Week 3 Flashcards
Herpes viruses
3 families, what viruses?
1) Alpha-herpes viruses = HSV1, HSV2, VZV
2) Beta-herpes viruses = CMV, HHV6, HHV7
3) Gamma-herpes viruses = EBV, HHV8 (KSHV)
Herpes Viruses Shared Features
1) shape?
2) envelope?
3) labile or stable?
4) genome?
5) capsid?
1) Spherical
2) Lipid Envelope - derived from host golgi
- Coated with surface glycoproteins for cell-binding, cell-cell spread, and immune evasion
3) Labile, easy to kill in environment → spread requires close contact
4) dsDNA linear
5) icosahedral capsid
Primary infection with herpes viruses typically results in __________ infection in specific cells
Reactivation of herpes virus infection typically results in _________ infection
All herpes virus infections are more severe in patients with ______________
Primary infections → LATENT infection in specific cells
Reactivation → LYTIC infection
Infections more severe in patients with T cell disorders
Features of reactivation infection with herpes viruses
Reactivation → LYTIC infection - can be subclinical (shedding) or cause clinical disease resulting in spread of infection to new hosts
Less severe than initial infection
Alpha Herpesvirus:
HSV1, HSV2, VZV
think NEURONS
Replicate quickly and lyse epithelial cells
Neurotropic (like to infect neurons) and establish latency in neurons
Pathogenesis of HSV1 and HSV2:
1) Invasion through _____________ → replicate in ______ and ______ _______ cells → lyse, provoke inflammatory response → PAPULE
2) Lysis of many cells and production of cytokines → virus-filled fluid collection between dermis and epidermis → _________
3) Leukocytes enter vesicle and transform lesion to ___________
4) Forms a scab = _______________
1) Invasion through BREAK in mucous membranes/skin → replicate in BASAL and INTERMEDIATE EPITHELIAL cells → lyse, provoke inflammatory response → PAPULE
2) Lysis of many cells and production of cytokines → virus-filled fluid collection between dermis and epidermis → VESICLE
3) Leukocytes enter vesicle and transform lesion to PUSTULE
4) Forms a scab = DISEASE RESOLUTION (no virus in there)
Latency reservoir of HSV1
trigeminal ganglion
Can shed without any symptoms
Characteristic disease of HSV1
ORAL lesions
Herpetic gingivostomatitis
Typically due to HSV1
systemic symptoms, multiple painful oral/perioral lesions, tender adenopathy
Occurs in 20% of people during primary infection
Lasts 5-7 days then heals
Responds to antiviral therapy
HSV1 reactivation lesions
Mild tingling/pain for 6-12 hours → tender papule → vesicle formation → crusting/ulcer formation
Triggered by fever and sun exposure
HSV1 infection complications (2)
1) Keratitis
2) Herpes virus encephalitis
Keratitis
typically due to reactivation, involves cornea and can cause scarring
Herpes virus encephalitis
due to reactivation, causes necrotizing encephalitis traveling via trigeminal ganglion
Typically due to HSV1*
Latency reservoir of HSV2
sacral sensory ganglion
Can have asymptomatic shedding
Characteristic disease of HSV2
Genital lesions (sexually transmitted)
Primary infection with HSV2
usually asymptomatic
Headache, painful genital lesion, painful urethritis with tender inguinal adenopathy
Within first year of primary infection with get 3-4 recurrences of lesions/year
Complications associated with HSV2 infection (4)
usually with first episode
1) Viral meningitis (HSV2)
2) Urethritis
3) Candida superinfection
4) Anal and rectal HSV
Diagnosis of HSV1 and HSV2
PCR: detect HSV in late lesions - MOST COMMON
VZV pathogenesis:
initially infects __________ –> spreads to _____ and ________ via _______ and ______ cells
Infection then remains latent in _____________
initially infects upper respiratory epithelium → spreads to lymph nodes and RES (liver/spleen) via dendritic and T cells
Latency reservoir: Dorsal root ganglion
Primary chickenpox:
spread how?
symptoms?
spread via respiratory droplets or direct contact
Mild malaise, low grade fever → papules → vesicles → pustules → scabs (Vesicular rash)
Characteristics of rash present in primary chickenpox?
Characteristic “dew drop on a rose petal” = vesicle on erythematous base
Crops of vesicles at VARYING AGES
On trunk and face - distal extremities spared
Infectious just prior to onset, until scabbing
Complications associated with a primary chickenpox infection
1) Bacterial superinfection of skin lesions
2) Pneumonitis
3) hepatitis
4) **encephalitis (in immunocompromised)
The vaccine for chicken pox is made up of what?
LIVE ATTENUATED vaccine
Reactivation zoster:
clinical presentation (3)
1) Dermatomal rash in distribution of dorsal root nerve where it escaped latency
2) Does NOT cross midline
3) Painful prodrome can precede rash by 3-5 days
Complications associated with reactivation zoster (4)
1) bacterial superinfection
2) eye involvement (V1, includes tip of nose)
3) muscular weakness
4) Post-herpetic neuralgia → prolonged pain after
Reactivation zoster vaccine is for who?
VZV vaccine for immune competent people > 60 years (boost CD8+ T cell response which can decline with age)
Beta Herpesvirus:
CMV, HHV6, HHV7
think MYELOID LINEAGE
Replicate slowly in myeloid cells
Like to be in myeloid lineage cells and sometimes endothelial cells
Restricted to humans
Pathogenesis of CMV infection:
infects __________ cells –> local replication –> dissemination via ________ and ________
viral secretions in ______, _______, and ______ –> transmission
Infect mucosal epithelial cell surfaces → local replication → dissemination via peripheral blood monocytes and DCs
viral secretions in saliva, urine, breast milk → transmission
Latency reservoir for CMV virus
CD34+ myeloid cells
Mononucleosis-like syndrome
-main features (5)
characteristic disease of CMV infection
1) Mimics infectious mononucleosis (EBV)
2) Fever, malaise, adenopathy
3) Mild hepatitis, sore throat
4) Lymphocytes in blood
5) NO HETEROPHILE AB PRODUCED (in contrast to EBV)
CMV infection in immunocompromised person can cause what complications?
Immune compromised (T cell deficiency)→
systemic disease with end organ damage
Interstitial pneumonia common (can be fatal up to 50%)
Can also involve liver, colon, esophagus, bone marrow, retina
CMV Primary vs. reactivation infection in pregnant women:
which one is more likely to cause symptoms in baby?
FIRST CMV infection → baby more likely to be symptomatic at birth, serious illness
Reactivation → baby unlikely to have sx, but can have non-fatal sx (hearing loss) later on
Symptomatic congenital CMV after in utero infection (7)
1) Jaundice
2) enlarged liver/spleen
3) MIcrocephaly
4) seizures
5) decreased platelets
6) can be fatal
7) Can interfere with brain, eye, and ear development of fetus
Transmission of CMV (4)
1) Perinatal infection - CMV shed from mom into birth canal
2) early childhood infection via saliva
3) Adolescence - sexual transmission
4) in utero infection
Diagnosis of CMV (3)
1) PCR for CMV DNA from tissue
2) Tissue Histology of CMV Disease (viral inclusions)
3) IgM ab against CMV (IgG to CMV indicates PRIOR infection)
Treatment of CMV
Ganciclovir (NOT acyclovir), can become resistant to Ganciclovir → use Foscarnet
Latency reservoir for HHV6 and HHV7
Latency reservoir: B cells, myeloid progenitor cells (T cells)
Characteristic disease associated with HHV 6 (and sometimes 7)
Exanthema Subitum (Infant ROSEOLA)
Exanthema Subitum (Infant ROSEOLA)
3 main clinical features
1) HIGH FEVER
2) Rash begins as fever abruptly subsides**
- Rash: begin on trunk, spread to face, neck, extremities - No pigmentation or desquamation
3) NO conjunctivitis or pharyngeal exudate
Gamma Herpesvirus
EBV, HHV8
ATYPICAL CELLS
Replicated in lymphoid cells and undergo LYTIC replication in epithelial cells, endothelial cells, and fibroblasts
Pathogenesis of EBV infection?
infects _________ cells and ________ cells –> latency in ___________ cells and travels throughout the body
infect oral mucosal epithelial cells and adjacent B cells → latency in resting memory B cells and travels throughout the body
Two proteins expressed by EBV virus during latency that can be used as a marker of CHRONIC (latent, NOT ACUTE) infection?
Expresses EBNA1 and EBNA2 proteins during latency → ab to EBNA used as marker of CHRONIC or old infection (NOT ACUTE)
Latency reservoir of EBV
Naive B cells
Infectious Mononucleosis
3 main features
Characteristic disease of EBV
1) Fever, profound malaise
2) Exudative pharyngitis with palatal petechiae**
3) Lymphadenopathy, Splenomegaly, Hepatomegaly**
Improved within 14 days, but can have prolonged fatigue
Antibodies to which 2 proteins will be present during an acute EBV infection?
Viral capsid antigen (VCA) and Early Antigen (EA) antibodies present
Heterophil Antibodies
(+) indicates what?
(-) indicates what?
EBV induces B cells to make ab for which there is no prior immunologic memory
–> POSITIVE MONOSPOT TEST
Monospot negative IM → CMV, rubella, HepA, HHV6/7
EBV specific antibodies
IgG ab to VCA vs. IgM ab to VCA means what?
IgG ab to EBV capsid antigen (VCA) → infection has occurred (either acutely or in past)
IgM ab to VCA → acute infection
KSHV (HHV8) is latent in what cells?
B cells
KSHV (HHV8) causes what 2 characteristic diseases?
Kaposi sarcoma in HIV/AIDS patients
B cell lymphoma
Kaposi sarcoma in HIV/AIDS patients
Angioproliferative inflammatory lesion caused by HHV8 infection
sexually transmitted, and sometimes transmitted via saliva (Africa)
Lytic replication
occurs in permissive cells and is CYTOPATHIC (kills cells)
Histological features of herpes virus infection
1) Significant numbers of infectious particles released
2) Nuclear and cytoplasmic inclusions present
- -> Viral capsid proteins trapped in nucleus
3) Cytomegalic cells and syncytia formation
Inclusion bodies associated with herpes viruses:
1) Intranuclear Acidophilic = ______ and _______
2) Intranuclear Basophilic = ______
3) Intranuclear and intracytoplasmic = _____ and _______
Intranuclear Acidophilic = Cowdry Type A (HSV, VZV)
Intranuclear Basophilic = CMV “owl eyes”
Intranuclear and intracytoplasmic = HHV6, CMV
Replication cycle of herpes virus:
1) Attachment and entry
virus attaches to cell specific receptors (determines cell type of herpes infection) and dumps viral capsid into cytoplasm
Herpes virus Viral glycoproteins
mediate this attachment/entry
In lipid envelope mediate cellular tropism and are targets of adaptive immune response
Replication cycle of herpes virus:
2) Uncoating
Capsid transported to nucleus and dsDNA genome inserted into nucleus → forms episome (circle) → latency or acute replication
Episome
Episome is where virus maintains itself during latency
circular dsDNA of herpes virus inside host cell nucleus that can either undergo latency or acute replication
Herpes virus replicates in ____________ using ________.
The herpes virus acquires its capsid in the _______ resulting in what?
Replicates in NUCLEUS using viral-encoded DNA polymerase and gets capsid in nucleus
**Intranuclear inclusions (accumulated viral capsid proteins) often present in herpesvirus infection
3 major sets of genes expressed by the herpes virus during genome replication
1) Immediate early genes
2) Early genes
3) Late genes
Immediate early genes
transcribed soon after viral entry, set up environment conducive for viral replication
Early genes
encode replication enzymes (DNA POLYMERASE) and nonstructural viral proteins
Late genes
encode viral structural proteins needed for packaging new virion and egress from infected cell
*Capsid proteins are transported into the nucleus for ENCAPSIDATION → nuclear viral inclusions
Latent replication
Genome persistence in NUCLEUS of specific cells
Small subset of viral genes expressed, but NO infectious particles are produced
REACTIVATION = source of majority of disease
Antiviral Therapy for Herpesviruses:
what is the general mechanism by which they act?
Mechanism: NUCLEOSIDE ANALOGS → interrupt viral DNA synthesis by integrating into growing viral DNA and preventing chain elongation
1) Acyclovir
2) Ganciclovir
Acyclovir
activated by _________
used to treat _______ and ______, but not _______
nucleoside analog activated by thymidine kinase → treat HSV/VZV
NO activity against CMV (no thymidine kinase)
Ganciclovir
activated by _________
used to treat _______
nucleoside analog activated by viral UL97 protein kinase → treat CMV and B-herpesviruses
Mechanism to resistance of herpes viruses to acyclovir of ganciclovir?
mutations or deletions of viral kinase required for initial phosphorylation/activation of prodrug
Neisseria gonorrhoeae
gram \_\_\_\_\_ shape? aerobe/anaerobe? oxidase? catalase? capsule? intra or extracellular?
Gram-negative diplococci Strictly aerobic Oxidase + Catalase + NO CAPSULE Facultative intracellular (often found within neutrophils)
Neisseria gonorrhoeae
culture medium?
5% Co2 atmosphere on Thayer Martin agar (VPN) (selective medium for pathogenic Neisseria)
Rapid autolysis at 25 C and alkaline pH
Neisseria gonorrhoeae
main virulence factors?
1) Produces IgA protease → allows oropharynx colonization
- Cleaves Fc portion of IgA → prevent opsonization
2) Pili (fimbriae)
Neisseria gonorrhoeae
Pili (fimbriae)
→ attachment to mucosal surface and prevention of phagocytosis
Highly variable → allows for recurrent infection in same person
Can use phase variation to switch on/off expression of pili
Neisseria gonorrhoeae
deficiency in _________ predisposes to Neisseria bactermia
Deficiency in complement factors C5-C9 (MAC) predisposes to Neisseria bacteremia
N. Gonorrhoeae can ferment ________ while N. Meningitis can ferment ___________
N. Gonorrhoeae can ferment glucose
N. meningitidis can ferment maltose AND glucose
Gram stain of urethral/endocervical exudates when diagnosing N. gonorrhea will show what?
diplococci WITHIN PMNs
Gold standard for diagnosing gonorrhea?
*NAATs (Nucleic Acid Amplification Tests)
Asymptomatic carriers of gonnorhea:
Men vs. women?
WOMEN much more likely to be asymptomatic →risk of developing PID
Problem for control of gonorrhea transmission
Clinical Manifestations of gonorrhea infection: (6)
1) Cervicitis, Urethritis
2) Septic arthritis
3) Neonatal conjunctivitis
4) Pelvic inflammatory disease
5) Fitz-Hugh Curtis Syndrome
6) **Increases likelihood that HIV and other STDs may be more efficiently transmitted through unprotected sex
Gonorrhea: Cervicitis, Urethritis (3 sx)
1) Pain/discomfort with urination
2) Pain during sex
3) Yellow/white thick mucopurulent discharge from urethra or vagina (chlamydia is clear/watery discharge)
Gonorrhea: Septic arthritis
most common cause of septic arthritis in sexually active people
Usually affects the knee
Gonorrhea: Neonatal conjunctivitis
timeline of infection?
(Ophthalmia neonatorum)
Eye infection of neonate born to infected mothers
Occurs 1-5 days after birth (Chlamydia is 5-12 days after birth)
Gonorrhea: Pelvic inflammatory disease
N. gonorrhoeae infection that ascends genital tract and infects uterus, oviduct, and ovaries
Gonorrhea: Fitz-Hugh Curtis Syndrome
perihepatitis, infection of liver capsule and peritoneal surfaces of anterior RUQ
SX = patchy purulent and fibrinous exudate = “Violin String” adhesions
can also occur with Chlamydia
Treatment of gonorrhea
ceftriaxone (single IM dose) + doxycycline or azithromycin (for possible coinfection with chlamydia)
Patients infected with N. gonorrhoeae often co-infected with C. trachomatis
MUST treat known sexual contacts of a patient with this disease
Chlamydia trachomatis
Does not gram stain because it is ___________ and lacks ___________
stains with ________
OBLIGATE INTRACELLULAR
-CANNOT synthesize ATP or oxidize NADP → COMPLETELY dependent on host cell for energy production
Lacks peptidoglycan due to absence of MURAMIC ACID component of bacterial cell walls → penicillin resistant
Can visualize by staining infected cells with Giemsa stain
Chlamydia trachomatis:
Virulence factors: (3)
1) Lipopolysaccharide: group antigen common to all Chlamydia
2) Specific outer membrane proteins → serotype chlamydia
3) Survives in endosomes in cells by inhibiting endosome/lysosome fusion
Biphasic life cycle of Chlamydia:
1) Elementary bodies = infectious
2) Reticulate bodies = multiply (replicate by BINARY FISSION)
Elementary bodies
infectious form, enter epithelial cells by endocytosis and phagocytosed by macrophages
Form reticulate bodies (dividing type)
EBs are INFECTIOUS, but metabolically inert outside human cell
Reticulate bodies
divide by binary fission, and reorganize into EBs within cytoplasmic inclusions
Cell fills with cytoplasmic inclusions → cell bursts → release EBs to infect nearby cells
C. Trachomatis: A-C
“above the belt”
trachoma, conjunctivitis - transmitted by hand-eye contact
Chlamydia: Trachoma
chronic keratoconjunctivitis → progressive scarring of conjunctiva and cornea, can lead to blindness
Chlamydia: Inclusion conjunctivitis
acute disease in infants and adults (usually neonatal conjunctivitis in US)
Mucopurulent conjunctivitis 7-12 days after delivery
Infection can disseminate and cause pneumonia
C. Trachomatis: D-K
5 types of manifestations
Infects columnar epithelium of GU tract, common co-infection with gonorrhea
1) Urethritis, Cervicitis
2) PID
3) Fitz-Hugh-Curtis Syndrome (perihepatitis)
4) Neonatal conjunctivitis and atypical pneumonia (due to infected mother)
5) Reactive arthritis (Reiter’s Syndrome)
Chlamydia urethritis/cervicitis symptoms?
75% of women and 50% of men asymptomatic
Lower abdominal pain = PID
Dysuria = urethritis
Genital discharge = cervicitis
Males → watery/mucous discharge, dysuria, unilateral testicular pain (epididymitis)
PID caused by chlamydia can result in what complications?
scarring of fallopian tubes causing ectopic pregnancy, infertility, and chronic pelvic pain
C. Trachomatis
L1-L3
causes Lymphogranuloma venereum
Lymphogranuloma venereum:
Necrotizing granulomatous inflammation of inguinal lymphatics and lymph nodes
PAINLESS genital ulcers + PAINFUL lymphadenopathy (buboes) → fibrosis that can lead to rectal strictures with perianal involvement
Typically occurs in Africa and South America (rare in North America)
C. Psittaci
pathogenic for birds → transmitted to humans via inhalation of bacteria in droplets or dust = psittacosis
Primary Syphilis - presentation?
PAINLESS CHANCRE
One or more CHANCRE - painless, ulcerating papule, non-exudative, clean, hard base with indurated margins (punched out base with rolled edges)
Secondary syphilis
weeks to months after primary infection = PAINLESS RASH (palms of hands and soles of feet)
Secondary syphilis
5 main symptoms?
1) Maculopapular rash: discrete copper, red, or reddish-brown on trunks and extremities, notable on PALMS and SOLES
2) Condyloma lata:
3) Systemic symptoms (fever, headache, malaise, myalgias)
4) Generalized lymphadenopathy
5) Hepatitis
Condyloma lata
raised, infectious, gray/white wart-like lesion in moist areas and mucous membranes (mouth, perineum)
Tertiary Syphilis can include what 3 main things
not infectious anymore
1) CNS (neuro) syphilis
2) Gumma formation on skin, bones, and internal organs
3) Cardiovascular (aortitis)
Neurosyphilis
demyelination of ________
4 main manifestations?
demyelination of posterior column
1) Broad-based ataxia
2) Argyll Robertson pupil (eye accommodates to near objects, but does not react to light)
3) Positive Romberg sign
4) Charcot joints
Syphilis Gummas
Gumma formation on skin, bones, and internal organs
Gumma = ulcers or granulomatous lesions with round, irregular shape, visceral gumma is a mass lesion
Syphilis Aortitis
affects ascending thoracic aorta, presents as dilated aorta and aortic valve regurgitation
Proliferative endarteritis affecting vaso vasorum of aorta → medial necrosis and loss of elastic fibers
Tree barking
Congenital Syphilis
maternal syphilis → neonate (TORCHeS)
Can result in stillbirth, early congenital syphilis, and late congenital syphilis
Early congenital syphilis: 5 main manifestations
1) Hepatomegaly, jaundice, cholestasis
2) Rhinitis (“snuffles”) - discharge contains spirochetes
3) Maculopapular lesions on palms and soles
4) Generalized lymphadenopathy
5) Anemia, thrombocytopenia
Late congenital syphilis: 8 main manifestations
due to scarring or persistent inflammation from early infection
1) Gumma formation in various tissues
2) Frontal bossing, saddle nose
3) Interstitial keratitis
4) Sensorineural hearing loss
5) Hutchinson teeth, mulberry molars
6) Intellectual disability
7) Saber shins
8) Paroxysmal cold hemoglobinuria
Yaws
T. pallidum infection - destructive lesions of skin and bone
Endemic among children in humid, TROPICAL countries
Ulcerating papule on legs or arms → scar formation, bone destruction
Endemic syphilis or Bejel
T. pallidum
Children in Africa, Middle East, SE Asia (Desert)
Skin lesions
Syphilis:
Direct visualization via _______ or ________
Direct visualization- darkfield microscopy or direct fluorescent antibody testing
VDRL test can be falsely positive in what 6 cases?
1) Mononucleosis, hepatitis
2) Drugs (hydralazine, procainamide)
3) IV drug use
4) Rheumatic fever
5) Lupus
6) Leprosy
Serologic testing for syphilis includes… (2)
RPR test (cardiolipin coated carbon particles)
VDRL test
Treatment of syphilis
Penicillin G benzathine (IM, slow release into muscle)- unless allergic, then use Azithromycin
Jarisch-Herxheimer reaction
complication of penicillin therapy due to release of endotoxin-like factors from lysis of T. pallidum organisms
Fever, headache, sweating, exacerbation of syphilitic lesions 6-12 hrs after penicillin therapy
Associated with treatment of secondary syphilis
Pediatric vaccine schedule: at what age are these vaccines given? what kind of vaccine are they?
HepB Rotavirus DTaP Tdap H. influenza
1) Hep B = SUBUNIT VACCINE birth-18 months
2) Rotavirus = LIVE ATTENUATED
1-2 months
3) DTaP = POLYSACCHARIDE 2-6 months
4) Tdap = POLYSACCHARIDE give only > 7 years
5) H. Influenza = type B CONJUGATE VACCINE 1-2 months
Pediatric vaccine schedule: at what age are these vaccines given? what kind of vaccine are they?
Inactivated poliovirus Influenza MMR Varicella HepA HPV Meningococcal
Inactivated Poliovirus: 2 months
Influenza: > 6 months, annually
- intranasal = LIVE ATTENUATED
- IM = KILLED VACCINE
MMR = LIVE ATTENUATED 12 months
Varicella = LIVE ATTENUATED 12 months
HepA = KILLED VACCINE 12 months
HPV = SUBUNIT VACCINE - 11-12 years
Meningococcal = CONJUGATE VACCINE 11-12 years
Adult vaccine schedule:
Adults > 60 –> ?
Adults > 65 –> ?
Adults > 60 years → Zoster
Adults > 65 years → Pneumococcal (13-valent conjugate), Pneumococcal polysaccharide
Which vaccines are contraindicated in pregnancy (3)
Varicella
Zoster
MMR
Key contraindications to giving a live attenuated vaccine? (3)
Leukemias
immunosuppression
Pregnancy (low risk contraindication)
HPV vs. Herpes Virus:
- who makes its own DNA-dependent DNA polymerase?
- who has an envelope?
- what genes do they each express
HPV:
- no envelope
- no DNA-dependent DNA-polymerase (relies on host cell)
- Expresses early genes and late structural genes (L1, L2)
Herpes virus:
- enveloped
- encodes DNA-dependent DNA polymerase
- Expresses immediate early, early, and late genes
What kind of immune response is important for herpes virus?
BOTH antibody-mediated and cell-mediated immunity important to herpesvirus
Neutralizing antibodies prevent systemic spread of infection - prevent virus spread beyond cells innervated by reactivating neuron
Cell-Mediated Immunity (CD8+ T cells) critical for clearance of virus from lesions
Genomes:
Rotavirus
Calciviruses (norovirus)
HPV
Herpes virus
Rotavirus = dsRNA (11 genome segments)
Calciviruses (norovirus) = (+) sense ssRNA (nonsegmented)
HPV = naked, nonenveloped, dsDNA
Herpes virus = enveloped, dsDNA
