Wk13, final lecture

• Primary pathogens


  Cause damage in the setting of appropriate immune responses. They can cause damage in normal hosts.
• Opportunistic pathogens


  Are associated with disease only in individuals with impaired immune function and almost never cause symptomatic or clinically apparent infections in individuals with normal immunity.
• Moulds


  • Hyaline moulds
  • Dimorphic environmental moulds
• Hyaline moulds


  • Always filamentous
  • Change according to environment
• Hyaline moulds


  • Aspergillus fumigatus
  • Rhizopus oryzae
• Dimorphic environmental moulds


  • Blastomyces dermatitis
  • Coccidioides immitis
  • Histoplasma capsulatum
• Aspergillus fumigatus

  • The 'deadly mould'
  • Cosmopolitan
  • No genetic recombination detected
  • Growth optimum 25-40˚C
  • Present in large quantities in decaying organic matter
  • Class 2 HSE human pathogen group
• Infectious life cycle of A. fumigatus


  1. Airborne spores

  2. Mortality rate up to 95%

  3. Diagnostics: microscopic examination and culture of body fluids and tissue

  4. Risk factor: cancer chemotherapy, compost heaps, dirty air conditioning units
• Rhizopus oryzae


  • Common saprophytic fungi of plants - thermotolerant
  • Global distribution
  • Amongst the most common fungi in the world
  • Grows fast (3 mm/hour)
  • Aseptate hyphae facilitate cytoplasmic streaming and intrahyphal transport
  • Class 2 HSE human pathogen group
• Mycormycosis


  • Rare but lethal if left untreated
  • 3rd most common mycosis in neutropenic patients
  • Risk factor: uncontrolled diabetes
  • Global distribution
  • Common forms: pulmonary (30%), rhinocerebral (27%), soft tissue (26%), disseminated (15%)
• Blastomyces dermatitis


  • Endemic in the Mississippi and Ohio River basins, extending into Canadian provinces bordering the Great Lakes in into northern Ontario
  • Small foci in Africa and India
  • Ecological niche unknown, soil-dwelling
  • Class 3 HSE human pathogen group
• Blastomycosis


  1. Inhalation of conidia from environment into lung can cause asymptomatic or active disease

  2. If not contained in the lung, dissemination to skin, bones, GI tract or CNS may occur

  3. Men at greater risk for extrapulmonary blastomycosis

  4. Not communicable between humans
• Coccidioides immitis/posadasii


  • Ecological niche - desert soil
  • Endemic to southwestern US, Mexico
  • Hyphae fragment into barrel-shaped arthroconidida
  • Hydrophobic cell wall remnants from empty cells produce flange-shaped structures aiding in aerial dispersion
  • Class 3 HSE human pathogen group
• Coccidiomycosis - valley fever

  • Most infections symptomless, 40% flu-like symptoms, 2% develop chronic pulmonary form
  • 95% of pulmonary infections resolve without specific therapy
  • Risk factor: activities associated with dust and airborne dirt
  • Symptoms: influenza-like, fever, cough, headache, muscle pain
  • Coccidioidal meningitis 3rd most frequent granulomatous meningitis after tuberculosis and cryptococcosis
• When facing an invasive fungal infection, diagnose promptly, reverse immunosuppressive treatments, do not use steroids, surgically remove dead necrotic tissue, remove medically indwelling devices, start aggressive antifungal treatment
• Cryptococcus neoformans


  • Unicellular, haploid yeast that replicates by budding
  • Forms polysaccharide capsule
  • Environmental niche - trees, pigeons
  • Forms basidio spores
  • Can diversify by monokaryotic fruiting
• Cryptococcal meningitis


  • Over 1,000,000 infections/year
  • Infection of the brain
  • AIDS-defining illness (70% dead at 10 weeks)
  • Mortality up to 70% in sub-Saharan Africa
  • Basidiospores are the causative agent
  • No human-to-human transmission described
• Cryptococcal meningitis - diagnosis and treatment

  Diagnosis: Culture - gold standard, India ink, CrAg testing in CSF, serum
• Opportunistic pathogens: Almost never cause symptomatic or clinically apparent infections in individuals with normal immunity
• Primary pathogens

  Cause damage in the setting of appropriate immune responses. They can cause damage in normal hosts
• Cryptococcus neoformans


  • Unicellular, haploid yeast that replicates by budding
  • Forms polysaccharide capsule
  • Environmental niche - trees, pigeons
  • Forms basidio spores
  • Can diversify by monokaryotic fruiting
• Cryptococcal meningitis is a neglected disease
• Cryptococcal meningitis


  • Over 1,000,000 infections/year
  • Infection of the brain
  • AIDS-defining illness (70% dead at 10 weeks)
  • Mortality up to 70% in sub-Saharan Africa
  • Basidiospores are the causative agent
  • No human-to-human transmission described
• Cryptococcal meningitis manifestations


  • Meningitis
  • Cutaneous
  • Pulmonary

  
• Cryptococcal meningitis diagnosis


  • Culture - gold standard
  • India ink (86% successful, success depends on cell density)
  • CrAg testing in CSF, serum, plasma
• Cryptococcal meningitis management


  • Induction antifungal therapy (2 wks of AmpB + flucytosine)
  • Consolidation therapy (8 wks of fluconazole)
  • Maintenance therapy of fluconazole to prevent relapse
• Candida albicans


  • Ascomycetous, unicellular yeast that replicates by budding
  • Member of the human microbiome - commensal
  • 1/3 of the human population carries C. albicans in their oral cavities
  • 70% of people have C. albicans in their gastrointestinal tract
  • Obligate diploid that generates genetic diversity in parasexual cycle
  • Parasex contingent on white-opaque switching
• Candidosis (Candidiasis)


  • Systemic infection (bloodstream, organs)
  • Over 400,000 infections/year
  • Mortality rate up to 75%
  • Fourth leading cause of hospital-acquired bloodstream infections
  • Risk factors: cancer chemotherapy, abdominal surgery, low-birthweight, catheters
  • Neutropenia - lack of neutrophils
• Candidemia manifestations

  • Superficial infections of mucosal surfaces
  • 75% of women will experience at least one episode of vaginal thrush
  • 65% of denture wearers experience 'stomatitis'
  • 5% of newborns will suffer oral thrush
  • Risk factors: smoking, antibiotics, dry mouth, uncontrolled diabetes, diet
• Candida glabrata

  • Urinary tract and blood stream infections
  • Most frequent cause of blood stream infections after C. albicans
  • Haploid, asexual
  • Rising prevalence due to intrinsic resistance to azole resistance
  • Does not form hyphae
  • Phenotypic switching has been observed
• Candida parapsilosis


  • Diploid
  • Forms pseudohyphae
  • Associated with neonate ICU - transmission via hands of health care workers
  • Not an obligate human pathogen (like C. albicans)
  • Causing over 25% of all invasive fungal infections in low-birthweight infants
• Fungal cell wall

  • Pressure vessel
  • Shape, rigidity and strength
  • Chitin is the principal polymer
  • 'Calling card' - immunogenic components of the cell wall
  • Antifungal drug target
• Adherence to host surfaces

  • One of the most important determinants of pathogenesis
  • Prerequisite for host colonisation
  • Hydrophobic interactions - plastics, catheters
  • ALS genes encode cell-surface glycoproteins
  • Als receptors mediate interactions with epithelial and endothelial cells, extracellular matrix proteins
  • Mannose receptors facilitate interactions with immune cells
• Secretion of lytic enzymes

  • Hydrolytic enzymes (also found in bacteria, protozoa)
  • Hydrolyse peptide bound
  • Secreted aspartyl proteases (SAPs)
  • Ten SAP genes in C. albicans
  • Saps transported via secretory pathway
  • Provide nutrition for C. albicans
  • Sap production associated with hyphal formation and phenotypic switching
  • Saps also degrade human proteins
• C. albicans morphogenesis


  • Changes in cell wall composition permit morphogenetic changes
  • C. albicans transition to hyphae temperature-dependent
  • C. albicans mutants unable to switch between morphologies not pathogenic
  • Yeast form better suited for distribution in bloodstream
  • Hyphae state amenable to piercing of tissue and organs
  • Yeast and hyphae cells have distinct gene expression profiles
• C. albicans biofilm formation

  • Biofilms are surface-associated microbial communities
  • Form on medical implant devices, catheters
  • Act as reservoir for further distribution through the bloodstream
  • Intrinsically drug resistant
• Epithelial adhesins of C. glabrata

  • Genes located in subtelomeric regions
  • Telomeric location affects gene expression - mass expression phenomenon
  • Evolutionarily divergent
  • Functionally diverse
• Slime production in C. parapsilosis

  • Produces slime in glucose-containing solutions
  • 83% of blood and catheter isolates form slime
  • Aids in adherence
  • Supports biofilm formation
• C. neoformans polysaccharide capsule


  • Made of polysaccharides
  • Provides physical barrier
  • Interferes with phagocytosis and clearance by the immune system
  • Inhibits production of pro-inflammatory cytokines
  • Reduces leukocyte migration to site of infection
  • Major diagnostic feature for cryptococcosis
  • Capsule-synthesis mutants are not pathogenic
• Fungal virulence factors and pathogenicity


  • Adherence to host surfaces
  • Secretion of lytic enzymes
  • Morphogenesis
  • Biofilm formation
  • Polysaccharide capsule