FUNGAL PATHOGENESIS

Dr. dr. Mardiastuti H Wahid, M.Sc., SpMK(K)

M Helmi A 1906 345 370

PROGRAM STUDI MIKROBIOLOGI KLINIK UI-RSCM

OUTLINE

1. Fungal infecting agent: Primary and Opportunistic pathogen.

2. Fungal virulence factors

3. Host factors – Susceptibility to fungal infection

4. Classes of infection based on site – 1: Subcutaneous and systemic fungal infection

1. Fungal Infecting Agent
 INTRODUCTION

 The virulence of fungi involves interaction of agent and host.

 No single factor that causes or permits fungi to be agents of the diseases.

 Fungal pathogens can be divided into two groups based on their virulence:

 Primary pathogens  Environmental reservoir, infect in large dose, or infect naïve people.

 Opportunistic pathogen  Fungi take advantage of immunocompromised state of the host;

Can be found in environment but also exist as commensals in the host.

Walsh TJ, 1996; Van Burik 2001

 PRIMARY FUNGAL PATHOGEN

 Several fungi are able to cause infection in immunocompetent hosts such as

Coccidioides immitis and Histoplasma capsulatum.

 Infection by primary fungal pathogen  Asymptomatic - Subclinical disease.

 Occurs in people who live or travel in endemic areas (soil-related).

Walsh TJ, 1996; Van Burik 2001

 PRIMARY FUNGAL PATHOGEN

R.G. Lewis, 2015

 OPPORTUNISTIC FUNGAL PATHOGEN

 Increasing due to medical practice  survival of debilitated and immunosuppressed

patients.

 Host factors play major role  Local and systemic immune system impaired.

 Virulence factors switching in absence of normal immune systems  Opportunity 

Unregulated growth  Invasive infection.

 Example of opportunistic fungi  Candida albicans and Cryptococcus neoformans.

Walsh TJ, 1996; Van Burik 2001

 OPPORTUNISTIC FUNGAL PATHOGEN

Naglik JR, 2014

FUNGAL INFECTING AGENT
2. Fungal virulence factors
(Brunke, Mogavero, Kasper, & Hube, 2016)
 FUNGAL GROWTH

 Ability to grow at body temperature and within fever range (37°C-42°C).

 S. cerevisiae  not a pathogenic fungi  able to grow from pseudo-hyphae, infect-

persist in mice.

 C. neoformans  Calcineurin protein which required for growth 37°C. Disrupted

calcineurin  avirulent strain of cryptococcal meningitis.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL GROWTH

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL ADHERENCE

 Adherence  Ability to resist from physical clearing.

 HWP1 and INT1 gene  Adherence of C. albicans in buccal epithelial cells and

filamentous growth of integrin-like-proteins  When the gene is disrupted 

Virulence of C. albicans was attenuated.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL ADHERENCE

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL PENETRATION AND DISSEMINATION
 Infection of fungal may be limited to portal of entry or may become systemic.

 In order to disseminate, fungal needs tissue damage which has already existed or the fungal

create the damage by mechanical penetration / tissue necrosis.

 Candida has hyphae that can grow through the host cell walls.

 A. fumigatus is able to penetrate blood vessel and grow in the lumen of blood vessel.

 Fungal hyphae  thigmotropically  towards or away from touch stimulus.

 Fungal also can spread by the host phagocytosis process (H. capsulatum, C. albicans).

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL PENETRATION AND DISSEMINATION

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL PENETRATION AND DISSEMINATION

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL PENETRATION AND DISSEMINATION

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL NUTRITION AND METABOLISM

 Fungi able to carry biosynthetic reactions during the scarce of nutrients, synthetic

fatty acids, and glycolytic enzymes.

 C. albicans auxotrophs (parent dependent) mutant experiment  Diminish virulence.

 H. capsulatum uracil auxotroph  still virulent in cultured macrophage and mouse

model.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 FUNGAL NECROTIC FACTORS

 Vehicles of virulence  Overcome structural barrier to prevent invasive infection.

 Most of the necrotic factors are enzymes, that usually used for nutritional enzymes

during saprophytic phase  proteinase and phospolipases.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube,

 MORPHOLOGY AND ADAPTATION -1
 Almost all pathogenic fungi can grow in more than one form (except C. neoformans which only exist in the

yeast form in vivo).

 Aspergillus  Classical filamentous molds has conidia as the infectious agent.

 Transition phase  specific gene expression (i.e. in H. capuslatum)  blocking acidification of phagosome.

 Protect fungal from environmental changes  aerobic to fermentative = switch to yeast to filamentous growth

of Candida.

 Phenotypic switching  white colonies (yeast cell-virulent) to opaque colonies (bean shaped cells-

colonization).

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 MORPHOLOGY AND ADAPTATION

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 MORPHOLOGY AND ADAPTATION - 2

 Able to grow at different pH  C. albicans can grow at acid and basic pH  can colonize

vagina (acid) and oropharyngeal (neutral)  regulated by PHR1 and PHR2 genes.

 Produce toxin  A. fumigatus produce toxin that can evade macrophage phagocytotis.

 Surface properties  C. neoformans produce polysaccharide capsule to prevent from

phagocytosus, downregulate cytokine secretion, prevent leukocyte accumulation, inhibit antigen

presentation, and inhibit lymphoproliferation  Perfect host barrier defense.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 MORPHOLOGY AND ADAPTATION - 2

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

3. Host factors - Susceptibility to
fungal infection
 IMMUNOCOMPETENCE
 Estrogen-binding proteins  Men are more likely than women to experience

disseminated infection (C. immitis) due to protective effect of 17β-estradiol (inhibiting

mycelial to yeast forms).

 Underlying disease such as diabetes mellitus and pregnancy.

 Diabetes  Impair opsonisation and decreased chemotactic activity of immune cells.

 Pregnancy  Glycogen increase in vaginal tissue  Vaginitis candida.

 Burn wound vitims  10-fold-increase of fungal infections  Topical antibacterial agents.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 IMMUNOCOMPETENCE

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 INFECTION ROUTES OF THE HOST

 Endogenous  C. albicans is part of the normal flora. Become pathogenic if it moves

from its site where us reacts to its presence. Breakdown of gut mucosa (chemotx,
radiation, trauma) allows commensal Candida to relocate from the gut to the
bloodstream.

 Exogenous  Fungi are carried in the air and inhaled.

 Also can spread via hematogenous, direct inoculation, or ingestion.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 IMMUNOLOGY AND FUNGAL INFECTION

 Humoral immunity  Partial role in fungal infection.

 Cell-mediated immunity  Destroy fungal through phagocytosis or cytotoxicity.

 Platelets  against invasive aspergillosis.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 IMMUNOLOGY AND FUNGAL INFECTION

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

4. Classes of infection – Part 1

Subcutaneous and Systemic Fungal

Infection
 SUBCUTANEOUS FUNGAL INFECTION

 There are three general types of subcutaneous mycoses:

 Chromoblastomycosis,  Verrucoid lesions. Non-destructive.
 Mycetoma  Suppurative and granulomatous. Destructive.
 Sporotrichosis.  Spread along lymphatic channels.

Van Burik 2001; Brunke, Mogavero, Kasper, & Hube, 2016

 SYSTEMIC FUNGAL INFECTION

 Deep mycoses are caused by primary pathogenic and opportunistic fungal pathogens.
 The primary pathogenic fungi are able to establish infection in a normal host 
Respiratory spread.
 Opportunistic pathogens require a compromised host in order to establish infection 
Spread from respiratory tract, alimentary tract, or intravascular devices.

WHO SEARO, 2012; Arora D R 2004

REFERENCES
 van Burik, J. A., & Magee, P. T. (2001). Aspects of fungal pathogenesis in humans. Annu Rev Microbiol, 55, 743-772. doi:

10.1146/annurev.micro.55.1.743

 Walsh TJ, Dixon DM. Spectrum of Mycoses. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University

of Texas Medical Branch at Galveston; 1996. Chapter 75. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7902/

 R. G. Lewis, Eric; R. Bowers, Jolene; M. Barker, Bridget (2015): Life cycle of Coccidioides.. PLOS Pathogens. Figure. https://

doi.org/10.1371/journal.ppat.1004762.g001

 Naglik JR, Richardson JP, Moyes DL (2014) Candida albicans Pathogenicity and Epithelial Immunity. PLoS Pathog 10(8):

e1004257. https://doi.org/10.1371/journal.ppat.1004257

 Brunke, S., Mogavero, S., Kasper, L., & Hube, B. (2016). Virulence factors in fungal pathogens of man. Current opinion in

microbiology, 32, 89-95. doi: https://doi.org/10.1016/j.mib.2016.05.010