VIRULENCE FACTORS OF FUNGI

and
PATHOGENESIS OF
FUNGAL INFECTIONS

Nelun de Silva
 About 1,000,000 species of fungi in nature
 These fungi inhabit different niches
 symbiotic
 commensalism
 mutualism
 parasitism with other organisms.
 Only some of the fungal species are pathogenic
to man
 understand the relationship among parasite, host
and the role of virulence factors
Host – parasite/symbiotic relationship
 Direct imbalance in this relationship
 leads to an infectious process
 leads to lesions of host tissues
 Establishment of disease
The host provides conditions for growth that
usually differ markedly from the ecological niche
.that the fungus normally inhabits
In order to survive in this new environment,
potential pathogens must withstand
high temperatures
hormonal influences
attack by phagocytes and other cells of
the immune system
.Factors that affect the transition from the saprophytic to parasite form in host-fungus relationship
 These factors are known as
virulence factors
favor the infection process and -
pathogenesis of systemic mycoses caused by
Cryptococcus neoformans -
Histoplasma capsulatum -
Blastomyces dermatidis -
Coccidioides imitis -
Paracoccidioides brasiliensis -
 Virulence factors enable
fungal adhesion

Colonization

dissemination and the ability to

survive in hostile environments

and evade the immune response

mechanisms of the host
Virulence factors are
Thermotolerance
Dimorphism
Cell wall components
Capsule
Enzyme production
 Thermotolerance
The ability to survive and replicate at 37°C is a
. common property of pathogenic fungi
This phenomenon, known as thermotolerance
,is seen in
Cryptococcus neoformans
Histoplasma capsulatum
Sporothrix schenckii
Most isolates of Cryptococcus neoformans var gattii
that do not grow efficiently at 37oC
are not able produce fatal infection in mice

But, isolates of C. neoformans var neoformans that

germinate and grow at 37°C produce lethal infections

Low-virulence strains of H. capsulatum require more

time for mycelium-to-yeast-phase transition at 37ºC
The more virulent strains withstand drastic
temperature changes and transforms more quickly
 Dimorphism
 is a fungal characteristic
 depends on alteration to temperature and/or nutrients
 favour fungal infection
 help the fungus to withstand host aggression
In nature, dimorphic fungi frequently occur in their mycelial
form.
The mycelial form induces production of conidia,
capable of establishing disease in lung tissue.
Eg. Histoplasma capsulatum, Blastomyces dermatidis
Cell wall components and capsules of fungi
protect them from the host attacks -
considered the major targets for studies on virulence -
 Adhesion Molecules

 Adhesion of pathogenic microorganisms to host tissues is regarded

as the 1st & major step in colonization and dissemination of the
fungus
 The cell/cell and cell/extracellular matrix adhesion observed in some
fungi such as:
 C. albicans, H. capsulatum, and C. neoformans
 occurs when the yeast forms have molecules on the cell wall or
capsule
.
 which permit adhesion and/or dissemination of the fungal cell to
other tissues
 Fungal adhesion to the host tissues plays a critical role in infection
 Enzyme Production
 Fungi secrete several hydrolytic enzymes such as proteinases, lipases
and phospholipases in culture media.
 These enzymes play a major role
 in fungal metabolism
 in the pathogenesis of infection, causing damage to the host cells
 providing nutrients in a restricted environment
 Extracellular proteinases may play a role in
 survival of the pathogen on mucosal surfaces
 invasion of host tissues
 Adherence
 digestion of immunoglobulins
 Mycotoxins
Aflatoxin
 are a small group of mycotoxins
 produced by the fungi of the genus Aspergillus
 Aspergillus flavus
 Aspergillus parasiticus
 produces a natural occurring human carcinogen
bis-furanocumarin
Aflatoxins are known contaminants on corn, peanuts, tree
nuts, cottonseed and certain meats and hypoallergenic milks
Pathogenesis of Fungal
infections
PATHOGENIC FUNGI

TRUE OPPORTUNISTIC
PATHOGENS PATHOGENS
 TRUE PATHOGENS
Cutaneous infective agents Subcutaneous infective agents

Actinomadura madurae
Epidermophyton species Cladosporium
Microsporum species Madurella grisea
Trichophyton species Phialophora
Sporothrix schenckii

Systemic infective agents- Dimorphic fungi

Blastomyces dermatitidis
Coccidioides immitis
Histoplasma capsulatum
Paracoccidioides brasiliensis
OPPORTUNISTIC PATHOGENS

Aspergillus fumigatus
Candida albicans
Crytococcus neoformans
Pneumocystis jirovecii
Absidia corymbifera
Rhizomucor pusillus
Rhizopus oryzae (R.arrhizus)
 Fungal Infections - MYCOSES
There are four types of mycoses:
 Hypersensitivity. An allergic reaction to molds and their airborne conidia.
 Mycotoxicoses. Poisoning of humans and lower animals by ingestion of food or feed
contaminated by low molecular wt fungal toxins produced by pre-harvest infestation or
during storage of peanuts, grains (Pitt and Miller 2016).
 Mycetismus. Poisoning after ingestion of certain mushrooms (50-100 cases/year in
U.S.A). (Smith and Davis 2016.)
 Disease resulting from infection with pathogenic fungi
 Infection
 Inhalation, ingestion, or implantation of infectious spores
 progresses to disease via tissue invasion
 evoking a host immune response.
 Host and Microbial Factors affecting Pathogenicity

Host Risk Factors (Muskett et al., 2011)

 Patients receiving immunosuppressive therapy for
maintenance of a transplanted organ or stem cell
transplant,
 cancer chemotherapy, autoimmune disease, and in
persons living with HIV/AIDS.
 Prolonged ICU stay, mechanical ventilation.
 Very young (< 1 mo.) or aged (>65 y) patients
 Host and Microbial Factors affecting Pathogenicity

Host Risk Factors (Muskett et al., 2011)

 Inborn or acquired deficits:
 chronic granulomatous disease, cystic fibrosis, diabetes.
 Invasive diagnostic and surgical procedures: abdominal surgery,
prosthetic implants, indwelling catheters, renal dialysis.
 Travel to or residence in an endemic area.
 Occupational or recreational exposure: Barefoot labor, gardeners
exposed to thorny plants, workers in demolition of old buildings.
 Microbial Factors
 Adhesins
 Adherence to endothelial cells is a prime requisite for tissue
invasion. Examples : ALS of C. albicans,
BAD1 of Blastomyces dermatitidis.
 Biofilm formation on biomaterials
 Ability of fungi to adhere to and embed in biofilms
increases their resistance to antifungal agents.
 Capsule.
 Encapsulated microbes are resistant to phagocytosis and
are implicated in CNS disease.
 Cryptococcus neoformans has an acidic high molecular
wt polysaccharide capsule that is antiphagocytic and may
facilitate endothelial crossing into the CNS
 Microbial Factors
 Melanin. Melanin in fungal cell walls makes them resistant to
phagocytosis and killing.
 Eg.Cryptococcus neoformans, Paracoccidioides brasiliensis 
 Resistance to the oxidative burst of polymorphonuclear
neutrophilic granulocytes.
 Primary respiratory pathogens
e.g. Blastomyces, Histoplasma, Paracoccidioides,
 “Shape shifters”. Ability to grow in different tissue forms
facilitates tissue invasion.
 e.g. Histoplasma is dimorphic and the yeast forms multiply
within host macrophages.
 Thermotolerance. Pathogenic fungi that can grow at 37oC.
 Using these strategies, fungi are able to
withstand host defenses.
 Fungi are ubiquitous in nature so that human
and animal exposure is common but disease
is uncommon and linked to:
 (a) host factors, outlined above,
 (b) in the case of primary respiratory
pathogens the inhaled dose of infectious
propagules
Classification of fungal infections
Superficial mycoses
Cutaneous mycoses
limited to the skin, hair & nails
Subcutaneous mycoses
when infection penetrates
significantly beneath the skin
Classification of fungal infections

Systemic mycoses - when the

infection is deep within the body
or disseminated to internal organs
 due to primary pathogens
 due to opportunistic pathogens