Download Copied and pasted from his email, and answered. For the exam, you

Copied and pasted from his email, and answered.
For the exam, you should focus your attention first on the major microbes which cause infective
pericarditis, myocarditis and endocarditis. (listed the bolded only)
Pericarditis:
Viral – Coxsackievirus B (COX-B) #1 overall
Bacterial – Staphylococcus aureus
Fungal – Histoplasma capsulatum, Candida
Myocarditis:
Viral – Coxsackievirus B, Adenoviruses
Bacterial – Corynebacterium diphtheria, Borrelia burgdorferi
Parasites – Trypanosoma cruzi, Trichinella spiralis
Endocarditis:
Bacterial –
Acute – Staphylococcus aureus
Subacute – Viridans Streptococcus, Enterococcus spp.
Secondly, for infective pericarditis slides 8 and 9 discuss the general mechanisms of how disease
symptoms are generated by the microbial invasion.
Slide 8:
Organism comes into the pericardial cavity through the blood, filters into the cavity. Extracellular ones
(Staph, etc.) can just attach to the tissue and start colonizing, intracellular ones have to get inside the
cells. **The visceral pericardium (epicardium) is the main target usually** The organisms infect the cells
and either lyse them or lead to immune recruitment (which causes the symptoms.
Slide 9:
He made a point of saying that this is a viremia, so it has colonized elsewhere and replicated, and is now
spreading out through the blood. He also noted that it can be spreading through the blood by itself or it
can be a cellular viremia (inside a macrophage/dendritic cell). It then infects the pericardial epithelia and
the endothelia can be activated by innate cytokines (TLR activated and causes secretion of IL-1, TNF,
INFa). When the endothelia is activated, it expresses the adhesion molecules (selectins, integrins),
chemokines, and it then captures the circulating cells (monocyte, neutrophil, macrophage). Those three
cell types accumulate in the pericardial cavity and infiltrate the tissue (cells can also be infected). This
leads to a Th1 response and the release of IFNgamma. The local Th1 response drives fluid production by
visceral pericardium – the continued presence of Th1/IFNgamma ensures you will continually stimulate
the visceral pericardium to produce fluid, leading to a pericardial effusion (**due to immune response
trying to get rid of the pathogen**).
All depends on the antibody response, the better it is, the less virus (present in the viremia) that can get
into the heart and cause all this downstream effect after invading the epithelia. You have a time period
for the B cells to get activated to make antibodies (about 10d – 2wk) to neutralize the virus and prevent
the attachment. **strength of the antibody response can prevent viremia to heart**
For infective myocarditis, a general mechanism underlying symptoms is given on slide 33 but you will
also need to scan over each major microbe for specific modes of pathogenesis.
Slide 33:
Myocyte damage as a result of infection in one of four ways – direct damage by microbe (lysed),
cytokines (IFNgamma, TNF – leading to apoptosis of cells when chronic), immune-mediated cytotoxicity
(T cells killing, if immune complexes present then macrophages and neutrophils can kill too), or toxinmediated cytotoxicity (bind and kill myocytes).
Mode of pathogenesis for each (bolded only):
Viral
Coxsackievirus B – +sense ssRNA virus that is nonenveloped. Enters via foodborne fecal/oral and
respiratory. Enveloped viruses have the VAP (viral attachment protein) in their envelope that lets them
attach to the host cell target, so if they are exposed to a hostile environment and lose their membrane,
they will lose the ability to attach. Therefore, because COX-B is naked it is resistant to stomach acid,
protease, bile, heat, sewage treatment. Replicates in epithelia (likely gut), spreads via viremia to lymph
nodes, then replicates again (could be in heart at this point). In the heart you get replication, cytopathic
effects (CPE), and a Th1 response. CPE can be things like lysis of cells, giant multinucleated cell
formation, or other things, for COX-B it is mainly via lysis of cells. The lysis of cells causes fluid to
accumulate and causes chest pain. Cytolytic to host cells, excreted in stool for about 4 weeks.
Adenoviruses – dsDNA virus that is nonenveloped. Enters via fecal/oral direct contact, fomites, or
respiratory (sneezing). Uses same host cell receptor as coxsackieviruses. Encodes vDNA pol (requires the
cell it is entering to be in an active replicating state of some sort, so this means the cells have to be
stimulated by another factor. This could be another virus involved or a latent infection. Once it has the
vDNA pol translated it can express its early genes, E1A – host cells entering S phase to increase
replication, E1B – preventing host cell death). All of this means the virus causes lytic, persistent, and
latent infections. Note that it replicates in epithelial cells and then spreads via viremia to many tissues,
including the heart myocardium. Lose myocytes due to the second replication in the myocytes leading to
lysis.
Bacterial
Corynebacterium diphtheria – gram+ bacillus (no capsule), nonmotile. It is ubiquitous in nature,
colonizes the skin, URT, GI tract, and urogenital tract, and humans are the only reservoir. Spread via
respiratory. Pt can have an exudative pharyngitis due to the diphtheria itself. The vaccine for diphtheria
was developed in order to prevent the dissemination to the heart, because the DTX inhibits protein
synthesis and causes necrosis of the heart muscle. Virulence factor is the Diphtheria toxin (DTX). There is
a lot of detail on the slide but he only put the DTX in red. **Toxins (DTX) like to bind to myocytes, stops
the protein synthesis, and cells die**
Borrelia burgdorferi – weak gram- spirochete (no capsule), nonmotile. Vector borne by Ixodes scapularis
deer tick. Enters at bite site through skin, replicates at site (brings in immune cells – tick
transfers organism in saliva, gets into blood, hypersensitivity immune reaction,
inflammatory lesion appears – stage 1). Disseminates to skin other than bite site,
replicates nearby, disseminates a second time to the heart this time (stage 2 – spread
to CNS and heart by blood). Replicates again, associated with the cardiac connective
tissue and blood vessels in the muscle, leading to immune complexes, persistent
antigen and chronic arthritis (stage 3 – arthritis). Damage to heart…immune related,
cytokine mediated?? (unclear) Virulence factors are the outer surface proteins (Osp A
and Osp C – more detail in slides but these are in red and blue). Mice, deer, and ticks are reservoirs.
Parasites
Trypanosoma cruzi – protozoan (blood and tissue), vector-borne by triatomine bug (kissing bug,
reduviid bug). Trypomastigotes enter skin through bite site via mixing with bug
feces, invade host cells through parasitophorus vacuole, replicate as amastigotes
in acute phase in muscle cells’ cytoplasm. Parasitemia as trypomastigotes in blood
(can stain for trypomastigotes in the blood), chronic phase to CNS, liver, heart.
Replicates in myocytes (reforms amastigotes in the seeded tissues – can stain a
biopsy to see amastigotes). Newly transformed trypomastigotes can lyse the host
cells. Immune-mediated inflammation due to persistence of T. cruzi in heart
muscle.
Trichinella spiralis – nematode (GI and tissue), foodborne (raw contaminated meat). Larvae are
encysted in raw meat (muscle tissue), replication (excyst in GI mucosa, mature into adults and mate),
disseminate (new larvae enter portal venules to liver  blood  chest, arm, and
leg muscles, CNS, heart), encyst in heart (larval numbers determines myocyte
damage). Cysts will stay forever until larvae die in the cyst, when they die they
release toxins  shock  immune response kills organ. 10 larvae/g of tissue –
asymptomatic, 100/g - mild-mod symptoms like the flu, 1000-5000/g – lower
(persistent fever, GI distress, periorbital edema) and higher (encephalitis, myocarditis, and pneumonitis
– death in 6 wks). Rats and pigs are hosts and reservoirs.
Important information regarding infective endocarditis is given in slides 48-50 where it is clear for this
condition, a risk factor of some kind must be prerequisite.
Slides 48 – 50:
Infective endocarditis requires a predisposing abnormality of the endocardium (except for the fact that
45% don’t have an abnormality…), usually the heart valves of the left side (mitral or aortic valve).
Examples: congenital heart defect, rheumatic valve disease, MVP, HCM, prosthetic valves, previous
endocarditis/myocarditis/pericarditis. It also obviously requires microbes to be in the bloodsteam (they
can originate at distant infected sites or enter by catheter or drug injection site, implants are at risk for
colonization, asymptomatic viremia or bacteremia via dental, medical, or surgical procedures).
1) Valve surface must be altered to make a suitable site for bacterial colonization
a. Blood turbulence, trauma, damage by Ig, congenital defect
b. Deposition of platelets, fibronectin, fibrin (and other ECM) – sterile vegetations. Lesions
of nonbacterial thrombotic endocarditis (NBTE) “reorganizes ECM and messes it up”
2) Bacteria have to reach the site via bacteremia
3) Colonization of bacteria
4) Mature vegetation – local damage, bacteremia to other sites, embolization, immune complex
deposition
For each of the different infective carditis, an infectious agents slide is given (example is slide 10) and
you will see the different types of microbes that can cause the particular carditis. Those in bold are the
most often diagnosed and clinical relevant pathogens. Make sure you go over the slides referring to
these pathogens. The exam questions concentrate on these organisms as well as the general disease
symptoms and modes of pathogenesis for each carditis.
Slide 10 (pericarditis- viral, bacterial, fungal) bolded organisms:
Pericarditis:
Viral – Coxsackievirus B (COX-B) #1 overall
Already outlined above.
Bacterial –
Staphylococcus aureus: Gram+ coccus (encapsulated), nonmotile. Spread by direct contact or
fomites, normal flora, autoinfections. Most common cause of pericarditis within 3 months of
surgery. Enters by bacteremia, replicates on pericardial epithelia and
within tissue. Heart has immune-mediated inflammation that can
damage the pericardial epithelia. Virulence factors are the structural
components that allow it to adhere to host tissues and antiphagocytic
(capsule, protein A), cytolytic toxins (destroy WBCs), superantigens (T
cell proliferation and cytokine storm), and enzymes (coagulase,
hyaluronidase, fibrinolysin, lipases, nucleases). Risk factor for cardiovascular infection=patients
with intravascular catheters.
Fungal – Histoplasma capsulatum, Candida
Histoplasma capsulatum: dimorphic fungus (endemic) in Mississippi to ohio river valley,
respiratory spread. Septate hyphae produce conidia, associated with bird and bat droppings.
Enter URT and LRT and convert to yeast, replication (engulfed by alveolar
macrophages), cellular dissemination (to lots of places including the heart),
replication when immunosuppressed, immune-mediated inflammation in the
heart because the macrophages stick around in the pericardia and induce the
inflammatory response. Virulence factors include dimorphism (conidia
convert to yeasts to access macrophages and resist killing by the macrophages), prevent
phagolysosome acidification, siderophore and calcium binding protein (CBP).
Candida: dimorphic fungus, opportunistic, normal flora and in nature. Enters GI tract/normal
flora, replication - needs a predisposing event  candida crosses
gut mucosa to bloodstream, dissemination to lots of place and
heart, replication in immunocompromised/immunosupp., leads to
immune-mediated inflammation in heart. Virulence factors include
adhesins for many tissues, dimorphism (yeast promote Th2, which
lets it stick around, hyphal forms can infiltrate epithelial surfaces),
phenotype switch (to avoid Ig, adapt to changing environment,
proteinases (break down ECM), lipases.
Slide 34 (myocarditis- viral, bacterial, parasitic) bolded organisms:
Myocarditis:
Viral – Coxsackievirus B, Adenoviruses
Bacterial – Corynebacterium diphtheria, Borrelia burgdorferi
Parasites – Trypanosoma cruzi, Trichinella spiralis
All outlined above.
Slide 47 (endocarditis- bacterial acute and subacute) bolded organisms:
Endocarditis:
Bacterial –
Acute – Staphylococcus aureus
Outlined above.
Subacute – Viridans Streptococcus, Enterococcus spp.
Viridans streptococcus (VGS): gram+ coccus (encapsulated), nonmotile.
Normal inhabitants of oral cavity, GI, and GU tract, autoinfection with
immunosuppression. Enter by bacteremia (neutropenia in chemo patients
and dental manipulations), replicate on mitral and aortic valves, in heart
have large, friable vegetations and frequent major systemic emboli. Catalase
negative, alpha hemolytic and nonhemolytic, non typable (made a note of
saying alpha hemolytic is VGS, beta is strept nonviridans, and gamma is
enterococcus).
Enterococcus spp: gram+ coccus (encapsulated), nonmotile. Group D
streptococcal antigens. Normal inhabitants of GI tract, spread by
autoinfection or direct contact. Enter by bacteremia or primary infection
of heart, UTI, wound infection, peritonitis. Replicate on mitral and aortic
valves. Forms large, friable vegetations and frequent major systemic
emboli. Virulence factors include adherence (forms biofilms on tissues),
antibiotic resistance.
The recommended labs on the slides are inserted into the disease process where they are commonly
ordered and most useful. For the exam, mention of them in exam questions will be supplemental to the
other supplied information for answering the question.
Organism
Coxsackievirus B
Labs
Lab
Immunofluorescence for Ag in
stool culture
Staphylococcus aureus
RT-PCR (vRNA) in blood
Blood agar, use blood – look for
hemolysis
Viremia
Bacteremia
Catalase/coagulase
Bacteremia
Stage
Replication
Histoplasma capsulatum
Stain for infected macrophages
- sputum
Replication
SDA for dimorphism – sputum
Replication
Stain for infected macrophages
– sputum or blood
Cellular dissemination
SDA for dimorphism – sputum
Cellular dissemination
ELISA (Ag) – blood
Stain for forms – blood
Cellular dissemination
Dissemination
Adenovirus
SDA for dimorphism – blood
IF for Ag or CPE – throat swab
or stool
Replication
Corynebacterium diphtheria
PCR for vDNA – blood
Tellurite Agar for black colonies
– nose/throat swab culture
Viremia
Replication
PCR (DTX) – culture
ELISA (IgM or IgG) – blood, after
rash
Stain for trypomastigotes –
blood
Replication
Replication
Stain for amastigotes - biopsy
CBC (eosinophils)
Replication in chronic phase
Replication
Stain for larvae in cysts – biopsy
Replication
ELISA (Ig) – blood
Blood agar – blood, look for
alpha or gamma hemolysis
Blood agar- blood, gamma
hemolysis
Replication
Replication
Catalase – blood culture,
negative
Replication
Media – blood, look for growth
in NaCl
Replication
Candida spp.
Borrelia burgdorferi
Trypanosoma cruzi
Trichinella spiralis
Viridans group streptococcus
Enterococcus spp.
Replication in acute phase
Replication
Like most exams I give, you will be asked to identify a causative agent, or a virulence mechanism of
action particular to a pathogen or link up a host response to a symptom.