fungal infections

Question 1

what are the different type of fungi

Answer 1

chytridiomycota

zygomycota

basidiomycota

ascomycota

(last 3 are what can cause fungal infection in people)

Question 2

describe aspergillus

Answer 2

is an ascomycota

has spores that are dispersed in the air - cause infection in the lung - penetrate into the lower areas of the lung

see white mass in lung - this is a fungal pool

haemorrhages in lung because the fungus has invaded the bv

Question 3

describe cryptococcus neoformans

Answer 3

is a basidiomycota

at host temperature it exists as a yeast - can be hypha or branching form out of the host

cause meningitis mainly in HIV pts

has a large capsule and adhesive fimbrae

Question 4

describe candida albicans

Answer 4

yeast

cause mucosal infection mainly - can invade into the body

yest cells that germinate - form germ tubes as it transitions from yeast to hypha form

can invade from the mucus membrane under the right immunocomp conditions = invasion of bv - cause bloodstream infections and lodge into tissues

Question 5

what type of pathogen are fungi and effect of this *

Answer 5

opportunists - only cause infection when host defences are breached eg in cancer when immunocomprimised, AIDS, transplant pts

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii is associated with AIDS.

pts with prolongued and profound neutropenia

Question 6

what does the immune response of fungi depend on *

Answer 6

varies with the species and site of infection

fungal morphotype effects it - yeasts and spores are often effectively phagocytosed, the larger size of hyphae precludes effective ingestion.

Question 7

describe cellular immunit to fungal infection *

Answer 7

there is opsonisation by pentaxin 3 and mannose-binding lectin

phagocytes are a critical 1st line of defence - by macrophages, neutrophils and epithelial cells

NK provide early IFN gamma - protect against invasive fungal infection

a failure of innate immunity leads to adaptive responses - adaptive are driven by DC-T cell interactions

DC influence T cell differentiation

Th1 and Th17 are involved in mucosal immunity to fungi

Question 8

describe how fungi are virulent *

Answer 8

normally fungi are unicellular - can change their form to cause infection - hyphal transition

Candidal dimorphism (yeast/hyphal forms) allows tissue invasion

Crytpococcus forms a capsule to evade phagocytosis, capsule also has immunomodulatory properties; only becomes multicellular out of the host

Aspergillus species inhaled as conidia, invade tissues as hyphae

Question 9

describe Toll like receptor *

Answer 9

it is a PRR

activate NFKb

Question 10

describe C type lectin receptors *

Answer 10

carbohydrate receptors

activate inflammatory pathways

also main phagocytic receptors for fungi

Question 11

describe damage receptors *

Answer 11

recognise sterile receptors secondary to infection

Question 12

what receptors are involved in innate immunity against fungal infection *

Answer 12

scavenger

toll like

c type lectin

damage

Question 13

describe the effect of dectin-1 deficiency *

Answer 13

causes mucocutaneous infection eg chronic candidal mucocutaneous infection - thrush like infection that is hypertrophic across mucus membranes, invasion of the nail beds

this is because of a mutation in dectin 1 - it is a c type lectin receptor (PPR)

dectin 1 mutation mean cant make inflammatory response with IL6 to candida

Question 14

describe CARD9 deficiency *

Answer 14

CARD9 is an adaptor protein for dectin 1 receptor

in deficiency the receptors dont work - cant make macrophages, dont make Th17, IFN gamma in CD4 T cells, IL17

mean candida invades CNS = infection, and get mucocutaneous infection

Question 15

describe risk of toll like receptor polymorphisms *

Answer 15

TLR SNPs = risk of fungal infection in transplant patients - increased risk of pulmonary aspergillosis

mutation in TLR4 is important

intersect with CMV that paralyses the immune system

Question 16

effect of heterozygous dectin-1 deficiency *

Answer 16

increased risk of transplant related aspergillosis

Question 17

effect of SNPs *

Answer 17

they can increase the suseptibility to fungal infections

Question 18

effect of mutation in plasminogen *

Answer 18

increased suseptibility to fungal disease

Question 19

importance of knowing that people have increased suseptibility to fungal infections *

Answer 19

know who might get an infection when you give them a transplant - so give prophylactic antifungals/not transplant if risk too high

Question 20

describe the importance of macrophages and neutrophils for suseptibilty against aspergilus fumigatus *

Answer 20

macrophage depletion doesnt increase suseptibility

neutrophil depletion = death of mice - the fungus grow freely in airway (uninhibited growth in neutropenic mice)

neutrophils release DNA traps that bidn aspergilus fumigatus ex vivo when they degranulate - stop the fungi germinating

neutrophils also kill hyphae because hyphe cant be phagocytosed

Question 21

describe the effect of fungal morphogenesis on the immune response *

Answer 21

if you give DC single cell fungi (yeast/spore form) drive Th1 cytokine inflammatory response

if give hyphal form/multicellular form - Th2 type response - characterised by IL4 production

Question 22

what type of immune responses against fungi can you get *

Answer 22

depending on cytokine response and mucosal immunity can get Th1 2 or 17 responses

modulated by interactions with metabolites, fungi and microbiota

Question 23

describe adoptive immunity (

Answer 23

we engineer T cells to respond to attack any stimulus with fungal ligands

when giving someone a stem cell transplant - take out peripheral immune cells - see which are anti-fungal by exposing them to fungal ligands and see which respond expand the T cells ex vivo and return them to the body - protects people against fungal diseases - this is T cell chimeric ag receptor

people with the T cell therapy have low ag load and less infection

Question 24

describe gene therapy for chronic granulomatous disorder *

Answer 24

it is a primary immunodeficiency with mutations in NADPH oxidase - NAPH oxidase is imoortant for ROS generation in neutrophils which is important for immunity to lots of different infections

restoring gp91 subunit of NADPH oxidase by removing the bone marrow, and doing gene therapy ex vivo = more expression of gp91, aslo able to make DNA traps that couldnt before the gene therapy (relationship between ROS production and trap production) able to clear the disease

Question 25

role of TNFa in immunity *

Answer 25

important - drives the phagocytic cells to phagocytose the fungus

Question 26

effect of aspergillus niger *

Answer 26

cause sensitisation in the lungs

ear infections - otitis externa

Question 27

describe penicillum *

Answer 27

similar to aspergilis

common in env - causes allergy

Question 28

fungi that can cause allergy

Answer 28

cladosporium

penicillum

aspergilus niger

aspergilus funigatus

Question 29

describe the damage response framework of microbial pathogenesis *

Answer 29

if you have weak immune system = infection

normal = colonisation

if excessive immune reaction = allergic fungal disease eg asthma or allergic bronchopulmonary aspergilosis

Question 30

fungi that cause allergy

Answer 30

alternaria

aspergillus

candida

ladosprium

penicillium

trichophyton

Question 31

describe the immunology of allergic fungal diseases

Answer 31

asthama and allergic brochopulmorary aspergilosis - type 1 hypersensitivity response which are IgE mediated, and type 4 hypersensitivity responses which are T cell driven

hypersensitivity pneumonitis can be triggered by fungi - Th1 IgG response to fungi but not actually fungal infection - get nasty fibrotic lung disease driven by neutrophils

Question 32

describe fungal cross-reactivity *

Answer 32

fungi have multiple allergens that cross react with other fungi and host proteins and can cause autoimmune attacking of host

Question 33

describe the pathophysiology of allergic bronchopulmonary aspergilosis *

Answer 33

there is abnormal DC that leads to aberrent Th2, Th17 responses in the lung

this causes priming of B cells and class switching to produce IgE rather than IgG

IgE leads to mast cell degranulation and eosinophilia

Question 34

Criteria for allergic bronchopulmonary aspergillosis *

Answer 34

people have asthama/CF

IgE to aspergilis fumigatis

Positive immediate hypersensitivity skin test or Aspergillus-specific IgE

>2 supportying criteria

• Eosinophilia >500cells/ul
• Serum precipitating or IgG antibodies to Aspergillus fumigatus
• Consistent radiographic abnormalities eg bronchiectis (widening of airways with fibrosis and mucus production)

Question 35

radiological features of allergic bronchopulmonary aspergillosis

Answer 35

Dilated bronchi with thick walls

Ring or linear opacities

Upper or central region predeliction

Proximal bronchiectasis

Lobar collapse due to mucous impaction because no air is getting into the airway

Fibrotic scarring

Question 36

how do we manage aspergilis

Answer 36

Corticosteroids

Itraconazole for steroid sparing effect

Benefit of itraconazole past 16 weeks unclear

Reduction in circulating IgE, steroid dependency and improved PFT

Itraconazole indicated if not responding to steroids or steroid dependent

Role of inhaled steroids and other antifungals less clear

Recombinant IgE monoclonal antibodies (omalizumab) may be useful - stop mast cells and eosinophils degranulating

Question 37

describe asthma and fungal sensitisation *

Answer 37

possible association but also sensitisation to house dust mites etc so difficult to say if it is fungal cause

Question 38

what is used for diagnosis of fungal infections

Answer 38

skin test, IgE and IgM in clinical relevant populations

Question 39

describe aspergillus rhinosinusitis *

Answer 39

May be allergic or invasive

Increasingly common

Association with atopy and nasal polyposis

Raised total IgE, skin test and Aspergillus-specific RAST IgE (or sometimes IgG)

May also be caused by Bipolaris or Curvularia

Obliterated sinuses with hypo attenuated mucosa and enhancing material on imaging

Question 40

treatment of fungal sinusitis

Answer 40

Oral corticosteroids

Surgical removal of obstructing nasal tissue

Systemic anti-fungal treatment has not been shown to be effective

Topical therapies being investigated

Question 41

describe hypersensitivity pneumonitis *

Answer 41

Also known as extrinsic allergic alveolitis

Allergic response requiring long-term allergen exposure

As a consequence often occupational

Cell-mediated delayed sensitivity reaction

Allergen-specific precipitins usually present