PLP 130 Exam 3

fungi are most important group of __ pathogens

plant

impact of fungal plant pathogens

Dutch elm disease (Ophiostoma ulmi)

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Coffee Rust

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Panama disease: changed the banana industry

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Rice blast

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wheat stem (black rust)

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Banana black sigatoka

why fungi are so destructive

* large amounts of inoculum
* short latent period
* efficient dissemination
* production of toxins & hydrolytic enzymes
* high rates of evolution

anthropogenic factors contributing to emergence & spread of fungal disease

* global warming
* pathogen introduction
* industrialization of agricultural
* microbial adaptation/evolution & fungicide resistance
* lack of political will

the disease triangle

pathogen

host (plant)

environment

nutritional lifestyles & pathogenic strategies of fungal plant pathogens

necrotrophs: kills host plant cells & feeds on dead tissue, lots of toxin

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biotrophs: colonize & derive nutrients from living plant tissues

* can be obligate or facultative

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hemi-biotrophs: 1st establish a biotrophic phase & then switch to being necrotrophs

* many produce host-specific toxins & variable

main stages of fungal infection

1. spore adhesion & germination
2. penetration/invasion


1. passive entry via natural openings
2. appressoria
3. neutralization of host defense


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4. colonization of host tissues
5. reproduction on the host

infection stage I

adhesion of fungal spores & germlinngs on plant surface via

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extracellular matrix material (aka mucilage)

* fungal glue, varies in composition b/t sp, consists of water-insoluble glycoproteins, lectins, lipids, & polysaccharides

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adhesins

* highly glycosylated cell surface proteins that confer the ability of attachment to cells, tissues, and/or abiotic surfaces
* consist of N-terminal carbohydrate or peptide binding domain, central Ser- & Thr- rich glycosylated domains, C-terminal region that mediates covalent cross-linking to the wall through modified anchors (GPI: glycosylphosphatidylinositol)

infection stage II: gaining entry into plant host

passive = entry via natural openings ie stomata or wounds

* no specialized structures req’d
* usually req high humidity for germination
* mainly in apoplastic pathogens (don’t enter host cells, but grow in b/t plant cells)

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enzymatic = plant cell wall degrading enzymes

* necrotrophs use mostly


* cutinases → pectinase/cellulase/ligninase → protease, lipase, amylase

mechanical = special structure ie appressoria & haustoria or both

cutinases

fungi constantly produce cutinases in small amount → cutin monomers releases → these signal fungus to produce more cutinases, PCWDEs, formation of appressoria

appressoria

* formed by germ tube
* build up extreme turgor pressure
* melanin, accumulation of glycerol to inc osmotic potential of cytoplasm

infection stage IV: obtaining nutrients from the host

infection process of hemi/biotrophic fungi → don’t cause cell death for a couple days → feeding structures

* haustoria = by obligate biotrophs
* intracellular hyphae = hemi-biotrophs
* arbuscules = arbuscular mycorrhizae fungi

haustoria

* characteristic of fungi w/long-term obligate biotrophic relationships w/plant
* branches of inter/intra/epicuticular hyphae that terminate w/in a host cell → only 1 haustorium per cell
* common for some fungi which ultimately

intracellular hyphae

* go inside host cell, can cross into different cells (not determinate)
* mostly in hemi-biotrophic
* can develop necrotrophic hyphae

arbuscules

* used by arbuscular mycorrhizae

fungal secreted phytotoxins

definition = SM that are bio active in small amounts, move inside plant, NOT including lytic enzymes

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phytotoxin criteria

* toxin in diseased tissue
* reproduction of disease symptoms by purified toxin
* relationship of toxin production to pathogenicity or virulence
* production of toxin by pathogens vs non-pathgoens
* host genetic control of disease and toxin sensitivity

phytotoxins effect on plant host

* interfere w/protein synthesis
* undermine membrane integrity & structure
* disrupting biosynthesis of crucial metabolites
* inhibit plant enzymes, hormones, photosynthesis

host-selective toxins vs non-host specific toxins

HST

* required for virulence/infection
* not all genotypes of host plant are sensitive to toxin
* not all isolates of pathogen produce the toxin
* mainly in Pleosporales (Dothideomycetes)

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nHST

* vast majority of toxins made by fungi
* bio active against broad spectrum of plant sp
* may/not be host sp of producing fungus
* not sole determinant of pathogenicity
* mainly in necrotrophic pathogens

neutralization of plant immunity defense

virulence = more severe disease vs less severe

pathogenicity = does it cause disease or not?

plant immunity overview

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plant passive immunity

pre-existing, passive

physical strucutural barriers: wax layer, epidermal layer, actin cytoskeleton, cell wall

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preformed biochemical barriers: anti microbial cmpds, toxic inhibitors, phyoanticipin, phytohormones

plant induced immunity

non host-specific: innate or PAMP triggered immunity

* mediated at PM receptors ie PRRs, expresses as chemical and physical defense ie stomatal closure, making phytoalexins

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host-specific: effector-triggered immunity

* based on recognition of pathogen derived effector proteins
* mediated by PM or intracellular resistance proteins (R)
* ETI is most typically manifested as a hypersensitive response (HR)

innate or PAMP triggered immunity

based on recognizing pathogen-associated molecular patterns or plant-derived damange-associated molecular patterns

* PAMPs: flagellin, elongation factor Tu, peptidoglycan, LPS, chitin/B-glucan
* DAMPs: oligogalacturonides, cutin oligamers

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example of respsonses

* stomatal closure, callose at infn site to isolate invader, antimicrobial cmpds (phytoalexins, defensins) reactive oxygen species

plant PRR’s

structure

* on PM & monitor apoplast (in b/t cells)
* have extracellular domain that recognizes ligand recognition & transmembrane domain, and often a cytoplasmic kinase domain
* receptor-like kinase: if kinase domain is present
* receptor-like proteins: if kinase domain is absent
* ECD ligand recognition domains often have horshoe-shaped structure, built for leucine-rich repeat motifs!!

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function

* some PRR need a co-receptor while others fxn via dimerization → triggers signaling cascade → recruit regulatory receptor kinases & signal via receptor-like cytoplasmic kinases

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effector-triggered susceptibility - how do pathogens overcome host immune system?

* what is an effector?

pathogens produce effectors

* small in size, highly diverse, secreted pathogens in a spatio-temporal manner during infn
* secreted into host cell (cytoplasmic effectors) or the apoplast (apoplastic effectors)
* promote infn (virulence factors) by reprogramming host metabolism or interfering w/host innate immunity
* via pathogen recognition, signaling to the nucleus, mounting of defenses

ex of effector function from Cladosporium fulvum

Avr2, Avr4, Ep6 are effectors from Cladosporium fulvum (tomato pathogen)

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Avr2: inhibits host Cys-proteases req for basal host-defense

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Avr4: bind to fungal chitin & protects against chitinases during pathogenesis

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Ecp6: bind to chitin & sequestrates chtin fragments that trigger PTI → suppress PRR recognition

strategies used by pathogens to promotes infns

breaking physical barriers to infestation

* manipulate stomata
* degarde plant CW
* attack plasmodesmata-callose regulation
* destroy cytoskeleton
* creating conditions for infn: hydrophobic space, extracellular alkalization

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masking or protecting pathogens from host immune system

* inhibition of PTI: protect from plant chitinases, inhibit of LysM R recognition, isolation & masking of chitin oligosaccharides, degrade chitinases
* antagonism w/anti-microbial cmpds: detox enzymes to degrade these antimic cmpds

host-specific resistance: how did plants evolve immune receptor which recognize effectors?

Effector-triggered immunity (ETI)

* avirulence protein (Avr): when effector gives away presence of pathogen to plant
* hypersensitive response: apoptosis that kills inf’d host cell (most common ETI) → can act to pathogen’s favor
* rapid accumulation of reactive oxygen sp at infn site → oxidative burst
* expressing pathogenesis related proteins w/antifungal activity
* cell wall fortification
* produce signaling MAP kinases
* release of systemic signals ie salicylic acid → systemic acquired resistance → sensitizes whole immune system

systemic acquired resistance

ETI responses are amplified by salicylic acid, jasmonic acid, ethylene

SAR is a long distance signaling mech that provide broad spectrum & long-lasting resistace to secondary infn throughout the plant

plant resistance (R) proteins

* plant immune receptors that recognize effectors = resistance proteins
* can be on PM but most are intracellular R “nucleotide-binding domain & leucine rich repeat containing NBS-LRR or NLR) family

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NLR are multidomain proteins

* a variable N-terminal domain: signals
* a central nt-binding domain: bind ATP or GTP
* a C-terminal: protein-protein interxns

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based on N-terminal domains, divides into:

* toll/IL R (TNLs)
* coiled-coil NLR (CNL)
* NLR w/N-terminal RPW8 domain (RNL)
* NLR w/integrated domains (NLR-ID)
* NLR-like proteins w/o

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recognition modes of effectors by plant resistance (R) proteins

direct recognition: effector interacts directly w/LRRs of R protein

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guard model: most common, monitors for potential targets

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decoy model: plants deploy a 2nd protein that resembles the actual plant target of effector → monitored by R proteins

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integrated decoy model: R proteins carry seq that resemble effector targets

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sensing through NLR-like proteins: lack regulatory domains, ie NB & LRR, but fxn as effector sensors

the plant resistosome (wheel of death)

animal NLRs: oligomierize into wheels upon activation, usually in ETI-mediated responses → inflammasome

plant NLR: same → resistosome

* N-terminal domains into central hub → form pore in PM → disrupts pathogen PM → cell death

gene-for-gene interactions

R proteins recognize effectors in highly specialized manner via gene-for-gene relationship ie effectors can mediate virulence in absence of cognate R proteins in host & avirulence in their presence (pathogen races)

zig-zag model

the contemporary view of arms-race of plant immunity


1. plant innate immunity: recognize PAMPs
2. pathogens evolved effectors to inhibit innate immunity
3. plant develop cognate R proteins recognize effectors as microbial signatures & initiate effector-triggered immunity
4. microbes evolved new effectors that inhibit fxn of R proteins → block effector triggered immunity

PAMP-triggered immunity vs effector triggered immunity (PTI vs ETI)

fungi negative impacts on human health

1. mycotoxicosis
2. allergy (hypersensitivity)
3. mycetismus (mushroom poisoning)
4. infection (most are opportunistic pathogens)

fungal infections

* most are opportunistic
* inc if have HIV/AIDS, COVID
* most are on skin
* death is often result of severe respiratory illness & fungiemia (?) → septic shock/sepsis

factors for emergence & inc in fungal diseases

* inc # of ppl w/weakened immune systems: cancer patients, HIV, organ transplants
* advancements & changes in healthcare practices: leads to drug-R
* changes in environment: ie coccidiodomycosis (valley fever) & histoplasmosis from climate change
* inc in T → can jump to humans (high body T)
* inc seasonal migration & int’l travel

host factors in fungal infns

* PRRs that sense PAMPs
* ancestry: racial groups are more susceptible to certain fungi
* non-genetic: envir factors, lifestyle

6 deadliest fungal diseases in humans

* candidiasis
* crytpotcocosis
* aspergillosis
* histoplasmosis
* pneumonocystis pneumonia
* mucormycosis

fungal virulence factors for animal/human infns

adhesion molecules

production of specific hydrolytic enzymes ie proteinases, lipases, phospholipases & elastase

capsule formation: reduces host immune response

metabolic adaptation: for intracellular survival

thermotolerance: need to grow at 37C

dimorphism: nearly ALL primary endemic respiratory infns are caused by dimorphic fungi

plant vs human immune system

human immune system

* anatomic/physiological barrier
* innate immunity
* adaptive immunity

An/Ph: dessicated most outer layer of epidermis on skin, ciliary, low stomach pH, lysozyme in tears/saliva

innate: NK cells, eosinophils, neutrophils, macrophages, mast cells, DCs, complement, antimic peptides, LPS binding protein, C-reactive protein, mannose-binding lectin

* acidity of skin, mucous membranes to trap microbes, ciliated cells propel microbes out of body via cough, body temp/fever, competition w/microbiome
* when these are breached fungi can enter the host

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adaptive: T/B lymphocytes

human innate vs adaptive immunity

innate: fast (hours), general, ephemeral protection; anatomaical/physical, biochem barrier, to mediate inflammation, activates long-lived adaptive immunity

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adaptive: acquired response

* slow (days), specific, prolonged protection
* humoral: antibody or B-cell mediated immunity
* cellular: aka T-cell mediated immunity

white blood cell aka leukocytes

* circulate in blood/lymphatic vessels
* on constant patrol for pathogens
* phagocytes: formed in BM, also leads to rbc
* lymphocytes: develop in BM or various lymph organs ie LN, spleen, thymus

lymphocytes vs phagocytes

lymphocytes: keep memory of past invaders, develop in BM

* B cell: stay in BM, produce Ab against extracellular pathogens
* T cell: mature in thymus; destroy compromised cells (kill T cells) & help alert other wbc (helper T cells)

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phagocytes

* neutrophils: most common, attack bacteria/fungi
* macrophages: eat pathogens, dead cells
* monocytes: develop into macrophages
* mast cell: help heal wounds & defend against pathogens

innate immune system

recognition of PAMPs via PRRs ie TLR & NLRs

reactions:

* cytokines/chemokines to promote inflammation, recruit wbc, fever
* activate phagocytes
* inflammation to isolate/destroy pathogen & trigger tissue repair
* maturation of APCs: ie macrophages & DCs

phagocytosis

1. trapping microbe via pseudopodia
2. internalize microbe w/phagosome
3. phagolysosome formation containing hydrolyzing enzymes
4. digestion: lysosome digest
5. excretion: Ag egested into blood or lymph
6. antigenicity: Ag presented by APCs via MHC to activate adaptive immune system

inflammation

symptoms: redness, heat, swelling, pain, loss of fxn if chronic

* small bv become wider/leaky, inc blood flow to infd area
* loss of fluid makes it easier for immune cells to enter infd tissue
* hormones (bradykinin, histamine) to mediate inflam response irritate nerves & cause pain signals alerting you to protect the tissues
* blood clotting to prevent further spread

innate immunity TLRs

10 fxnal in human and 12 in mice

* dimerize when activated

connection b/t innate & adaptive IS

* PRR bind to PAMPs → maturation of macrophages & DCs into APCs
* they present their Ag to naive helper T cells via MHC (major histocompatibility complex) proteins
* → activation of B cells & cytotoxic T cells

adaptive IS

* mediate recognition of specific non-self Ag & differentiate from self Ag
* make pathogen-specific response to eliminate
* develop immune memory to quickly eliminate a specific pathogen

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cells that mediate adaptive IS

* B cells → plasma cells to produce Ab
* T cells

adaptive IS: humoral & cellular response

humoral: mediated by B cells that produce= immunoglobulins

cellular: mediated by killer/cytotoxic T-cells

antigen recognition

* B-cell receptor
* T-cell receptor

innate vs adaptive immunity table

fungal infections classified according to

route of acquisition

type of virulence

site of infn

superficial & cutaneous mycoses

superficial = stratum corneum, hair

cutaneous: into epidermis, dermatophytic fungi

subcutaneous = involves dermis & muscle underneath

deep, pulmonary or systemic mycoses: involve internal organs

fungi in skin & hair

cause 2 types of disease

* dermatomycosis: fungal infn of skin
* trichomycosis: of hair

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* most common
* dermatophytes: Malassezia sp,
* inf’d by exposure to skin/hair in soil or hard surface
* cause discomfort, cosmetic problems, inflammation; rarely cause severe diseasae

human fungal microbiome

* Malassezia dominates majority of body sites
* feet have the greatest diversity of fungal sp

Malassezia sp

* lipophilic yeast w/in Basidiomycota
* specialized to live on skin & are ubiquitous on human skin microbiome
* assoc’d w/dandruff, eczema, skin disease ie pityriasis, versicolor, psoriasis

Malassezia infns

Pityriasis versicolor: discoloration of skin via impairing melanocytes

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Malassezia folliculitis: caused by fungus growing in hair follicles → inflammation

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Seborrhoeic dermatitis, dandruff, sebopsoriasis, facial or scalp psoriasis: lipases & phospholipase made by fungi cleave ffa from triglycerides in sebum → inflammation

White & Black Piedra

black: caused by Piedraia hortae, common in tropical areas, black concentration in scalp hair

white: caused by 5 diff Trichosporum sp in more temperate areas; white or light brown nodules that are loosely att’d to axillary, pubic, and facial, and eyelashes

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→ both hair breaking, may spread to purpuric or necrotic cutaneous papules

* control via shaving & topicals eg ammoniated mercury, miconazole,

Dermatophytoses

caused by Microsporum, Trichophyton, Epidermophyton

* produce keratinases → break down keratin in epidermis, nails, hair, feathers, horns, hooves
* usually stops spreading when contacts living cells
* most sp in soil

Dermatophytes infns aka tinea infections

* Tinea capitis: hair/scalp
* Tinea faciei/barbae: skin hairs (beard)
* Tinea corporis: ringworm, trunk & extremities
* T. cruris: groin
* T.pedis/manuum: feet/hands (Athletes foot)
* T. unguium: nail

Tinea corporis

aka ringworms

* inflammation most at edges w/erthema, scaling, blisters w/clear center

Tinea pedis

most common fungal skin infn

3 types: toe-web, moccasin type, vesicular infn

* v easy to transmit (in swimming pools)
* caused by Trichophyton sp ie T. rubrum

Tinea unguium

onchomycosis; caused by Trichophyton sp (T. rubrum)

* 50% of all nail problems → secondary bacteria infn

dermatophyte treatment

topical: clotrimazole, miconazole

systemic: orgal

Griseofulvin: a fungal toxin made by Pencillium sp.; used orally

* MOA: inhibits fungi mitosis

deep systemic mycoses

* primary endemic respiratory infns
* opportunistic infns

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* commonly via inhaling fungal spores, mainly affect resp system
* most asymptomatic
* caused by dimorphic fungi

primary or endemic mycoses

* able to cause disease in non-immunocompromised patients
* mainly enter/spread in lungs; each sp occupy different niche
* have temperature dimorphism (hyphae in env, yeast in body temp)

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most common

* Histoplasmosis (H. capsulatum) in US
* Cocciodiodomycosis (San Joaquin valley fever) (C. immitis) in US
* Blastomycosis (B. dermatitidis) in US
* Paracoccidiomycosis (P. brasiliensis)
* Penicilliosis (P. marneffei)

Histoplasmosis

“Pharoah’s curse” after opening mummy tombs → killed ppl

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acquisition in nature: found in soil where bird/bat feces

common in US Mississippi River & Ohio valleys

dimorphic fungi

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pathophysiology

* spores inhaled → yeast at body T
* yeast are eaten by neutrophils/macrophages → reproduces
* healthy: control infn by T cells activating macrophages
* immunocompromised: may enter circulation & spread to organs

Histoplasmosis clinical manifestations

3 main forms

acute pulmonary: initiation form; symptoms 3-21 days after, fever

chronic cavitary: stays in lungs, weight loss, night sweates, fever, can recover w/o treatments 2-6 mo

disseminated & progressive: if weak immune system; from lungs to bloodstream; feel weak, pneumonia may dev but rarely severe except in AIDS

* w/o treatment → 90% fatal

Coccidiodomycosis (SJ valley fever)

C. immitis & C. posadasii

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risk factors

* immunodeficiency
* ethnicity: Filipino, Hispanic, African Americans
* Gender: more male
* pregnancy

C. immitis & human pheromones

* when treated w/human sex hormone estradiol → inc size & infectivity

Coccioidomycosis life cycle & pathophysiology

1. in env is hyphae
2. hyphae cells differentiate & undergo autolysis → arthroconidia (infectious form for mammals)
3. when inhaled → isotropic growth → remodels into spherule (unique to sp)
4. spherule expands → endospores
5. spherule ruptures → endospores released into lungs → acute inflammation
6. in susceptible patients, spherules may leave lung

Coccidioidomycoses clinical manifestations

acute: goes away w/o treatment

chronic: can occur up to 20 years later; lung abscesses, lung/rib scarring

disseminated/systemic: disease outside the chest, inflammation of membranes surrounding brain & spinal cord

Blastomycosis

aka North American blastomycosis or Gilchrist’s disease

* dimorphic fungus
* pneumonia
* via inhaling conidia
* mostly id-eastern US & Canada

disseminated: may be resistricted to upper neck/face area

Paracoccidiomycosis

in South/Central America; common in coffee plantations

* mickey mouse disease: discrete yeast form
* mainly affects lung
* female estrogens may inhibit development

US endemic mycoses chart

exogenous or endogenous route of infn

opportunistic mycoses

* most common type
* result in systemic infn only in immunocompromised patients or sick ppl
* see inc before & after COVID pandemic
* enter through multiple parts
* most are monomorphic fugni
* cosmopolitan fungi have a very low inherent virulence

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Candida, Aspergillus, Penumocystis, Mucor, Cryptococcus, Fusarium

invasive fungal infections

* systemic infns
* mostly opportunistic sp: Candida, Aspergillus, Cryptococcus
* high mortality rate; due to misdiagnosis
* mainly spread in hospitals

factors triggering opportunistic mycoses

AIDS: depletion of T cell

Bone marrow & organ transplants

cancer: leukemia, lymphoma

Drugs: cytotoxic drugs, steroids

Endocrine related: diabetes

Failure of organs

Greater lab expertise in detection of fungi

Candidiasis

* most important, C. albicans; others C. tropicalis, drug-R is C. auris
* yeast infn or thrush
* 4th most common cause of nosocomial (hospital acquired) systemic infn in US w/50% mortality rate
* polymorphic fungi: yeast-like cells, pseudohyphae, hyphae, biofilms

type of Candidasis

* oral or oesophageal thrush
* vaginal yeast infn
* balantitis (penis infn)
* invasive & Candidemia → enter bloodstream, fatal

pathophys of Candida albicans

yeast form: non-pathogenic & filamentous form is pathogenic

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induced endocytosis: fungus expresses invasins to bind to ligands on host epithelial cells → phagocytes engulf → switch to hyphal forms → inflammation

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activate penetration: req viable hyphae; fungal adhesion via secreted aspartic proteases (Saps); not fully understood

Candida overgrowth

Candida is normal microbiota w/host immune system & gut bacteria → overgrowth is promoted by

* unhealthy diet rich in sugars, carbs, dairy, fermented & processed foods
* xs alcohol
* high stress
* chemotherapy
* drugs eg Abx

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overgrowth →

* leaky gut syndrome: Candida can drill into intestinal tissues → inflammation → pores for toxins & pathogens to enter bloodstream, delays healing of inflammation
* digestive issues, autoimmune disease
* xs cravings for sugar, carbs
* chronic fatigue (candida die off); brain fog
* diagnosis is commonly missed

DIY Candida overgrowth test

Candida overgrowth treatment

* azoles
* Amphotericins
* micafungin

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best treatment

* more vegetables in diet

Aspergillosis

allergic bronchopulmonary aspergillosis

* allergies or asthma, shortness of breath, coughing, sneezing

chronic pulmonary aspergillosis & aspergilloma

* growth (fungal ball) that dev in are a of past lung disease or lung scarring ie TB

invasive aspergillosis

* mostly in immunocomp; high fatality

Mucomycosis (aka Zygomycosis)

Rhizopus sp are most common; Mucor, Absidia, Apophysomyces, Cunninghamella, Rhizomucor, Saksenaea

* affects immunocompromised
* mostly affects sinuses, lungs, → fast necrosis → extend into brain
* Saksenae vasiformis: flesh eating disease

fungal infn following tornadoes

tornadoes → wood splinters, soil, gravel → fungal infns → mucormycosis

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Apophysomcyes trapeziformis & Mucor circinelloides ; common in soil, decaying veg, water w/leaves

acute myeloid leukemia patient

* low neutrophil counts; pancytopenia for 12 weeks
* erythrematous nodules → Fusarium solani, oxysporum, moniliforme
* metastatic skin lesions, target like central necrotic lesions
* spread via spores inhalend
* 2nd most common fungi infn in immunocompromised patients

Phaeohyphomycosis

* dark, melaninated, dermatiaceous funi
* cause cutaneous infns
* many are plant pathogens
* eye infns

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….

Corynespora cassiicola

* plant pathogen; cause necrotic spots
* rare in human; but inc → severe ulcerations

diagnosis of fungal infns

clinical: fever, skin lesions

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radiology: chest x-ray, CT scans

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microbio: wet mount, skin test, serology, fluorescent Ab, biopsy, culture, DNA probes

diagnosis w/molecular probes

probe binds to fungal cell wall carbohydrate ie chitin, mannans, beta-glucans absent in human tissues

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Avr4 from Cladosporium fluvum binds to chitin

fungal diseases in animals

* invertebrates
* cold-blood vert
* warm-blooded vertebrates

fungi are only group to

to show to cause extinction

fungi and dinosaur connection

* large-scale deforestation → fungal bloom
* fungi made a fungal filter that selected for mammalian lifestyle (endothermy) and against reptiles (ectothermy)
* thus releative resistance of endothermic vertebrate to fungal disease is now bc of higher body temp combined w/innate immune defenses