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Gram-positive: Staphylococci and Streptococci. Medical Microbiology SBM 2044. Staphylococcus aureus. The most common pus-forming (pyogenic) bacteria Can produce focal abscess, from the skin (furuncles, boils) to the lungs, osteomyelitis, kidneys and endocarditis

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Gram-positive: Staphylococci and Streptococci

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Gram-positive: Staphylococci and Streptococci

Medical Microbiology

SBM 2044


Staphylococcus aureus

  • The most common pus-forming (pyogenic) bacteria

  • Can produce focal abscess, from the skin (furuncles, boils) to the lungs, osteomyelitis, kidneys and endocarditis

  • Include S. aureus, S. epidermidis, S. saprohyticus (UTI)

  • S. aureus can persist in the body because they have numerous cell surface virulence, exotoxins and enzymes


S. aureus

  • Staphylo = grape clusters (Greek)

  • A large 1µm Gram-positive coccus growing in cluster-of-grapes shape.

  • Can survive in long period of dry, on inanimate object. Heat resistant.

  • Identification: large, creamy colonies on nutrient agar; catalase +


Staphylococci


S. aureus

Encounter

  • Major reservoirs = humans

  • Live on skin – grow at high salt and lipid concentrations because they make lipases and glycerol ester hydrolases, that degrade skin lipids

  • Colonise skin and mucosal surfaces using MSCRAMMs:

    • Fibronectin–binding proteins (FnbpA, FnbpB)

    • Collagen-binding

    • Clumping factors A and B

  • Spread person-to-person by direct contact or airborne


S. aureus pathogenesis

  • Entry

  • Tissue penetration upon skin or mucosal membrane damaged by cut

  • Spread and Multiplication

  • Survival in tissues dependon

    • no. of entering microorganisms

    • site involved

    • speed of body’s inflammatory responses

    • immunological history of the host


S. aureus pathogenesis

  • Damage

  • Local infections  pus collection, i.e. abscess

  • Staphylococci can spread into subcutaneous and submucosal tissues and caused cellulitis

  • Activate acute inflammatory reaction, pouring in chemotactic factors

  • Damaged area are usually localised by the formation of thick-walled fibrin capsule : center of abscess is necrotic with debris of dead cells

  • Why many virulence factors?


  • Surface structures:

  • Capsules – inhibit phagocytosis

  • Peptidoglycan – interacts with TLR-2, activate alternative pathway

  • Teichoic acid – C’ activation and adherence to mucosal cells

  • Protein A – binds to Fc terminus of IgG

  • Secreted factors:

  • Catalase – H2O2 H2O

  • Coagulases – fibrinogen  fibrin

  • Pore-forming toxins – create channels to disturb cellular homeostasis

  • Haemolysins –

  • Leukocidin

  • Hyaluronidase – hydrolyse matrix of connective tissues

  • Β-lactamase – hydrolyse penicillin

  • Penicillin-binding protein (PBP2a)


S. epidermidis

  • Normal flora, rarely caused disease

  • Infections of S. epidermidis with other catalase-negative staphylococci in patients implanted with artificial devices e.g. prosthetic joints or IV catheters

  • Results in septicaemia and endocarditis

  • Possibly peptidoglycan or slime layer allows the organisms to stick to the surface of plastics


S. saprophyticus

  • Caused cystitis in young women


Staphylococcal toxin diseases

  • Staphylococcal scalded skin syndrome (SSSS)

    • Exfoliative toxins A and B – highly tissue specificserine proteases that causes separation of the layers of the epidermis at the desmosomes

  • Staphylococcal toxic shock syndrome (TSS)

    • characterised by fever, skin rash, hypotension, peeling of the skin

    • use tampons – oxygenated vagina and stimulate toxin production

    • TSST-1, staphylococcal enterotoxins AE

  • Virulence gene regulation – two-component regulatory systems

    • Accessory gene regulator (Agr), staphylococcal respiratory response (Srr)


  • Diagnosis

  • Gram stain and culture

  • Treatment

  • Methicillin-sensitive S. aureus – Rx: semi-synthetic penicillins and cephalosporins

  • Methicillin-resistant S. aureus – Rx: vancomycin

  • vancomycin-resistant S. aureus –acquired the genes of resistance from vancomycin-resistant Enterococcus species


Streptococci

  • Classification

    • Haemolytic pattern – in blood agar media, colonies formed may be surrounded by a clear zone of haemolysis (α,β, γ)

    • Group-specific antigens (Lancefield classification) – by serological reactivity of extracted cell wall antigens (A  U)

    • Species – biochemical tests


  • Homofermentative

[Glucoselactic acid]

Streptococcus

  • Gram-positive

  • Grow in chains

  • Non-motile

  • Facultative anaerobes

  • Early studies distinguished 3 broad groups on blood agar

  • a-haemolytic

  • non-haemolytic

  • b-haemolytic


  • Streptococci


  • GAS diseases – changing patterns

  • Changes in virulence of prevailing GAS strains ?

  • Changes in social conditions – less crowding?

  • Changes in herd immunity to prevailing virulent strains?

  • Reemergence of severe invasive infections

  • Sporadic cases since mid-1980s – new virulent strains?

  • Streptococcal toxic shock

  • Some cases associated with obviously severe tissue infections

  • Many others – shock following mild or unapparent infections

  • Sporadic – implies predisposing factors


Group A Streptococci

  • Epidemiology

    • Ubiquitous worldwide

    • Common diseases are acute pharyngitis or pyoderma infections (skin and soft tissues)

  • Encounter

    • Carriers appear asymptomatic

    • Person-to-person spread is mediated by respiratory droplets or by direct contact to skin

  • Entry

    • For pyodermal infections, streptococci need to gain entry into deeper layers of skin

    • In pharyngeal infections, to prevent from being swept away, GAS must lipoteichoic acid (LTA),protein F and M protein


  • Spread and multiplication

    • Most GAS remain localised to the site of initial infection

    • In pharynx and tonsils, may result in erythema and exudate associated with strep throat

    • Peritonsillar abscess (quinsy) or spread to adjacent structures (mastoid and middle ear)

    • Impetigo in skin

    • Erysipelas and cellulitis in deeper layers of skin

    • GAS may spread laterally in deep tissues, by secreting enzymes

      • necrotizing fasciitis and myositis


GAS virulence factors – Excreted products

  • Both lyse wide range of cells, including PMNs

  • suppuration and/or necrosis

  • Cytolytic toxins

  • Streptolyxin O (SLO)

Produced by all strains

  • Streptolysin S (SLS)

  • Various subtle effects at sub-lytic concentrations

  • SLO – ‘sensitive’ to O2

  • SLS – stable in O2

b-haemolysis

“Thiol-activated” toxin

(NB: Salyers & Whitt misleading - neither are “enzymes” )


SLO- and SLS-defective mutants

  • murine s.c. model - weight loss at 24h post infection

Sterile

~3 x 108 cfu

~3 x 106 cfu

+ 0.5

~3 x 107 cfu

~3 x 105 cfu

~3 x 109 cfu

0.0

- 0.5

- 1.0

Weight gain (grams)

- 1.5

- 2.0

- 2.5

sloΔ1-

sagBΔ1

sagBΔ1

sloΔ1

WT

PBS


M protein

  • Important for cell adherence to keratinocytes

  • Prevent opsonization by complement

    • bind to fibrinogen and interferes with the alternative pathway

    • bind with host complement control proteins and inhibit opsonins formation

  • Hypervariable regions of M protein are antigenic, but there are > 100 M protein serotypes


Hyaluronic acid capsule

  • Antiphagocytic structure on bacterial surface

  • Hyaluronic acid is abundant in human connective tissue - hence GAS can camouflaged themselves

  • But capsule may interfere with the adherence of GAS to epithelial cells

    • so GAS shed the capsule during the early stages of infection using hyaluronidase


Damage

  • GAS can evoke an intense inflammatory responses in tissues

  • Streptococcal pyrogenic exotoxins (SPE)

    • SPE A, B and C cause rash, a characteristic of scarlet fever

    • SPE A and C are bacterial superantigens that activate a large subset of T cells

  • Immunologically mediated disease (nonsuppurative sequelae)

    • acute rheumatic fever (ARF)

    • acute post-streptococcal glomerulonephritis


Diagnosis

  • Impetigo – a cluster of small vesicles on a pink base that breaks down to honey-coloured crusts

  • Erysipelas – a raised, bright red patch of skin

  • More difficult to diagnose streptococcal pharyngitis

    • rapid strep tests

    • throat cultures (throat swab)


Treatment and Prevention

  • Penicillin – 10 day oral therapy

  • Erythromycin or other macrolide antibiotics for individuals allergic to penicillin


  • M-type specific antigen was sensitive to proteases M proteins

Streptococcus pyogenes

  • Natural habitat: Humans

  • Strains distinguished by M serotyping

  • Devised by Lancefield in 1920s, using panels of absorbed sera

  • to hot-HCl extracted antigen, she called “M antigen”

  • > 100 distinct M types of GAS distinguished since then

  • - called M1, M2, M3, M4,……..etc.

  • Highly versatile pathogen

  • Suppurative infections

  • Toxinogenic diseases

  • Immunologically-mediated diseases


Group A Streptococci

Principle sites

of infection:

Invasive infections

Local spread (e.g.)

Other tissues

Pharyngitis, tonsillitis,

otitis media, sinusitis.

Pharynx

Bacteraemia or septicaemia

Skinpyroderma, erysipelas

Occasionally

Streptococcal

Toxic Shock

Extensive necrosis

(necrotizing fasciitis)

Deep-seated

tissues

  • Puerperal fever (childbirth fever) in women – major killer in past


Streptococcus pyogenes

Tonsillitis

Follicular tonsillitis


Streptococcus pyogenes

Impetigo

Erysipleas

Cellulitis


Streptococcus pyogenes

Necrotizing fasciitis

(< 24 hours post surgery)


Streptococcus pyogenes


Streptococcus pyogenes

Scarlet fever


Toxic Shock

  • In past – probably linked to scarlet fever

  • Since mid-1980s – associated with ‘new’ highly virulent

    strains - rapidly fulminating

  • some cases in previously healthy young adults, no obvious

  • predisposing factors

  • Associated with production of superantigenic toxins, but

    other factors also involved


Acute rheumatic fever (ARF)

  • autoimmune disease - triggered only by GAS pharyngitis

  • associated with strong immune response to GAS.

  • antibodies and/or T cells X-react with host antigens? (later)

  • Symptoms arise > 10days + after GAS infection

  • responsible GAS strain already ‘cleared’

  • Symptoms may include:

  • inflammation multiple sites, starting with major joints (arthritis)

  • neurological disorders (Sydenhams chorea)

  • rheumatic heart disease (RHD) (ca 50% cases)

  • - damage to heart valves, permanent scaring in survivors


Acute rheumatic fever (ARF)

  • Initial attack rates low (3% in untreated pharyngitis)

  • High recurrence (up to 50%) - increasing in severity

Widespread prescription of penicillin for ‘sore throats’

Remarkably, GAS have not (yet ?) developed resistance to penicillins


GAS infections - complications

Post-streptococcal acute glomerulonephritis (PSGN):

  • Common, but rarely life-treating - some GAS infections

  • of either pharynx or skin.

  • Symptoms arise some 10 days after infection

  • reflect kidney dysfunction, probably involving inflammation

  • of glomeruli

  • Pathogenesis:

  • Most probably entrapment of GAS antigen-host antibody

  • complexes at basement membranes of glomeruli

  • might also involve an ‘autoimmune’ response


Normal glomerulus

Glomerulonephritis

Mesangial cell

Mesangial cell

intrusion

Endothelial

cell, has

100 nm

pores

PMN

Basement membrane

Inflammation

Too much large immune

complex entrapment ?

Small complexes diffuse thro’

basement membrane into urine,

but the occasional larger complex

can’t & is normally removed by

mesangial cell

Example: Sequel of some

S. pyogenes infections


Group B streptococci

  • Streptococcusagalactiae are aerobic G+ diplococci that are β-haemolytic on blood agar plates

    • found in lower GIT and female genital tracts

    • GBS is a leading cause of neonatal sepsis and meningitis

    • prevent opsonization and phagocytosis with a polysaccharide capsule


Enterococci

  • Enterococcusfaecalis cause UTI, wound infections, endocarditis, intraabdominal abscesses and bacteremia.

    • Normal flora of GIT and GUT

    • resistant to bile and high salt concentrations

    • nosocomial infections

    • resistance to many antibiotics, often bacteriostatic

    • bacterial killing must use a combination treatment of a β-lactam and an aminoglycoside


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