Immunity to Microbes

Part 4

Immunity to Fungi
 Introduction
 Fungi: Diverse group of organisms
 Used in fermentation
 Used in antibiotics production (Penicillin)
 Infection: Due to exogenous organisms due to: Injury or inhalation
 Infection: Due to endogenous organisms due to: commensals in the gut or on the
skin
 1st human fungal disease is the ring worm
 Ringworm = known as dermatophytosis, dermatophyte infection, or
Tinea = fungal infection of the skin

 Most of them are opportunistic = affects compromised people

 Fungal diseases = Mycoses and classified depending od:
1- Site of infection.
2- Route of infection.
3- Virulence
exogenous organisms due to: Injury or
inhalation
endogenous organisms due to:
commensals in the gut or on the skin
Predisposing Factors
 Hypersensitivity or granuloma
 Environmental Factors:

1- Moisture 2- career
3- Host’s metabolic status 4- Immune status
 Fungi ????
 Unicellular and yeast-like (Spherical): Candida
species

 Multicellular and filamentous: Aspergillus

Fungi and Diseases: Examples
Organism
Aspergillus spp. (A. funigatus, A.
flavus and A. niger)
Blastomyces dermatitis
Candida spp. ( C. albicans, C.
tropicalis)
Cryptococcus neoformans
Histoplasma capsulatum
Pneumocystis carinii
Epidermophyton floccosum
Disease
Airway and pulmonary infections
and allergic reactions
Blastomycosis (pulmonary
infection)
Yeast infection, vaginitis, cystitis
Cryptococcosi (pulmonary infection
and meningitis)
Histoplasmosis (TB-like disease)
Pneumonia and severe lung
damage
Infection of skin, nails and hair
Balstomyces dermatitis
Cryptococcus neoformans
Histoplasma capsulatum
Pneumocystis carinii = Pneumocystis jirovecii (New name)

Pneumocystis jirovecii is a tiny fungus

that lives in the lungs of many people.
Most people's immune systems keep the
fungus under control. But if you have a
weakened immune system, the fungus
can make you very sick. The most
common type of infection is
pneumocystis pneumonia (PCP).
Epidermophyton floccosum

Athlete's foot, medically = tinea pedis

 Fungal infections (mycoses)
• Fungal infections (mycoses)
– important causes of morbidity and mortality in
humans
– Endemic or opportunistic
– Compromised immunity is the most important
predisposing factor for clinically significant
fungal infections

Aspergillus fumigatus

• Different fungi infect humans and may live in

extracellular
tissues and within phagocytes => combinations of the
responses to extracellular and intracellular bacteria
Fungal infections (mycoses)

Microbe Examples of Human Mechanisms of Pathogenicity

Diseases
Candida albicans Candidiasis Unknown; binds complement
proteins
Aspergillus Aspergillosis Invasion and thrombosis of
fumigatus blood vessels causing ischemic
necrosis and cell injury

Histoplasma Histoplasmosis Lung infection caused by

capsulatum granulomatous inflammation
Conditions leading to opportunistic fungal
infections
Although fungi are ubiquitous in the environment, they
generally colonize tissues and cause infection only when the
body's normal defenses or the normal flora are disrupted.

1– Disruption of the body's physical, chemical, or physiologic

barriers: Intact skin, pH, fatty acids in the skin, and various
humoral factors normally prevent fungal infection.

2– Immunosuppression (inherited or acquired), particularly loss of

CD4 TH1responses: opportunistic infections by normal flora
(e.g., Candida albicans) or increased susceptibility to
environmental fungi (e.g., Aspergillus species) may result.

3– Disruption of normal bacterial flora: use of antibacterial drugs

sometimes allows colonization by fungi that otherwise would not
establish infection.
Innate Immunity to Fungi
• Neutrophils and macrophages

– fungicidal substances, such as reactive oxygen

species and lysosomal enzymes
– phagocytose fungi for intracellular killing.
– Phagocytes and dendritic cells sense fungal
organisms by TLRs and lectin-like receptors called
dectins

-NK cell-cytolytic enzymes, IFNg: stimulate

macrophage to kill pathogen
 Complement System

 Fungal cell components: Trigger alternative

and lectin pathways
Pattern Recognition Receptor
(PRR) for Fungi
A. Dectin 1,2
B. TLR 2,4,9
C. Complement receptor -3
 Local Defense Mechanisms
Mucosal Infection can be prevented by salivary proteins like:
Lactoferrin
Beta-defensins
Histatins
Transferrin
Lactoperoxidase
Mucins
sIgA

Impair adhesion and growth of Candida in the oropharyngeal

cavity
 Innate Immunity
 Skin epithelia: pH, Lysozyme, sebum
 GI tract: acidic pH and enzymes
 Resp. Tract: inhaled spores trapped in mucosa +
coughing out
 Surfactant proteins in the lungs A & D prevent
pulmonary infection
 Urinary tract: Urine out flow +sloughing of epithelia

Definsins, long-term antibiotics ????

 Adaptive Immunity to Fungi
1- Cell-mediated adaptive immunity: major mechanism against fungi

(i) Virulent strains of Cryptococcus neoformans inhibit

the production of cytokines such as:
a- TNF and b- IL-12 by macrophages and stimulate
production of IL-10, thus inhibiting macrophage
activation.

CD4+ and CD8+ T cells cooperate to eliminate the yeast

forms of C. neoformans, which tend to colonize the
lungs and brain in immunodeficient hosts.
 Adaptive responses to Fungi.../ Cont.

(ii) Histoplasma capsulatum, a facultative intracellular

parasite that lives in macrophages, is eliminated by
the same cellular mechanisms that are effective
against intracellular bacteria.
(iii) Many extracellular fungi elicit strong TH17
responses, which are driven in part by the
activation of dendritic cells by fungal glucans
binding to dectin-1,
a receptor for this fungal
polysaccharide, and this results in the production
of TH17-inducing cytokines (IL-6, IL-23) from the
dendritic cells. The TH17 cells stimulate
inflammation, and the recruited neutrophils and
monocytes destroy the fungi.
 International Immunology, Vol. 23, No. 8, pp. 467–472 a The
Japanese Society for Immunology. 2011. All rights reserved.
doi:10.1093/intimm/dxr046 For permissions, please e-mail:
journals.permissions@oup.com Advance Access publication 15
June 2011
“Dectin-1 and Dectin-2 in innate immunity
against fungi”

Glucans are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes,
including bacteria, fungi, and yeast. Immune cells recognize these β-glucans through a cell surface
pathogen recognition receptor called Dectin
 Adaptive responses to Fungi.../ Cont.

(iv) Candida infections often start at mucosal surfaces,

and cell-mediated immunity is believed to prevent
spread of the fungi into tissues. TH1 responses are
protective in intracellular fungal infections, such as
histoplasmosis, but these responses may elicit
granulomatous inflammation, which is an important
cause of host tissue injury in these infections.

2- Fungi also elicit specific antibody responses that are of protective

value
Evasion Strategies

- Many fungi adopt different forms at different

stages in their life cycles------
making immune defense more complex

- Through the complex Cell wall structure

Fungi avoid complement lysis

 Evasion of the Immune System by Fungi
Immune System Element Thwarted Fungal mechanism
stop something from happening
PRR recognition have no LPS or peptidoglycan in cell wall
Specificity of T and B Cells Have a multi-stage life cycle

Complement Block access to cell membrane via cell wall

Phagocytosis Block pagocytosisvia polysaccharide capsule
T and B Cell function Induce immune deviation to TH2
Block NF –kb activation
Increase NO production to decrease
Lymphocyte proliferation
Block phagocytosis
Inhibit neutrophil migration
Decrease IL -12 and B7 expression by
monocytes
Activate regulatory T cells via polysaccharide
Capsule component
Produce melanin to decrease TH1and
TH2responses
Block TNF production
Thanks