IHO Virology EBV Case Flashcards
What is the genomic organization, envelope?, HHV #, Capsid Symmetry and Tropism of EBV?
dsDNA Yes, envelope HHV-4 Icosahedral Tropism: Lytic cycle in epithelial cells of oropharynx. Latent infections in B cells.
What malignancies are associated with EBV?
- Nasopharyngeal carcinoma
- Burkitt lymphoma
- Hodgkin disease
- Non-hodgkin lymphoma
- X-linked lymphoproliferative disease
What do B cells do in response to EBV infection?
- Proliferate to fight it off.
- Only B cells w/affinity for a specific antigen will undergo clonal expansion
- B cells are primed to want to proliferate!
How does EBV establish an infection?
- First it infects epithelial cells of the oropharynx.
- This is a lytic infection that kills the host cell and produces new infectious EBV particles.
- When these particles infect a B cell, a different pattern of gene expression produces a latent infection.
- Then, in the B cell infectious particles are not produced, but proliferation of infected B cells is increased.
- -Circular EBV genome gets tethered to host genes
What happens with B cells in a normal infection vs. an EBV infection?
Normal: monoclonal expansion of B cells
EBV: polyclonal expansion of B cells (all B cells proliferate!)
-Heterophile antibodies are produced that love/bind to a lot of things)
How does EBV establish infection within the B cell?
- The viral envelope proteins p350/220 bind the C3d complement receptor (a.k.a. CD21); this initiates endocytosis
- The genome circularizes, and immediate early genes, and late genes are expressed in sequence.
- Viral particle then buds through cellular membranes to make infectious particles
What’s unique about the EBV genome?
- Circular and has multiple promoters
- Different patterns of gene expression occur during lytic and latent infection
What three genes should you know about with EBV?
- EBNA3C
- LMP-2
- LMP-1
How does LMP-1 function?
- Acts as a constitutively active CD40.
- The signal it sends out is the same as if CD40 was binding CD40L but this is not happening
- CD40 is normally responsible for CD4+ T-cell dependent activation of B cells
What does LMP-1 activate?
- NF-kB transcription factors
- Promotes transcription of NF-kB regulated genes
- It only causes downstream signal function –> NFkB activation which then promotes proliferation
How does LMP-2 function?
- Functions as a constitutively active B cell receptor (even though an active BCR is not present)
- Normally, the BCR is responsible for antigen dependent B cell activation
What does LMP-2 activate?
- Fos/jun (et al) transcription factors
- It promotes MAPK activation (regulator of apoptosis and proliferation)
How does EBNA3C function?
It binds and activates cyclin D1 complexes, resulting in:
- Hyper-phosphorylation of retinoblastoma protein (Rb)
- De-repression (i.e. activation) of E2F family transcription factors
- Expression of genes that control DNA replication
- Cell cycle progression
What illnesses can cause similar symptoms to EBV mono?
CMV, HHV-6, HHV-7
What is the “classic triad” of symptoms associated with infectious mononucleosis (IM)?
- Pharyngitis
- Lymphadenopathy
- Fever
How do you diagnose mono and how does this test work?
- Monospot test - diagnostic for EBV IM.
- It detects heterophile antibodies produced by polyclonal expansion of B cells
How can you detect if the patient has acute or previous infection with mono?
Presence of VCA-IgM in blood = acute infection
Presence of VCA-IgG in blood = previous infection
How do you diagnose EBV with a blood smear?
-Atypical lymphocytes (or Downey cells)
How does X-linked lymphoproliferative disease present?
(a. k.a Duncan disease)
1. Fuliminant infectious mononucleosis (FIM)
2. Median age for FIM is 3 years old; average survival after FIM is 1-2 months
3. Patients who survive FIM develop lymphoproliferative disorders and dysgammaglobulinemias
What does X-linked mean?
Mothers will be carriers who give it to their sons who will have the disease.
What is the molecular basis for X-linked lymphoproliferative disease?
-A mutation that results in a non-functional SAP (SLAM (aka CD150) associated protein)
What is the significance of SAP?
- SAP is a protein that normally turns off the signal when an infection is beat down
- So, if you have a loss/mutation of SAP protein, you get X-linked lymphoproliferative disorder when you’re first exposed to EBV.
What does SAP do molecularly?
- It binds phosphorylated tyrosine on SLAM (CD150)
- SAP acts as an adapter protein and recruits kinases to the immunological synapse
- SAP depletion results in deficiency of IL-4 production by T cells
- IL-4 normally signals CD4H2 differentiation and regulates e.g. B cell class switching
How does SAP stop the immune response when a path open is gone?
- It controls apoptotic cell death of activated T cells.
- In XLP, SAP is absent, and the immune response has ‘no brakes’
- Not clear why this disorder is specific to EBV
What is p53?
Tumor suppressor
- Acts like a “brake”
- If it becomes non-functional, it promotes cancer
What is cyclin D?
-It acts as a proto-oncogene, if over-expressed, it promotes cell growth & proliferation of cancer
