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Expected Learning Outcomes

• By the end of this lecture, you should be able to:

a) Define types of human fungal diseases.
Introduction to Fungal Pathogenesis b) Name source of fungal pathogens and routes of transmission.
c) Describe virulence factors of human fungal pathogens.
Topic 14 d) Name fungal species that cause diseases in various human organs.

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• The human pathogenic fungi are broadly classified into two groups:
Fungi and Human Diseases
a) Commensals:
• Are normal constituents of the human microflora and generally cause • Fungal diseases (mycoses)
disease in the setting of altered host defenses.
a) Superficial mycoses
• Pathogens: Candida spp., dermatophytes, and Malassezia spp.
b) Environmental pathogens: b) Cutaneous mycoses
• They reside in specific environmental niches, and humans are c) Subcutaneous mycoses
exposed by inhaling spores or small yeast cells. d) Systemic mycoses (Also called - invasive fungal infections)
• Pathogens: e) Opportunistic mycoses
i. Cryptococcus neoformans. f) Mycotoxicosis
ii. Thermally dimorphic fungi: Namely, Histoplasma capsulatum,
Blastomyces dermatitidis, Paracoccidioides brasiliensis,
Coccidioides immitis, Penicillium marneffei, and Sporothrix
schenckii.
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Overview of fungal infections

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Fungal virulence factors

Virulence attributes of
a prototypic human
pathogenic fungus in
interaction with the
host. Host damage
and disease result
from the interplay
between fungal fitness
and virulence factors
(central ovoid) and
host responses (outer
ring). Potential
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damage-causing
interactions are
highlighted in red.
Human fungi defense mechanisms: In the human host, fungal infections are fought by both humoral (complement, antibodies) and cellular (phagocytes, T cells) immune
mechanisms. Protective mechanisms in both systemic and mucosal antifungal immunity are based on chemotaxis and activation of neutrophils, monocytes/macrophages,
and, in the case of mucosal immunity, epithelial cells, by chemokines and cytokines released by macrophages and proinflammatory T H1 and T H17 cells. In contrast, TH2 and
some other regulatory T lymphocytes (under the control of modulatory mechanisms such as indoleamine 2,3-dioxygenase) release anti-inflammatory cytokines that provide
the tolerance mechanisms necessary to balance inflammation and tissue damage. However, when activated inappropriately or too strongly, the anti-inflammatory T H2 and 8
other regulatory T cell responses can down-regulate antifungal immunity and increase susceptibility to infection. DOI: 10.1126/scitranslmed.3004404

Fungal virulence factors B. Immune evasion strategies

• Involves strategies to avoid, counteract or escape human immune responses.
A. Growth in the host
• These strategies include:
• In order for a fungal pathogen to infect a human host, it must be able to grow inside
o i) Concealment of immunogenic surface structures (Pathogen Associated Molecular
the host at 37 C. Pattern – PAMPs).
• The following factors promote the growth of fungi in humans; hence, considered as ii) Degradation of antimicrobial substances such as ROS, antimicrobial peptides
virulence factors:
(AMPs), complement factors or antibodies.
i) Metabolic flexibility
iii) Pigmentation.
ii) Ability to extract nutrients from host molecules
iv) Secretion of antimycotics
iii) Enhancement of physical robustness
v) Mechanisms to escape phagosome by membrane penetration, host cell lysis or
iv) Stress resistance expulsion.
v) Ability to manipulate environmental conditions like the ambient pH vi) Phagosomal intracellular survival

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C. Adhesion and invasion factors

• Adhesins are proteins (or other molecules) which mediate attachment of fungal
pathogens to host cells.
D. Direct host damage
• This avoids getting flushed away from mucosal surfaces, and provides the intimate
contact required to manipulate and invade host cells. • Pathogenic fungi can directly cause damage to host cells by physical forces
• Examples: during host cell invasion or escape, as well as by secreted factors.
• Majority of fungi often drive invasion by their own activities like filamentous growth • Such factors can comprise:
or turgor pressure increase (active penetration). i) Hydrolytic enzymes (e.g. proteases or lipases)
• Some fungi are known to use both invasion strategies. ii) Lytic toxins in the form of peptides or small metabolites
• Translocation into deeper tissue, however, does not always require cellular iii) Toxic secondary metabolites of molds
invasion. For example,
i) Some fungal pathogens may invade via disrupted interepithelial connections or
through necrotic host cells.
ii) Some, pathogenic fungi like Cryptococcus neoformans use host cells such as
macrophages as vehicles to overcome host barriers (‘Trojan horse’ strategy).
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Further Reading
E. Morphology and virulence programs
• Certain environmental human fungal pathogens can recognize typical host-
associated conditions and respond by initiating defined virulence programs.
• Jawetz, Melnick, & Adelberg’s Medical Microbiology (26th Edition),
• For example, many dimorphic fungal pathogens switch their morphology and its Chapter 45
associated gene expression profile in response to mammalian body temperature.
• Other host-related signals, such as contact to epithelial cells, can similarly trigger
morphological and transcriptome changes in commensal fungal pathogens.

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