Micro I Flashcards
What are the mechanisms that bacteria and protozoa use to resist complement mediated killing?
- Capsule and long LPS O antigens: the outer capsule prevents complement activation; Long LPS O antigens prevent complement receptors of the phagocytes from obtaining access to fixed C3b on the microbe
- Coating in immunoglobulins (S.aureus, S.Pyogenes)
- Membrane bound enzymes can degrade the complement
**whenever the bacteria has something coming off of its surface, it is usually to avoid opsonization or to facilitate adhesion to the host
What are the mechanisms by which bacteria and protozoa use to resist phagocytosis?
- Release of toxins that kill phagocytes (S.aureus, S.Pyogenes)
- Release of catalase to prevent oxidative killing (S.Aureus)
- Escape from the phagolysosome and live in the cytoplasm of the macrophage (and replicate there within the phagocyte; T. Cruzi)
- Prevention of Opsonization by releasing molecules (ie: protein A) that interact with the antibodies so that the organism doesnt, thus preventing phagocytosis
- Inhibition of fusion of phagosome and lysosome
- Prevention of contact with phagocyte via a capsule
- Defense against cytokines: ie: PLasmodia secretes IL-2 receptors that prevent T-cell activation during malaria; pseudomonas aeurinosa secretes enzymes that cleave IL-2 and IFN- G
How do persistent infections thrive?
persistent = reside in their host for long periods (years);
- The shed of persistent microbes into the environment can be continuous (ie: Hep B into blood), or intermittent (ie: Tubercle bacillus)
- Very relevant when it comes to viruses, which are well adapted to be persistent infections, for example, Hepesvirus may latently infect dorsal root ganglia becoming re-activated later; or it may be shed into salivary secretions and infect other
What are the strategies that microbes use to evade (avoid) the host immune response?
They attempt to conceal their antigens by:
- interfering with the display of Ag on the surface of infected cells (HIV)
- Readily shed, therefore making the Ag less accessible to circulating lymphocytes (ie: Skin and secretory duct colonizers)
- Molecular mimicry (molecules that cross-react with human proteins)
- Coat themselves with host proteins (ie: S.Aureus coats in Fc receptors to bind immunoglobulin; Viruses can secrete Fc receptors to bind immuoglobulins to the surface of infected cells)
- Induce tolerance or anergy (No B/T Response)
ie: Cytomegalovirus infects during embryonic life; Coccidiodes inmitis produces large quatities of antigen, thus inducing anergy
What are some molecules that produce Fc Receptors? what is the function of this?
= staphlococci, steptococci, herpes simplex virus, varicella-zoster, cytomegalovirus;
The point is so that antibodies attach to the microbe (that has Fc receptors on its surface) in a “backwards” position so that it doesn’t induce an immune response; The bacteria can avoid neutralization/opsonization/complement
Describe the concept of antigenic variation and its function in infection
= antigenic shift and antigenic drift
= variation of surface components during infection, confounds immune response to pathogen; whatever is on the pathogen’s surface is what the host responds to and produces immunity agains, so if the organism can change its surface characteristics then it can avoid the immune response and it cam lead to WAVES of infection where there is an initial microbial growth, but then an immune response decreases microbial growth rapidly, but then there is an antigen change resulting in a “new” epitope, and thus the cycle repeats itself
Relates to influenza, which can undergo antigenic drift (new mutations in genes) or antigenic shift (new combinations of strains leads to a new strain);
Relates to parasites which may carry unexpressed surface protein genes, in which movement of a gene 3’ to the promotes allows for its expression (thus sequential recombination permits the expression of different antigens during the life cycle)
What is the difference between antigenic drift and antigenic shift?
antigenic drift = the natural mutation over time of known strains of influenza (or other things, in a more general sense) which may lead to a loss of immunity, or in vaccine mismatch. IE: repeated point mutations in hemagglutinin and neuraminidase genes
antigenic shift = two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains.
IE: recombination of different strains of influenza leads to a new strain; CAN LEAD TO PANDEMICS!
What effect do micro-organisms have on the immune system? How do infections cause this?
If viruses infect T/B cells or macrophages, can cause an immunosuppressive effect;
Bacterial toxins can also disrupt the normal immune response by lysing lymphocytes, cleaving immunoglobulins, and inactivating complement;
EX: staph/strep superantigens disrupt the normal immune response
Some viruses (herpesvirus) can encode a cytokine homologue that interferes with the immune system
What are bacterial exotoxins? What are the two classes?
= hydrolytic enzymes that degrade DNA or connective tissue promoting spread of infection; the enxymes are secreted (type I, II, or III secretions), and have an effect somewhere other than the infection site
- Cytolysins
- Cytotoxins
** in Gram negative bacteria, the toxins form in the periplasm!
What is the difference between cytolysins and cytotoxins?
Both are exotoxins
Cytolysins = disrupt mammalian cell membrane and cause the cell to lyse (form a pore that causes loss of nutrients and filling of water, or they cause enzymatic lysis of the cell membrane)
Cytotoxins = classic bacterial toxins with an AB subunit (A = active portion; its an enzyme that gets translocated into the cell and produces effect. B = binding portion, it binds to a receptor so that A can be secreted)
- They disrupt the mammalian cellular physiology by modifying some substrate, usually by transferring ADP-ribose group from NAD to a substrate
- The effects range including: inhibition of protein synthesis, increase in cytosolic cAMP (causes hyperactivity), disruption of nerve transmission
What is bacterial endotoxin? What is its effect on the immune response?
= Gram-negative Lipopolysacharride (LPS)
Range of effects on immune response including: fever and vascular collapse (shock); primarily due to cytokines IL-1 and TNF
**staph and strep superantigens induce similar physiologic responses
HOW?
LPS on organism binds to macrophages which promote IL-1 and TNF secretion to cause fevers and increased adhesion of PMNs on endothelial cells; also they increase vascular permeability and vasodilate
Describe the damage response of microbial pathogenesis
A curve where Host damage/benefit = y axis, and host response = x-axis.
IF the host response to the microbial pathogen is too strong/too weak then there is lots of host damage; if the response is intermediate, then there is little host damage, but there isn’t any benefit;
IF the reponses is too weak, damage is due to the pathogen, if the host response is too strong, damage is due to the immune system damaging tissue
What is a macule?
flat, red with inflammatory response to microbe or toxin (has infiltrating leukocytes)
What is a papule?
raised, red with more marked inflammation than a macule; involves the invasion of neighboring itssue
What is a vesicle?
a blister; microbe invades the epithelium; includes HSV and VZV infections
What is a furuncle?
a boil; microbe invades the dermis by colonizing the hair follicle (folliculitis);
There is coagulation of fibirin around the lesion
= pus-filled bumps that form under your skin when bacteria infect and inflame hair follicles. Boils (furuncles) usually start as red, tender lumps. The lumps quickly fill with pus, growing larger and more painful until they rupture and drain.
What is a carbuncle?
A carbuncle is a cluster of boils that form a connected area of infection under the skin, and infect hair follicles;
- focal suppuration (decay in tissue forming pus; an abcess)
- May lead to entry of organism into bloodstream via lymphatics
What is impetigo?
a bullous, crusted, or pustular eruption; HONEY COLORED
What is erysipelas?
Well-defined, spreading inflammation of DERMAL LYMPHATICS
What is cellulitis?
acute inflammation due to infection of subcutaneous fat
What is Necrotizing fascitis?
inflammatory response in soft tissue below the site of infection
What dictates how aggressive a pathogen infects the host and the depth of the tissue of invasion?
VIRULENCE FACTORS!!! especially cytolysins
What are some of the virulence factors relevant to Staph infections?
- Alpha toxin:
pore-forming cytolysin that kills RBC and WBC; its a pore that assembles in the pepmbrane and permits fluid loss from the cell (complement-like MOA) - Toxic Shock Syndrome Toxin (TSST-1) :
pyrogenic exotoxin from Group A step; its a superAg (NOT A TYPE AB EXOTOXIN!) that cross links T-cell receptor and MHC II causing massive cytokine release enhancing endotoxic shock (IL-2, IFN-G, IL-1, TNF-A) - Exfoliative Toxins (in Staph Scalded Skin Syndrome SSSS):
2 types: chromosomal and plasmid encoded: induce intercellular splitting at desmosome between stratum spinosum and stratum granulosum causing bullous lesions - Exoproteins for spread:
Hyaluronidase that hydrolyzes CT, or staphylokinase that promotes fibrinolysis - Antiphagocytic components:
Protein A bind the Fc portion of IgG (to turn off immune response);
Coagulase promotes surface polymerization of fibrin to resist phagocytosis
Catalase neutralizes H2O2 - Quorum sensing to regulate virulence factor expression in response to cell density: causes upregulation of coagulase at LOW cell densities for colonization (promotes surface polymerization of fibrin), and upregulation of staphylokinase at HIGH densities for spread (promotes fibrinolysis)
How are skin/soft tissue infections transmitted?
- via skin/nasal carriage because there isn’t any acquired immunity here
- via fomites (inanimate objects)
What is scalded skin syndrome?
- caused by staph (SSSS)
- comes from the hands of HCW that have EXFOLIATIVE TOXIN on them, coming into contact with NEONATES and CHILDREN;
- causes a bullous impetigo that is localized
- exfoliative toxin induces intercellular splitting at desmosome between stratum spinosum and stratum granulosum causing bullous lesions
What is toxic Shock syndrome caused by?
-casued by TSST-1, a superantigen that colonizes vagina or wound infection and causes a huge T-Cell response that can lead to shock
How does wound contamination lead to infections?
- spreads into bloodstream via lymphatics (bacteremia)
- endocarditis, osteomyelitis, meningitis, and pulmonary infections result from bacteremia
What are the different tests performed for a suspected Staph infection?
- Collect the specimen: surface swab, blood, pus cultured on blood agar
- Determine Gram staining (Gram + in clusters = Staph/Strep in clusters);
- Catalase Test: to determine Staph vs. Strep:
+ = production of O2 bubbles when H2O2 added to culture; = STAPH - Coagulase Test: to determine the different strain of Staph (S. Aureus = highly virulent vs. S. epidermidis and S. Saprophyticus = low virulence)
- Tests the coagulation of citrated plasma by culture; if the serum coagulates, then its is the high virulent staph (S. AUERUS) if it does NOT coagulate = low virulence staph - Test Antimicrobial susceptibility (to see if what drug and what dose is the best to give the patient, so that higher resistant strains aren’t produced)
What is M-Protein and how is it related to skin and wound infections?
-Mediates binding to epidermis
Viruses, parasites and bacteria are covered in protein and sugar molecules that help them gain entry into a host by counteracting the host’s defenses. One such molecule is the M protein produced by certain streptococcal bacteria.
M proteins embody a motif that is now known to be shared by many Gram-positive bacterial surface proteins. The motif includes a conserved pentapeptide which precedes a hydrophobic C-terminal membrane anchor (anchored in peptidoglycan of well wall);
The Amino terminus is variable due to genentic recombination which leads to antigenic variation and type-specific immunity
M protein is strongly anti-phagocytic and is a major virulence factor. It binds to serum factor H, destroying C3-convertase and preventing opsonization by C3b. However plasma B cells can generate antibodies against M protein which will help in opsonization and further the destruction of the microorganism by the macrophages and neutrophilis. Cross-reactivity of anti-M protein antibodies with heart muscle is the basis for acute glomerulonephritis
-several factors embedded in the cell wall, including M protein, lipoteichoic acid, and protein F (SfbI) facilitate attachment to various host cells.[10] M protein also inhibits opsonization by the alternative complement pathway by binding to host complement regulators. The M protein found on some serotypes is also able to prevent opsonization by binding to fibrinogen.[1] However, the M protein is also the weakest point in this pathogen’s defense, as antibodies produced by the immune system against M protein target the bacteria for engulfment by phagocytes. M proteins are unique to each strain, and identification can be used clinically to confirm the strain causing an infection.
What is protein F?
A protein on the surface of Step Pyogenes that acts as a virulence factor by mediating fibronecting binding at wound sites
What is Steptolysin O (SLO) and Steptolysin S (SLS)
A protein on the surface of strep pyogenes that acts as a virulence factor
- causes Beta hemolysis on blood agar plates
- SLO is a cytolysin that attacks cell membranes and forms large pores, it is oxygen labile (sulfhydryl-activated)
- Ab to SLO mediate self-attack and augment cell lysis
What is Streptococcal Pyrogenic Exotoxins (Spe-A-C)?
- A virulent factor
- SpeA is produced by lysogenized (bacteriophage-carrying) Group A Strep
- it is superantigen that has a sequence homology with staph pyrogenic exotoxin
- induces cytokine release leading to fever, rash, T-cell stimulation, endotoxin sensitivity (Character of scarlett fever)
How are hydrolytic enzymes act as a virulent factor for strep? what is a hydrolytic enzymes of importance?
- responsible for the thin, runny pus in streptococcal infections; pus due to break down of DNA
- streptokinase dissolves fibrin to facilitate spread (used therapeutically because it also dissolves blood clots)
- Seen in impetigo as the honey crusted lesions `
What causes Impetigo (what is the pathogenesis?)
- infection through minor trauma, insect bite typically on face and/or lower extremities
- small vesicle that ruptures leading to serous exudate (secretion), superficial spread, honey colored crust (dried up serum)
- caused by strep pyogenes infection of skin
- Epidemics occur with children 2-5 y/o due to hot, humid climate, poor hygiene, crowding (HIGHLY CONTAGIOUS)
- Transmission is person-peron, and by fomites (shared towels)
- S. Aureas can be bullous (blister) impetigo, or contaminate stepcoccal lesions
- causative M protein types differ from respiratory serotypes
What is post-streptococcal sequelae?
= secondary to the infection of the skin (ie: impetigo), causing acute glomerulonephritis
- sx = edema, hypertension, hematuria, proteinuria 3 wks following skin infection
- caused by nephritogenic M serotypes due to cross-reactivity with M-protein leading to deposits of immune complexes in glomerulus leading to type III hypersensitivity ; large complexes deposit on the glomerular basement membrane, smaller ones pass through the basement and deposit on the epithelial side of the glomerulus, causing endothelial cell damage
What is Erysipelas? What is it caused by?
= “red skin”
= acute infection of the upper dermis and superficial lymphatics, usually caused by streptococcus bacteria.
Erysipelas is more superficial than cellulitis, and is typically more raised and demarcated. rapidly spreading infection of DEEPER layers, may progress to necrosis and septicemia
- Sx = infection related: edema, fever, lymphadenopathy
- common on face following streptococcal sore throat
What is Cellulitis? What is it caused by?
= a bacterial infection involving the skin. It specifically affects the dermis and subcutaneous fat. Signs and symptoms include an area of redness which increases in size over a couple of days.
= extension of skin infection or wound
Caused by: Group A S.pyogenes or S.aureus
What is toxic-shock like syndrome?
= rapid death following wound infection with S. pyogenes
- Sx = shock, renal impairment, rash, respiratory failure, diarrhea (due to superAg)
- caused by highly invasive (“flesh eating”) strains that produce SPE A
*super Ag in bloodstream leads to shock sx and in 30%, death
What are the different tests performed for a suspected Strep infection?
- Specimen collection: surface swab, blood, pus, cultured on BAP with 10% CO2
- Gram stain = + with cocci in CHAINS
- Beta-hemolytic on blood agar plates (SLO and SLS); pyogenic (pus-forming) = S.Pyogenes or S. agalactiae
- Lancefield classification (carb on Ag in cell wall) = Group A (S.Pyogenes)
- Biochemical tests: Catalase = negative (positive for Staph); Serotyping for Lancefield Group A Ag, Bacitracin sensitivity assay on agar plate
- Serologic tests: Rise in Ab titers to S.pyogenes Ag, titers of Ab to SLO and M-protein
What are the virulent factors relevant to Propionibacterium?
- skin flora which breaks down sebum lipids to Fatty acids
- Organic propionic acid produced by organism contributes to inflammatory process
- Hormone production at puberty alters sebum secretion and enhances growth of P.acnes
How does P.Acnes contribute to acne?
= an anaerobe of normal skin flora:
- found in high cell numbers in hair follicles and associated sebaceous glands, and causes increased sebum production in response to hormone levels in puberty
- acne vulgaris by P.acnes is due to an inflammation of hair follicle and associated sebaceous gland
- blackhead = due to formation of keratin, sebum, and bacteria
How does P.Acnes contribute to more significant infections (than acne inflammation)?
- can contaminate blood cultures
- can contaminate prosthetic heart valves and cerebrospinal shunts, contributing to endocarditis
- infections in severely immunocompromised
How is Propionibacterium Acnes identifiable?
= gram + robs, pleomorphic (multiple shapes) that resemble corynebacterium
-anaerobic or microaerophilic growth
What are the virulence factors associated with Candida Albicans?
- Adhesion factors: through MANNOPROTEIN complexes from cell wall, or fibronectin receptor site in human hosts
- Invasion induction
- hypahae bind to fibronectin, collagen and laminin to induce invasion into host by extending across mucosal barriers
- proteases and elastases may promote invasion - Immune system evasion
- PMNs are the first line of defense; chronic candidiasis indicates T-cell deficiency
What is the etiology/pathogenesis of candida albicans?
= a fungal infection (budding yeast, NOT dimorphic)
- Causes folliculitis (infection of hair follicle) and intertrigo (infection of the infolds of skin)
- skin infections occur in crural olds, especially wet, macerated surfaces that are chronically exposed
- presents as erythematous papules, tender cracked areas associated with chronic irritation
- occupational hazards = dishwashers (on their hands), babies (diaper rash)
- chronic mucocutaneous candidiasis (“thrush”) = localized to skin, hair or mucocutaneous junctions; indicates T-cell deficiency
How is candida albicans identified?
- specimen collection: exudate or epithelial scrapings
- KOH or Gram stain reveals budding round or oval yeast cells with hyphae
- Germ tube (Hyphae) formations speciate C. albicans
What is the etiology/pathogenesis of Sporothrix schenckii ?
= SUBCUTANOUS infection causing sporotrichosis
- Sporothrix schenckii = saprophyte in soil and on plants (therefore infection usually on extremeties of gardeners and farmers)
- mole = infectious form, caused by inoculation of conidia (spores) by trauma (thorn prick); mold spreads through lymph
-local multiplication at site leads to pyogenic granulomatous inflammatory reactions in which the initial stage is a painless papule weeks to months post-inoculation
the papule can ulcerate and become chronic with draining lymph channel, and spread to bone, eyes, lungs, CNS
What is the clinical identification of Sporothrix schenckii?
- definitive diagnosis requires culturing of infected pus/tissue
- dimorphic growth phases in which a cigar shaped yeast in tissue is cultured at 37 ‘ C; but the mold with thin septate hyphae and terminal conidia presents at 25’C
What are the virulent factors associated with Dermophytes?
- adaptation to nonliving keratinzed tissue of nails, hair stratum corneum of skin
- invasion of hair shaft by arthroconidia
What is the etiology/pathogenesis of dermpatophytes?
- General:
o Tricophyton: infects hair
o Epidermophton: never infects hair
o Microsporum: rarely infects nails
o Malassezia furfur: commensal that can cause superficial mycoses
• Results in pityriasis/tinea versicolor (a patchy discoloration) - Cause superficial infections of the skin (usually the extremeties);
o Common Names:
• Ringworm: tinea corporis
• Athlete’s Foot: tinea pedis
• Jock Itch: tinea cruris
o Lesions occur most often in moist skin folds (maceration/softening promotes infection)
o Arthroconidia can invade outside/within hair root, plugging the root and causing ring-shaped hair loss
o Invasion of nail bed causes malformed growth - Source of Infection:
o Domestic/wild animals or soil
o Have low infectivity and virulence; person to person transmission requires close contact with infected skin or hair - The infection induces advanced skin growth, limiting its spread
o Infection normally induces DTH reaction; because of cell-mediated response, immunity can be acquired
o Immunosuppressive agents prolong infection (decreased shedding of keratinized layers); chronic infections associated with impaired T cell function
How are dermophytes identified clinically?
- Sampling: scrapings from edge of lesion or infected hairs
- Stained with KOH or Calcifor: culture and microscopy used for identification
- Microsporum spp: fluoresce under UV light (Wood’s lamp)
What are the different subfamilies of Herpesviruses?
- Over 100 herpesviruses known; 8 are considered human herpesviruses
- Fall into 3 subfamilies based on genetic and biological properties
• Subfamilies: - Alphaherpesviruses:
o HSV 1
o HSV 2
o VZV
o Note: B virus, a monkey alphaherpes virus, can infect humans (ie. via a bite); usually results in fatal encephalitis - Betaherpesviruses:
o CMV
o HHV-6A
o HHV-6B
o HHV-7 - Gammaherpesviruses:
o Epstein Barr Virus (EBV)
o HHV-8/Karposi’s sarcoma associated herpesvirus
Describe the general infectious period of herpes simplex viruses
o Incubation Period: 4-5 days on average (can be longer or shorter)
o Primary Infection: takes ~2 weeks to run its course
o Recurrent Infections: are typically shorter and involve fewer lesions
Compare the different types of herpes-simplex diseases (the ages of onsets, the frequency, the severity, and caused by HSV 1 or 2)
- Gigivostomatitis OR Orofacial Herpes OR Herpes Labialis (recurrent form) OR “Cold sores”:
Age: Primary Infection: child/adolescent , Recurrent: any age
Frequency: very common
Severity: mild to moderate
Type: 1 > 2 - Genital Herpes
age: Once sexually active
frequency: Common
Severity: Moderate to severe
HSV: 2>1 - Keratoconjunctivitis (ocular infection)
Age: Any
Frequency: Fairly common
Serverity: Moderate to severe (can penetrate stroma and cause blindness)
HSV: 1
4. Dermatitis (other than face or genitals) Age: Any Frequency:Uncommon Serverity: Mild HSV: 1 or 2
5.Encephalitis
Age: Any
Frequency: Rare
Severity: Severe (over 50% death rate; those that don’t die have severe SEs)
HSV: 1 or 2 (in neonates), 1 (everyone else)
6. Disseminated HSV Age: Any (associated with immunosuppression) Frequency: Rare Serverity: Severe HSV: 1>2
- Neonatal Herpes (from infected mother during/after birth)
Age: Newborn
Frequency: Uncommon
Severity: Severe (disseminates because immune system not developed yet)
HSV: 2>1
Describe viral latency and how it is involved in herpesvirus
= Continued presence of viral genome, but absence of viral replication and viral particles
Mechanism:
• Lytic cycle genes not expressed during latency
• Latent virus can reactivate, causing recurrent disease or subclinical virus shedding (most common reactivation); latent viruses last lifetime of host
ALL herpesviruses establish latent infections*
ALL primary herpesvirus infections result in latent infections*
Latenet herpesvirus infections last the lifetime of the host–once you are infected you are always infected (don’t necessarily constantly shed the virus..)
•Different herpesviruses establish latency in different cell types
HSV Latency
o Entry into nerve cells: at primary site of infection
o Transport to nerve cell body: in ganglion; via retrograde transport
- Oral infection (trigeminal ganglion)
-Genital infection (sacral ganglion)
o Virus replication in ganglion: occurs for several days, followed by latency
Describe HSV Reactivation
o Frequency: depends on individual; ranges from never to monthly
o Reactivation stimuli: often spontaneous; others include sunlight, menstruation, infections, compromised immune system
oReactivation results in: replication in ganglion and travel back down the axon, causing infection near site of primary infection
What is the structure of HSV?
o Large, enveloped, DNA virus (linear, dsDNA; 75-80 genes)
o Icosahedral capsid
How does HSV Replication occur?
- Entry:
• Primary Route: attachment to host cell heparan sulfate, recognition of cell co-receptors initiates and fusion of viral envelope with plasma membrane
•Secondary Route: endocytosis followed by fusion with endocytic vesicle
2.Transport of capsid to nuclear pore via microtubule and release of viral DNA into nucleaus
- Gene expression = 3 phases:
(i) : immediate early genes adapt cell for virus replication
(ii) : Early gene products replicate viral DNA
(iii) : Late genes primarily encode structural proteins of the virus - Viral DNA is loaded into capsid in the nucleus.
- Envelopment and Release:
• Capsids first acquire envelope by budding through inner nuclear membrane
• Envelope fuses with outer nuclear membrane, and naked capsid released into cytoplasm
• Capsid buds into vesicles (golgi-derived) from cytoplasmic membrane (acquires envelope again)
• Enveloped virions release from cell via fusion of vesicles with plasma membrane
How do antivirals work agains HSV DNA Replication?
**HSV encodes its own DNA replication system:
• DNA polymerase is the target for most anti-herpes drugs (most are nucleoside analogs); HSV also codes for Thymidine Kinase (TK)
Steps of Activation (Phosphorylation):
• HSV-encoded TK phosphorylates acyclovir (or other) to monophosphate-acyclovir
• Cellular kinases synthesize di- and triphosphate forms
• Triphosphate form inhibits DNA synthesis by:
➢ Inhibiting viral DNA polymerase directly
➢ Becoming incorporated into DNA, resulting in termination of strand (inhibits elongation because it acts as a chain terminator)
**Acyclovir = prodrug Valacyclovir = active form
Describe the Varicella Zoster Virus primary infection and reactivation forms
Primary VZV Infection: typically manifests as varicella (chickenpox)
• Worse in adulthood than in children
• Latent infections established in dorsal root ganglia
Reactivation of Latent Virus: causes zoster (shingles)
- Incidence increases with age
Now use a live attenuated vaccine against VZV in the United States
What is the port of entry, infection and incubation period of Varicella?
Portal of Entry:
• Primary: upper respiratory tract (some replication occurs here)
• Secondary: fluids from vesicles containing high concentrations of infectious particles
Viremia:
• First Stage: spread to lymphoid organs (replication)
• Second Stage: spread to epithelial tissue (lesions) and respiratory tract (more transmission)
➢ Lesions appear on trunk first, spread outward (centrifugal spread)
➢ Lesion stages: macule, papule, vesicle, crusting
➢ Typically heal without scarring (unless secondary bacterial infection)
Incubation Period: 14-21 days
Describe the manifestation of Zoster
Reactivation of latent VZV: causes unknown; can happen more than once
Prodromal syndrome may exist: nerve pain/tingling before outbreak
Lesions: generally limited to skin/mucous membranes innervated by the reactivated ganglion (sharply demarcated areas)
Post-Herpetic Neuralgia is possible: persistent nerve pain after lesions disappear (can last for months)
What are the characteristics of Beta Herpes viruses?
General:
- Slow replication cycle (many days vs. ~24hrs for alphaherpesviruses)
- Restricted host range and cell type specificity
- CMV:
- Causes cell enlargement (cytalomegaly)
- Slow replication cycle
- Latent infections in cells of myeloid lineage - HHV-6:
- Common: by 12 months of age, nearly everyone is seropositive for HHV-6
- T cell tropic
- 2 Subtypes: HHV-6A: not associated with disease, HHV-6B = Establishes latency/replicates in monocytes and macrophages
Primary HHV-6B- Exanthem Subitum (Roseola): = fever, rash on trunk and face spreading to legs
➢ Common childhood infection
➢ Incubation Period: 5-15 days
➢ Transmission: saliva?
➢ Symptoms: fever (3-5 days), rash developing over trunk/face and spreading to limbs as fever diminishes
➢ Possible Complications: very high fever, neurological symptoms (convulsions, aseptic meningitis), hepatitis, mononucleosis-like syndrome
- HHV-7:
- Also T cell tropic
- Establishes latency in T cells
- May also cause exanthem subitum (roseola)
Describe the Gamma Herpesviruses affecting Humans and their presentations/complications
- Epstein-Barr Virus:
- B cell and epithelial cell tropism (growth)
- Latent in B cells - HHV-8 (Kaposi’s Sarcoma Associated Herpesvirus):
- Prevalence: sub-Saharan Africa and Mediterranean regions (rare elsewhere, besides in HIV-1 patients)
**- Associated with many forms of cancer (all forms of Kaposi sarcoma, body cavity based lymphomas, and multicentric castleman’s disease–lymphoid hyperplasia):
Kaposi’s Sarcoma:
Classic KS:
➢ Slow progression (disease you die with, not from)
➢ Found in older men of Mediterranean descent
➢ Nodular/plaque-like dermal lesions (often on lower leg)
Endemic-African KS:
➢ More aggressive
➢ LN involvement
Iatrogenic KS:
➢ Caused by a medical procedure (ie. solid-organ transplant patients)
➢ Also more common in those of Mediterranean descent
Lymphadenopathic KS (HIV Positive Patients): ➢ Disseminated and aggressive (involvement of internal organs, viscera, LN and skin)
Describe the general features of human papillomaviruses, their structure and their associated genes
- Virus Family: papovaviraidae
- Virus Subfamily: papilomavirinae
Structure:
- Small, DNA virus (circular, dsDNA; 8-10 genes)
- Nonenveloped icosahedral
HPV-16 Genome (Carinoma-Causing): - Composed of 8 genes (6 early, 2 late) - Transforming Genes: E6: destruction of p53 TSG E7: inactivation of Rb TSG (primary regulator of cell cycle) -Major Capsid Protein: L1 gene product Target of virus neutralizing Abs (active component of Gardasil HPV vaccine)
Gardasil Vaccine: against types 6, 11, 16, 18
What are the clinical manifestations of HPV?
- Cutaneous Warts:
A. Common Wart:
• Painless and hyperkeratotic (hypertrophy of striatum corneum)
• Round papules often occurring in groups
• Caused by HPV 2, 1, 4 and others
B. Plantar Wart:
• Painful, deeply set warts on weight-bearing surfaces of feet
• Caused by HPV type 1 (most commonly)
C. Flat Wart:
• Multiple flat, asymmetric, smooth papules
• Caused by HPV types 3, 10 and others - Mucosal Warts:
A. Laryngeal, oral, conjunctivival papillomas: HPV 6 and 11 (most common)
B.Anogenital papillomas:
• External genitalia, anus and near external opening of urethra
• Types 6 and 11 most common (low risk for carcinoma)
• Types 16, 18, 31, 33, and 35 are relatively uncommon (highest risk)
➢ Risk for cervical, vulvar, penile and anal carcinoma - Epidermodysplasmia Verruciformis:
- Associated with a rare uncharacterized genetic disorder
- Multiple flat wart-like lesions caused by unusual HPV types
- Frequent progression to cancer in sunlight exposed areas
What are the clinical outcomes for HPV infections?
- Subclinical infection with viral clearance
- Latent infection with possible subsequent reactivation
- Development of warts/condylomas/low grade neoplasia
- Progression to high grade lesion/carcinoma/invasive carcinoma
What is the pathogenesis of HPV and how does it progress to cancer?
- Transmission: direct contact or transfer to/from inanimate objects
- Infection: requires that virus reaches basal layer of epidermis; often requires minor injuries/breaks in skin to get access to these cells
- Process:
1. Hyperplastic growth of basal layer cells
2. Expression of HPV late genes (capsid proteins) and virion production
3. Mature virus contained in highly differentiated cells at the surface of the lesion (those in basal layer are not as differentiated)
Development to Cancer:
- Normal Circumstances: virus replicates like an episome/plasmid in the nucleus, but does not integrate into host DN
- Molecular Accident Occurs: integration into host DNA, and cell undergoes excessive cell division
HPV Cervical Intraepithelial Neoplasia :
- Stage 1: mild dysplasia in epidermis (less than 1/3); koilcocyte may be seen in higher layers
- Stage 2: moderate dysplasia in epidemis (2/3s); koilcocyte may be seen in higher layers
- Stage 3: severe dysplasia (entire epidermis)
- Invasive Carcinoma: cells penetrate basement membrane and invade surrounding tissue
Describe picornaviruses and their relationship to infections of the skin and mucous and what the clinical signs of infection are
Structure:
- Very small
- Non-enveloped
- ssRNA (plus sense)
Coxsackieviruses (type of picornovirus):
- Cause infections of the skin/mucous membranes
o Herpangina: mainly oral lesions
o Hand, Foot and Mouth Disease
Clinical Signs of Infection:
- Prevalence: most common in infants and children (often associated with epidemics- ie. outbreak at daycare; this is one way to differentiate from HSV)
- Symptoms: fever, sore throat, headache, anorexia, lesions
- Lesions:
• Arise within 2 days of symptoms
•Small, papulovesicular lesions on the tonsils, soft palate and tongue (can be confused with HSV lesions); enlarge within a day
•Lesions can also occur on hands, feet and diaper area (H,F and M Disease)
Resolution: more rapid than HSV (healing of lesions in 1-5 days)
What are the ways that micro-organisms cause disease in skin?
- Exogenous: direct infection by agents external to the skin (ie. bacteria entering through a cut)
- Endogenous: spread of organisms to the skin via the blood stream, along nerve pathways, or by extension from an adjacent site
- Indirectly: from toxins produced by bacteria located outside the integument
What are the most common infections of skin exogenously?
bacterial: S.aureus, S.pyogenes
Describe the: Location, Typical Organism, Clinical Information, and Treatment of: Impetigo
Location: Epidermis
Organism: S.aureus/S.pyogenes
Clinical Information:
-Common in children
-Weeping, crusted lesions (honey-colored)
-Patient is irritable and uncomfortable, but not febrile or seriously ill
-Post-Streptococcal Glomerulonephritis: can occur due to impetigo caused by S.pyogenes
Treatment:
Topical Abx (Mupirocin)
Oral Abx
Describe the: Location, Typical Organism, Clinical Information, and Treatment of: Erysipelas
Location: Epidermis and dermis
Organism: S.pyogenes
Clinical Info:
- More serious
- Common in older adults
- Elevation of involved tissue, forming sharp borders
- Bright red and painful
- Fever common
Treatment:
Oral or IV penicillin
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Cellulitis
Location: Epidermis, dermis and subcutaneous
Organism: S.aureus, Streptococcus
Clinical Info:
- Borders not as clear
- Fever is present
- Skin is edematous, warm, erythematous, tender and painful
- Vesicles/bullae common
- Ecchymosis in severe cases
Treatment:
Oral or IV penicillin
Cefazolin
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Folliculitis
Location: Hair follicle (superficial)
Organism: S.aureus
Clinical Info:
- Superficial
- Usually multifocal pustules
Treatment: None
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Furuncle (Boil)
Location: Hair follicle (deep)
Organism: S.aureus
Clinical Info: -Deeper and more extensive -Large, painful local boils -Surrounding inflammation or cellulitis Lance, drain (often all that is needed)
Treatment
Cephalosporin or Dicloxacillin
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Carbuncle
Location: Multiple furuncles in confined area
Organism:S.aureus
Clincal Info
- Typical area is back of the neck
- Patient often acutely ill
Treatment:
-Requires systemic Abx and surgical drainage
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Fasciitis
Location: Fascia
Organism: S.pyogenes, S.aureus Vibrio vulnificus (sea water exposure)
Clinical Info
- Patient acutely ill and in marked pain
- Skin overlying the infected area can be unremarkable
- Can also have changes such as gas in the tissue, hemorraghic bullae and ecchymosis
Treatment:
Emergency surgery and debridement
Systemic Abx (IV)
Describe the: Infection, Location, Typical Organism, Clinical Information, and Treatment of: Myonecrosis (Gas Gangrene)
Location: Muscle
Organism: Anaerobic streptococci, Gram (-) enterics, Clostridia spp. (gas gangrene)
Clinical Info
- Patient acutely ill and in marked pain
- Skin overlying the infected area can be unremarkable
- Can also have changes such as gas in the tissue, hemorraghic bullae and ecchymosis
Treatment:
Emergency surgery and debridement
Systemic Abx (IV)
What are the three ways that endogenous infections spread?
- Direct extension
- Hematogeneous Spread
- Spread along neurons
What is the typical appearance of endogenous skin infections?
- Hematogenous Bacterial Infections: lesions are circumscribed (confined to a limited area) and appear singly or multiply as macule, papules or pustules (not spreading cellulitis)
- Hematogenous Viral Infections: present as widespread, symmetric lesions that frequently become confluent after initially presenting as discrete macules, papules, or vesicles (these rashes are called exanthems)
- Viral Infections with Neuronal Spread: only local skin involvement (follow neuron)
What are the sources of direct extension endogenous skin infections?
- Osteomyelitis: draining sinus
- Septic Arthritis: draining sinus
- Lymphadenitis:
• TB
• Atypical mycobacteria
• Streptococcal infections - Oral/Dental Infection:
- Actinomycosis
- Mixed cellulitis
What are the sources of Hematagenous spread endogenous skin infections?
1. Bacteremia: • Menigococcus • Gonococcus: lesions spread out, usually on extremities (macules or papules) • S.aureus • Pseudomonas
- Endocarditis
- Fungemia (candidemia)
- Viremia:
• Measles (rubeola): exanthem (macular-papular)
- Koplik spots in oral mucosa very diagnostic;
• Rubella (German Measles): exanthema, macular-papular
• Chicken pox: exanthem (vesicles)
-Characterized by multiple different patterns in clusters (not all spots of same type due to the fact that break-outs occur in waves and not all at once) - Rocky Mountain Spotted Fever
- Secondary Syphilis: lesions on soles of the feet and palms of the hands (as well as elsewhere)
What are the sources of neuronally spread endogenous skin infections?
- Herpes Simplex Infection:
• Herpes labialis: HSV-1 (vesicles on lip)
• Herpes genitalis: HSV-2 (genital vesicles/ulcers) - Varicella Zoster (Shingles): dermatomal spread in older and immunocompromised (vesicles)
What is the causative agent, MOA, and symptoms of: Scarlett fever?
- Causative Agent: S.pyogenes
- Description: primary strep throat infection that releases an erythrogenic toxin that spreads systematically and causes diffuse red rash that feels like sandpaper
-Associated Symptoms:
• Circumoral pallor (white area around the mouth)
• Deep red lines (Pastia’s lines) in skin fold of neck, axilla, elbows and knees
• Strawberry tongue
• Extensive desquamation of superficial skin layers on recovery
What are the different toxins of S.Auureus that cause skin infections?
- Exfoliatin: results in bullous impetigo or scalded skin syndrome (more extensive)
• Bullous Impetigo: differs from the S.pyogenes impetigo due to the fact that there are large vesicles/bullae
• Scalded Skin Syndrome: widespread intra-epidermal cleavage, blistering and superficial epidermal sloughing (scary, but kids often make full recovery) - Toxic Shock Syndrome Toxin (TSST-1): spread of the toxin results in high fever, hypotension, multi-organ injury and diffuse erythematous rash that desquamates on recovery (especially around nail beds, hands and feet)
