M- Infectious Mono/ Mumps Flashcards
Describe the structure of the herpes virus family from out to in.
- envelope with large number of glycoproteins
- tegument- viral proteins and enzymes that initiate DNA replication and polymerase
- nucleocapsid- 162 capsomers (icosohedral)
- Core with dsDNA encoding 70-230 genes
What are the 3 major sets of genes the herpes virus encodes and whose expression is tightly regulated?
- immediate early- alter gene expression of host cell to allow preferential expression of viral genes
- early genes- TFs and other enzymes like DNApol
- late genes- structural proteins
Which is more likely to be a drug target for herpes viral replication, the DNA polymerase or RNA polymerase? Why?
DNA polymerase because it is a viral gene
The RNA polymerase is a cellular enzyme that has gained specificity for viral genes by the virally-encoded transcription factors
What are the 3 viruses in the alpha herpes family?
What is the tissue tropism and where is their cellular site of latency?
HHV1 HHV2 and varicella zoster virus.
They infect mucoepithelial cells in primary infection.
Latency - neurons
What are the 3 viruses in the beta herpes family?
What is the tissue tropism and where is their cellular site of latency?
HHV6, HHV7 and CMV (HHV5).
They infect monocytes, T cells and epithelial cells
Latency = monocytes and lymphocytes (which is why they resurface in immunocompromised)
What are the viruses in the gamma herpes family?
What is the tissue tropism and where is their cellular site of latency?
EBV (HHV4) and Kaposi’s sarcoma (HHV8)
They infect lymphocytes and epithelial cells
Latency = B cells
EBV is associated with what 2 presentations?
- febrile mononucleosis
2. Burkitt’s lymphoma
How is EBV transmitted?
What are the receptors for the virus?
It is transmitted through saliva and the primary receptors are CD21/CR2 which are the C3d complement receptors on B-cell and epithelial cells in the oropharynx.
Viruses also use MHCII on the B cells
When EBV infects epithelial cells in the oropharynx, how do they replicate?
They replicate lytically and then spread to B cells directly by contiguous spread or after viremia
How many B cells become infected by EBV as a result of viremia? What are the implications of this?
20% of B cells become infected.
The infection switches from lytic to latency where the virus replicates as an episome (extrachromosomal particle) in B cells.
In addition to latency, the B cell is immoratalized. Since 20% are infected this results in polyclonal B cell activation and transformation.
When EBV is in latency and has immortalized the B cell, what do B-cells secrete?
non-EBV related antibodies that incite an intense cytotoxic T-cell and NK-cell response. This kills the B cells, clears the infection and is responsible for the signs and symptoms of mono.
What causes the signs and symptoms of EBV mononucleosis?
T-cell and NK-cell response to the immortalized B-cells secreting antibodies.
They kill the B cells and clear the infection.
Why are antivirals ineffective at treating symptomatic EBV-related mono?
By the time symptoms show, there are little to no viruses in lytic phase (which is where antiviral drugs work to stop growth of actively replicating viruses)
What is the first test you do for EBV mono? What if this test is negative?
Do a monospot which shows heterophilic Ab due to polyclonal B cell activation.
If the monospot is negative, test for early antigens (EA) like polymerase and viral thymidine kinase.
What are the EBV antigens important for diagnostic purposes?
What phases of replication are they found?
- EA - polymerase and thymidine kinase which are expressed early in the lytic phase and are the site of action for antivirals
- Viral Capsid Antigens (VCA) - late structural genes for mature virion *only in lytic phase
- EBNA (nuclear antigens) to maintain latent infection (so if + dont know if its an old infection)
- Latent Membrane Proteins (LMP) - LMP1 has oncogenic potential bc it stimulates B cells through CD40 and LMP2 acts as a non-specific stimulus to proliferation
What is the clinical presentation of mononucleosis?
What is the incubation period?
What are the major symptoms?
When does it resolve?
Infection spread through saliva with a 15-45 day incubation period.
- Acute sore throat with fever
- exudative tonsillitis
- lymphadenopathy
- hepatosplenomegaly
Recovery is a week to a month but fatigue can last for several months
What do lab tests show for infectious mononucleosis?
- increased lymphocytes making them >50% of WBCs
- 10% are morphologically atypical (T cells)
- heterophile antibodies (+ monospot)
- IgM to EBV VCA
When are the two epidemiological peaks for infectious mononucleosis?
1st peak:
1/2 Us and UK children are affected before the age of 5 (less frequent in affluent households)
2nd peak:
late teens and early 20s (freshman year of college)
Why are most infected people not able to identify a sick contact in EBV mononucleosis infections?
The long incubation period and because the shedding of the virus after acute infection can last for a month
What are the acute complications of EBV-associated mononucleosis?
- upper airway obstruction - from large tonsils
- splenic rupture- from mild trauma which can cause massive internal bleeding
- aplastic anemia, granulocytopenia, hemolytic anemia, problems with Ig production
- myocarditis and conduction abnormalitites
- encephalitis, meningitis, myelitis
- X-linked immunoproliferative disorder (Duncan syndrome)
What is Duncan syndrome?
What is treatment?
X-linked immunoproliferative disorder due to a defect in SLAM (T-cell Signaling Lymphocyte Activation Molecule)
2/3 die acutely and the rest get Burkitt-like lymphoma
Treatment is bone marrow transplant
What is the most useful test for diagnosing EBV-associated mononucleosis?
Monospot- because EBV is a non-specific B-cell mitogen, it causes polyclonal secretion of Ab (IgM).
These Ab recognize antigen on sheep RBC (paul bunnell antigen) or antigen on horse, ox, bovine RBC.
Monospot tends to use formalin treated horse RBCs. Ab are present by week one of the infection and last for about a month past illness.
What is used to differentiate acute infection from chronic infection of EBV mono?
Specific anti-EBV antibodies
Which EBV antibodies are present in acute infection?
Which are present after the infection is done (convalescent)?
Acute: 1. VCA IgM 2. VCA IgG 3. Anti- EA Convalescent: 1. VCA IgG 2. Anti-EA 3. Anti-EBNA
What are the 5 differential diagnoses for EBV mononucleosis?
- False negative monospot
- CMV mononucleosis
- acute HIV - no mono on peripheral blood smear
- adenoviral pharyngitis- no mono on peripheral blood smear
- acute streptococcal pharyngitis- no mono on peripheral blood smear
What are the two types of Burkitt’s lymphoma?
Which is more associated with EBV?
- endemic- high malarial regions of Africa** more associated with EBV
- non-endemic
The tumor is poorly differentiated monoclonal B-cell lymphoma that usually has disfiguring masses on the face and jaw
In addition to mono, what 4 diseases has EBV been associated with?
- Burkitt’s lymphoma (endemic)
- nasopharyngeal carcinoma
- Hodgkin’s lymphoma, non-Hodgkin’s lymphoma with HIV, CNS lymphoma with AIDS
- post-transplant lymphoproliferative disorders (PTLD)
What region is most likely to have EBV caused nasopharyngeal carcinoma?
China and South and Southeast Asia- 100% of these tumors (which are epithelial in origin) are associated with EBV
What is the current hypothesis for the etiology of EBV being linked to PTLD?
It is most commonly associated with bone marrow transplants but can happen with solid organ transplants as well.
Immunosuppression inhibits immune surveillance which can lead to lymphoid cell proliferation.
What is the treatment for infectious mononucleosis?
- symptomatic treatment for fever and pain
- avoidance of abdominal trauma because of risk of rupture of the spleen
- for EBV-associated lymphoproliferative disorders, reduce the level of immunosuppression
- chemo for EBV-associated malignancies
**anti-retrovirals are ineffective because they work on the lytic phase and by the time people are symptomatic, barely any viruses are in the lytic phase
What is the difference between EBV and CMV latency?
What do they have in common?
EBV latency is in B-cells where they establish immortality.
CMV latency is in T-cells and macrophages where they do NOT immortalize the cell
They both require cell mediated immunity to clear acute infection and control latent infection.
How is CMV transmitted?
Contact with infected body fluids like saliva or large respiratory droplets (but also can be transmitted through blood, semen, across the placenta, and through transplant of organs)
What percent of adults are infected with CMV in the US and UK?
50-85% are seropositive by the age of 40.
Prevalence is higher in lower socioeconomic brackets, people in crowded conditions or in developing countries
Most CMV infections are asymptomatic, but if symptoms do occur, what is the most common presentation?
Infectious mononucleosis syndrome. Differentiate it from EBV with a monospot.
EBV + monospot
CMV - monospot
What percent of infectious mononucleosis cases are caused by CMV? How are these cases differentiated from EBV mono?
20% are CMV- differentiated from EBV mono by the Monospot test
In addition to mono, what else can CMV cause?
It can cause congenital infection (*it is the C in torch infections)
20% of seropositive women excrete CMV from the cervix, half the infants will be infected.
What are the characteristics of an infant with CMV infection?
When is the prognosis worse for the baby?
- SGA
- microcephaly
- deafness
- seizures
- MR
- thrombocytopenia
- hepatitis with jaundice
- hepatosplenomegaly
Prognosis is worse when the mother contracts primary CMV during the pregnancy
What is a CMV reactivation disease?
Who usually gets this?
What are the symptoms?
It is when chronically infected people have the virus become active again.
It is usually in immunosuppressed people because they lack the cell-mediated immunity necessary to control the latent phase of the virus.
- non-febrile syndrome
- chrioretinitis–> blindness
- ulcerative disease in GI (esophagus) and colon
One can make a presumptive diagnosis of CMV in a patient with characteristic clinical syndrome (fever, sore throat, lymphadenopathy with atypical lymphocytes) who is _____________ negative and _________________ negative.
To make a DEFINITIVE diagnosis, what needs to be done?
Monospot - and EBV IgM negative
Definitive diagnosis- isolation of the virus in cell culture
What biopsy findings would confirm CMV?
- Owl Eyes inclusion- basophilic intranuclear inclusions surrounded by clearing
- IgM to CMV + in acute infection
- IgG to CMV + in late or past infections
- antigen detection assay for pp65
What is therapy for CMV infections?
Gancyclovir - inhibits viral DNA synthesis by incorporating into viral DNA and terminating DNA chain synthesis. USed IV
Valganciclovir- better bioavailability
Foscarnet
Cidofovir
What is the structure of a paramyxovirus?
Enveloped, negative ssRNA.
All the genes are encoded by one genomic segment so there is no genetic reassortment and very little genetic variability
What are the three major groups of paramyxoviruses?
- morbillivirus
- parainfluenza
- pneumovirus
What is the major human pathogen that is a morbillivirus?
does it have hemagluttinin, neuraminidase or both?
Measles- hemagluttinin but no neuraminidase
What are the two major viruses in the parainfluenza virus group?
Do they have hemagluttinin, neuraminidase or both?
- mumps
- parainfluenza
They have a protein with combined hemagglutinin and neuraminidase activities
What are the viruses in the pneumovirus family?
Do they have H or N or both or neither?
- RSV
- metapneumovirus
They have fusion proteins (G or F) that allow direct cell to cell spread but have neither H or N.
What are the two envelope proteins of mumps?
How many serotypes are there?
- H-N protein
- fusion protein
There is only one serotype
How is the mumps virus transmitted?
When is it transmitted?
Spread by large respiratory droplets and by direct person to person contact with infected saliva.
It can be spread 9 days before the appearance of clinical disease and for several days after the development of parotitis.
Describe the infection and time course of the mumps viral spread in human host.
What are the most common organs affected during viremia?
There is only lytic phase (no latency)
The virus infects respiratory epithelium and then spreads to regional lymph nodes then viremia spreads it to all organs.
Incubation period is 2 weeks.
Viremia can last 12-25 days.
Parotid duct, testes and meninges are most commonly infected.
What is the clinical presentation of someone with a mumps infection?
Prodrome- headache, malaise, fever
Parotid gland swelling with pain (can be unilateral or bilateral)
What are the notable complications of the mumps infection?
- Meningitis- 50% of infected individuals
- Encephalitis
- sensorineural deafness
- orchitis- sterility
- oophoritis- rarely leads to infertility
- pancreatitis
How is the diagnosis made for mumps?
- Clinically - swollen parotid and fever
- If the presentation is atypical the virus can be cultured on monkey kidney cells where it forms syncytia
- mumps virus specific IgM in acute disease
What is treatment and prevention for mumps?
No effective antiretroviral, but there is an effective vaccine (MMR)
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