Virulence in candida species

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Virulence in candida species
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Candidiasis

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• Involvement may be localized or systemic
• Pathologic processes vary from irritation and
  inflammation to chronic and acute suppuration or
  granulomatous response

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History
Hippocrates described thrush in debilitated
patients Until 1940s Candidiasis was a common
infecting agent of the skin mucosa and vagina but
was rarely a cause of serious systemic
disease 1940 - Joachim and Polayes described
endocarditis as a hazard of heroin
injection 1980s - now Candidiasis is one of
the most protean of fungus infections Subsequent
to the use of antibacterial agents, Candida known
to be part of a delicate and balanced
ecosystem. Candidiasis also became associated
with the use of steroid therapy,
immunosuppressive drugs, cytotoxic agents and
immune defects Today, Candida is recognized as
one of the most frequently encountered fungal
opportunists and the most common cause of serious
fungal disease
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Etiology

• Candida spp. are thin walled small budding yeasts
  (4-6um diameter)
• 154 spp.
• 6 Candida spp. Regularly cause disease in humans
• C. albicans
• C. tropicalis
• C. glabrata
• C. parapsilosis
• C. krusei
• C. lusitaniae
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Ecology
It is a Pathogen, colonizer and is found in
nature Found on leaves, flowers, water and
soil Found on fomites, food and hospital
environments
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Distribution

• Importance of Candida infections has increased in
  the past 20 years
• New chemotherapeutic agents, new
  immunosuppressive agents, organ transplantation,
  intravenous nutrition, broad spectrum antibiotics
  and advanced surgical techniques
• Amon the leading causes of nosocomial infections
  (bacterial and fungal)
• The leading cause of fungal infection in HIV-AIDS
  patiens

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Clinical disease

• Clinical spectrum of candidiasis is extremely
  diverse
• Almost any organ/system in the body can be
  affected
• Can be superficial and local or deep-seated an
  disseminated
• Disseminated infections are a result of
  hematogenous spread from the primarily infected
  locus
• Forms of the disease
• mucocutaneous
• invasive
• miscellaneous

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Mucocutaneous infection

• Colonization any mucosa, asymtomatic, norma
  flora,
• Cutaneous prolonged exposure to moisure, diaper
  rash
• Esophagitis very common in AIDS patients
• Onychomycosis invasion of the nail by fungus
  (50)
• Oropharyngeal oral infection, (100)
• Vulvovaginitis 90 caused by Candida

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Invasive infection

• Complicatd collecion of diseases
• Only seen in immunocompromised patient
• Frequency of strains
• C. albicans 50
• C. tropicalis 15-30
• C. galbrata 15-30
• C. parapsilosis 15-30
• C. krusei 1
• C. lusitaniae 1

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Invasive infection (Candidemia)

• Isolation of Candida from a blood sample
• 4 overlapping forms of candidemia
• Catheter-related candidemia
• Acute disseminated candidiasis
• Chronic disseminated candidiasis neutropenia,
  liver, spleen, kidney
• Deep organ candidiasis
• C. lusitaniae 1

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What is Viruence determinant?

• May be essential for virulence
• Factors that interact directly with mammalian
  host cells
• A component of a pathogen that damages the host
• Generally confirmed by the inability of null
  mutants to cause disease in animal models to the
  same extent as wild type parental or complemented
  strains (Molecular Kochs postulates)

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Viruence determinant

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Adherence to host tissues

• ?????????? first stage of the infection process
• Candida adhere to host or other bacterial normal
  flora
• Biofilm formation is closely related to adherence
  (C. albicans has the greatest ability to form
  biofilm)
• Candida proteins interact with RGD motifs
  (fibronectin, iC3b)
• Int1p (integrin like, iC3b binding RGD protein)
• ALS family ( agglutinin-like sequences)
• EPA1 (lectin)

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Responses to environmental changes

• Often mediated by cell surface receptors that
  initiate signal transduction cascades
• Altered activity of transcription factors and
  modification of gene expression
• Ability to form hyphae is a key virulence factor

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• Tup1 repressor ( RBT1, RBT4, RBT5, HWP1 and
  WAP1)
• Altered activity of transcription factors and
  modification of gene expression
• Ability to form hyphae is a key virulence factor

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• The transcription factors exert pleiotropic
  effects, the most obvious of which is
  morphogenesis
• Tup1 repressor ( RBT1, RBT4, RBT5, HWP1 and
  WAP1)
• Gene homologues have diversed function
• CPH1 STE12 in Saccharomyces, CLS12 in C.
  lusitaniae (null-sterile but no defect)

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Secreted hydrolases

• Secreated hydrolases
• break down barriers to growth
• Break down polymers to provide accessible
  nutrients
• Inactivate host defense molecules
• Aspartic proteinase enzyme family in C. albicans
• 9 SAP genes, temporal and spatal differences in
  the expression (likely to play a different role)
• tropicalis, parapsilosis, guillermondii have
  homologues

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Secreted hydrolases

• Phospholipase
• PLB1 mutant in CA - impaired virulence
• Extracellular production of PL - CG, CP, CT, CL,
  CK
• Inactivate host defense molecules
• Lipase gene family

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Other attributes

• Phenotypic switching white-opaque cells
• SAP1, 3 opaque-cell specific
• SAP2, EFG1 white-cell specific
• Fungal efflux pumps
• ABC-tansporters CDR1, MDR1 (azole resistance)
• May be coincidental phenotype of other transport
  function ?