M21 - Respiratory pathogens 1 (toxins and virulence) Flashcards
What is virulence mechanisms?
The degree of pathogenicity of a disease causing organism is determined by the proteins it expresses & how effectively it can integrate environmental information
What is the cycle of infection?
- Entry
- attachment
- Multiplication
- Evasion of host defences
- Causes damage
- release and spread
Name some virulence mechanisms.
- Bacterial adhesion
- Bacterial invasion
- Bacterial evasion of host defenses
- Bacterial toxins
Name 4 of the ligands and their receptors of bacterial adhesion.
- Capsule S.pyogenes / Keratinocytes
- Fimbriae B. pertusis / Laryngeal epithelial cells
- Cell wall S. aureus / Epithelial cells
- Fibrils S. sanguinis / platelets , salivary proteins
Describe bacterial invasion.
- Can be superficial or systemic (metastasis)
- Can be extra or intra cellular
- Can gain access via general contact or injection (e.g. arthropods, malaria)
Give 2 examples of bacterial invasion.
- Organism erodes tooth - S.mutans (caries)
- Organism persists in epithelial - P.gingivalis (perio)
What happens in dissemination/metastasis after penetration of epithelium?
- Blood vessel endothelium –> circulates in blood
- Enter phagocytic cells –> circulates in blood/accumulates in lymph nodes
- Lymphatic tissue endothelium –>accumulates in lymph nodes
what multiple mechanisms do bacteria have to avoid host defences?
– Immunity at mucosal surfaces – Destroy Immune cells – Interfere with inflammatory response – Evade Innate Immunity – Overcome acquired Immune Responses
What provides immunity at mucosal surfaces?
- Production of Glycosidases & Sialidases :
e. g. Streptococci spp. & Veillonella spp
-Proteases -cleave hinge region of IgA1 normally protected by glycosylation (S. sanguini)
-IgA binding proteins :
M Family proteins - bind Fc region of Ig (wrong way round)
what is the key to the immune response?
• Cytokine balance is key to immune response
– Integrate & orchestrate myeloid, lymphoid & vascular
response to infection.
– TNF a, Interferon, Interleukins,
– Bacteria can induce septic & toxic shock
What are cytokines?
group of regulatory proteins key to immune response
What are endotoxins?
-Gram-negative cell wall constituent
-Lipopolysaccharide (LPS) outer membrane complex;
E.coli, Salmonella
Name the LPS components.
Toxicity; LipidA
Immunogicity; Polysaccharide
What do endotoxins do?
Induces variety of inappropriate inflammatory responses that impair hosts response to pathogen
How do endotoxins interfere with cytokines?
Bind to receptors on macrophages, B cells, & other cells that stimulates release of acute phase cytokines.
Describe the outer membrane of gram negative bacteria.
– Assymetricmembrane
– Lipopolysaccharides(LPS)
– Peptidoglycan
– Lipoproteins
What causes endotoxin shock or systemic inflammatory response syndrome (SIRS)?
Either :
- endotoxin or lipopolysaccharide and peptidoglycan acting on macrophages to release inflammatory cytokines
- exotoxins acting on T cells to release inflammatory cytokines
Describe complement evasion as a method to evade innate immunity.
Capsules
a) prevent activation via C3 and C3b
b) mask bound C3b
Describe evasion of phagocytic killing as a method to evade innate immunity.
PVL -S.aureus
Name 2 variations that can overcome acquired immune responses?
- phase variation
- antigenic variation
Describe phase variation.
– switching between “on” and “off” forms of a gene
• flagellin gene of Salmonella typhimurium
• opacity genes of Neisseria gonorrhoea
Describe antigenic variation.
– allows the bacterium to change the sequence of a gene
• pilin genes of Neisseria gonorrhoea
What do these variations make it hard to do?
Find effective vaccines
What is diphtheria?
- 2-6 day incubation
- mucous membranes infected (tonsils)
what are the early symptoms of diphtheria?
Sore throat, low fever, swollen neck glands
what are the late stages of diphtheria characterised by?
– Airway obstruction, breathing
difficulty
– Shock (hypotension, tachycardia, pale, cold skin, sweating, anxious)
What are outbreaks of diphtheria associated with?
– Unsanitary/crowded conditions
– Immunity gaps, vaccination failure
What does the toxin in diphtheria produce and what results from this?
• Toxin produces acute inflammation & formation of pseudomembrane
– Dead tissue, fibrin, polymorphs & bacteria
• Swollen neck
• Complications, breathing obstruction, cardiac arrhythmia, coma
Describe the features involved in diphtheria.
– Life threatening disease
– Cause toxigenic Corynebacterium diptheriae
• Gm +ve bacilli
• Chinese lettering morphology
• Aerobic, non-motile
• Tellurite agar (toxic for other throat flora)
• Albert s stain (metachromatic granules)
• Confirmation of Toxin production
– Transmitted by direct contact droplets/skin, or indirect via contaminated object
Describe corynebacterium diphtheria.
• DT Type III • Soluble 3 domain protein – Receptor-binding, translocation, & catalytic, • Heparin-binding EGF-receptor • Endocytosed • Proteolytic cleavage • Fragment A carries Catalytic domain • Fragment B Receptor domain and Translocase Domain
what is the treatment for corynebacterium diphtheriae?
– Immediate inoculation with diptheria
antitoxin
– Administer Penicillin or Erythromycin to eliminate bacteria
what is the prevention of corynebacterium diptheriae?
– Activeimmunisation
– Diptheria Formal Toxoid (DPTvaccine)
– Part of multiple vaccine, diptheria, tetanus & whooping cough given at 2, 3 & 4 months.
– Booster at approximately 5 years
What is whooping cough?
highly contagious, life threatening disease
what bacteria is associated with whooping cough?
Bordetella pertusis small Gm-ve cocci
how is infection of whooping cough caused?
exposure to infected individual
what population is whooping cough highly significant in?
children < 2 years old with the possibility of secondary bacterial pneumonia and neurological complications that may prove fatal
What are the characteristics of the disease for >15 years?
symptoms are milder, similar to viral upper
respiratory tract infection
what are the symptoms of whooping cough?
• Severe cough that persists for >7 days
• Low or no fever (limited to first week)
• Major Symptoms
– >2 weeks choking cough attacks (whoop in 50% of cases)
– Persist for 3 weeks to 3 months (100 day cough)
what symptoms may adults with whooping cough present?
– Shortness of breath during coughing
– Nocturnal coughing
– Tingling sensation in back of throat
– Post-tussive vomiting
how does bordetella pertusis enter the body?
respiratory tract
what does bordetella pertusis attach to?
ciliated epithelial cells of respiratory tract
what is bordetella pertusis mediated by?
Filamentous Hemagglutinin (FHA)
what is the outer membrane protein of bordetella pertusis that promotes atthachment to tracheal epithelial cells?
Pertactin (PRN)
what toxins are involved in bordetella pertusis?
– Pertusis Toxin
– Adenylate Cyclase/hemolysin
– Lethal (or Dermonecrotic) Toxin
– Tracheal cytotoxin (TCT)
( Kills ciliated cells & stimulates their extrusion (loss) from the
mucosa)
– Lipopolysaccharide (endotoxin) also contributes to disease
Describe the pathogenesis of bordetella pertusis.
• Growth on ciliate epithelial & toxin production
– Paralyse cilia Tracheal cytotoxin (TCT)
• Kills the ciliate epithelial cells
• Induce mucus secretions
– Stimulate inflammatory response
– Kill leukocytes (Pertusis toxin)
Describe the structure of the pertusis toxin.
-classically one A unit and five complex B units
-Bordetella pertusis:
>PT toxin
>A subunit S1
>B composed of S2,S3, S5 and 2 x S4
>S1 ADP-ribosyltransferase
>leads to increase in cAMP
what does pertusis toxin do?
– Disrupts cell function, increases mucus secretion, incapacitates phagocytes
– Systemic consequences, increase in insulin (hypoglycemia) & sensitivity to histamine
How do you diagnosis bordetella pertussis?
• Cough plate
– (hold BG culture plate in front of mouth when coughing)
• Perinasal swab of posterial pharyngeal walls
What is the treatment for bordetella pertusis?
• Erythromycin for 14 days
– (ideally pre-paroxysmal stage)
• Skilled nursing, remove mucus & vomit
• Antibiotic therapy for secondary infections
Describe the vaccination of B. pertusis.
– Includes 3 main antigenic types (acellular vaccine)
– Given as part of multiple vaccine
• (diptheria, tetanus, whooping cough, polio & Hib))
– 2, 3 or 4 months
Describe virulence mechanisms and what is included.
• Understanding molecular basis of disease, informs prevention, treatment & development of new mechanisms to control disease.
- • Bacterial adhesion
- • Bacterial invasion
- • Bacterial evasion of host defenses
- • Bacterial toxins & definition of an endotoxin
