
- autoimmunity
what viruses are known to cause encephalitis in humans?
flaviviruses (e.g. WNV, JEV, Dengue, ZIKV)
what is the possible causitive virus of leukoencephalitis patients 1 and 2
HPgV-1
describe the general characteristics of human pegivirus (HPgV)
- (+)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
what are three neuropathologies associated with HPgV
- infiltration CD8+ T cells (e.g CTLs) evident throughout the brain in LE-1
- abundant CD68+ macrophages in LE-1/2
- disrupted APP immunoreactivity in white matter of LE-1
what are the characterisitics of HPgV with an NS2 deletion?
- found in the brain
- replicates efficiently in astrocytes
has potential for neuroadaptation and neurovirulence
What therapy reduces HPgV viremia in HIV/HCV co-infected patients?
direct acting antiviruals (DAA) therapy for HCV
What is MS? what is it characterized by? who’s most at risk?
- 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
what are the possible causes of MS?
- adaptive and innate immune factors
- genetic susceptibility (MHC domain on chr 6)
- infections (EBV, HHV6, HERV, mycoplasma)
- environment (vit D, tobacco, latitude dependence)
what is the initial pathology of MS driven by?
myelin-reactive T cells penetrating CNS
what is the epidemology of EBV?
ubiquitous virus, >90% adults in NA
does EBV cause MS?
- 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
how might EBV contribute to MS?
- 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
