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Flashcards in Microbiology Deck (179)
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1

What are type I interferons? What is their function

Polypeptides secreted from infected cells
Three major functions:
1. Induce antimicrobial state in infected and neighbouring cells
2. Modulate innate response to promate Ag presentation and NK but inhibit proinflammation
3. Activate the adaptive immune response

2

What is the pathway for production of type I interferons?

- Cells infected with virus activate PRRs (by binding PAMPs) which stimulates production of IFN-β which is then secretes from these cells
- IFN-β diffuses and interacts with neighbouring cells
- Switches on genes in neighbouring cells to switch them into an anti-viral state
- Plasmacytoid dendritic cells (PDCs) are specialised cells that produce interferon (particularly INF-α)
- Secretion of type I interferon (α and β) will recruit APCs and adaptive immune cells so you amount an adaptive immune response

3

What are the different types of interferon?

Type I interferon = INFα and IFNβ
Type II interferon = IFNγ
Type III interferon = IFNλ

4

What produces type I interferon?

- IFNβ is secreted by all cells and IFNAR (receptor) is present on all tissues. IFNβ induction is triggered by IRF-3
- Plasmacytoid dendritic cells are specialist IFNα secreting cells. They express high levels of IRF-7 constitutively
- 1 gene for IFNβ, 13/14 isotypes of IFNα

5

What produces type II interferon?

IFNγ
- Produced by activated T cells and NK cells
- Signals through a different receptor IFNGR

6

What produces type III interferon?

IFNλ
- Signals through receptors IL28R and IL10β that are mainly present on epithelial surfaces
(important for respiratory and liver infections)

7

Where is IFNλ particularly important?

Important at epithelial surfaces
- Respiratory tract
- Liver
Polymorphisms in IFNλ associated with improved outcome from HCV and HBV both spontaneous clearance and response to antiviral therapy

8

How does the immune system detect self from non-self?

- Detects Pathogen Associated Molecular Patterns (PAMPs) (often sense nucleic acid)
- They bind to Pattern Recognition Receptors (PRRs)

9

What are the different types of pattern recognition receptor?

Cytoplasmic RIG-1 like receptors (RLRs)
- detect viruses in the cytoplasm
- signal through a mitochondrial located pathway
Endosomal Toll-like receptors (TLRs)
- found on plasma membrane and endosomal membranes
Cytoplasmic nucleotide oligomerization domain receptors (NLRs)
DNA sensors
- most famous is cGAS
- signals to STING on the endoplasmic reticulum

10

What is the pathway for interferon induction?

- The PRRs will detect PAMPs (e.g. ssRNA) in the cytoplasm of the cell
- RIG-1 will then signal through Mavs (on mitochondrion), which will then trigger signalling through various different pathways, resulting in the translocation of molecules from the cytoplasm to the nucleus
- These transcription factors will become phosphorylated, they bind to the promoter regions of target genes (e.g. IFNβ) and generate transcription
- IFNβ is then released from the cells and travels to neighbouring cells to induce antiviral state
- Host controls the amount of virus in the body

11

How do TLRs sense virus infection?

- Virus enters the cell and during life cycle will enter endosome, and expose their nucleic acids
(In normal healthy cells there is no nucleic acid in endosomes)
- TLRs detect nucleic acid in the endosome and signal to molecule outside the endosome (MyD88) to send various transcription factors to the nucleus of the cell
- Results in switching on of expression of INFα

12

How is DNA sensed in a cell?

- Single stranded RNA is a PAMP
- RNA unlike normal host RNA is detected
- cGAS is the main way that DNA viruses are sensed
- cGAS is an enzyme that binds to dsDNA in the cytoplasm and synthesises a second messenger- cGAMP
- This small dinucleotide then diffuses to STING (protein), found on the endoplasmic reticulum
- Triggers phosphorylation of the same signalling molecules and transcription factors that the RNA viruses were triggering
- STING is a central player in IFN induction through cGAS

13

What receptor does interferon bind to? What does activation of the receptor cause?

The IFN receptors are heterodimers of IFNAR1 and IFNAR2
On binding to the cell surface receptor, the interferon signals to the nucleus to switch on the transcription of a whole set of IFN stimulated signals

14

What is the process of IFN type I signalling?

Heterodimeric IFN receptor composed of IFNAR1 and IFNAR2 is present on all cells in the body and senses IFNα and IFNβ
- If IFN binds to IFN receptor it will activate Jak and Tyk which then goes on to phosphorylate the STAT molecules (STAT1 and STAT2)
- STAT molecules dimerise and combine with IRF9 - it then goes to the nucleus and binds to a promoter region that is responsive to that transcription factor

15

What are the IFN stimulated genes?

- PKR
- 2'5'OAS
- Mx
- ISG15, ISG54, ISG56
- PML bodies
- APOBECs and TRIMs
- ADAR
- Serpine
- Viperin
- miRNAs
- Apoptosis
- Cell cycle arrest

16

What is the role of IFITM3 in viral infection?

Interferon induced transmembrane protein 3
- IFITM3 sits on the membrane of endosomes, in cells previously stimulated with IFN
- If virus tries to enter the cell it gets trapped in the endosome because IFITM3 modifies the membrane and prevents the virus from being able to fuse with the membrane and release it's genome into the cell

People lacking IFITM3 get more severe influenza

17

What are the antiviral mediators Mx1 and Mx2? What do they do?

- GTPase with a homology to dynamin
- Mx can form multimers that wrap around the nucleocapsids of incoming viruses as they try to enter the nucleus

Mx1 = inhibits influenza
Mx2 = inhibits HIV

18

How long does the IFN antiviral state last?

- IFN response may only be maintained for several hours
- Subsequently the ability to respond to IFN is lost due to negative regulation
- SOCS suppressor of cytokine signalling genes turn off the response
- As a state it is very toxic so can only be maintained for a brief period

19

How do viruses evade IFN response?

- Avoid detection by hiding the PAMP in inaccessible parts of the cell
- Interfere globally with host cell gene expression and/or protein synthesis (to stop production of IFN)
- Block IFN induction cascades by destroying or binding
- Inhibit IFN signalling
- Block the action of individual IFN induced antiviral enzymes
- Activate SOCS
- Replication strategy that is insensitive to IFN

20

How does hepatitis C evade the IFN response?

Hepatitis C: NS3/4
- Protease acts as antagonist to IFN induction by cleaving MAVs
MAVs is important in detecting Hep C through the RIG-1 pathway
- Causes destruction of the sensor system
- Normally Hep C will be detected by RIG-1 receptors- which will signal to MAVs, which will switch on the IFN response
- Instead Hep C rapidly synthesises NS3/4, which cleaves MAVs away from the mitochondrion and prevents the signal from getting through

21

How does influenza evade the IFN response?

Influenza: NS1
- Acts as antagonist to IFN induction by binding to RIG-1/TRIM25/RNA complex and preventing activation of signalling pathway
- Also prevents nuclear processing of newly induced genes
- Normally influenza will trigger RIG-1 via the production of viral RNA in the cytoplasm, which would signal MAVs, but the NS1 protein in influenza binds to RIG/Trim25 complex, which detects viral RNA, and stops it triggering the pathway
- NSI also migrates to the nucleus where it prevents the export of newly synthesised genes

22

How do Pox viruses prevent IFN response?

- Pox viruses and herpes viruses are large DNA viruses
- More than half the pox virus genome is comprised of accessory genes that modify the immune response
- Pox viruses encode soluble cytokine receptors (vaccinia virus B18), that are being developed as possible future immune therapies, as they mop up IFN and prevent it reaching it's receptor

23

How does Ebola virus evade immune mechanisms?

It encodes 2 proteins that are particularly important:
- VP35: inhibits the RIG-1 pathway
- VP24: stops the signal from getting through from the IFNβ receptor to the nucleus (stops STAT1 molecules from getting to the nucleus)
Production of these proteins means that the virus can continue to replicate to incredibly high titres because the patient is unable to amount a proper immune response

24

What determines the viral load and therefore outcome of the infection?

Combination of damage of infected cells by the virus and damage of infected and bystander cells by the immune response
- Host senses the presence of the virus and switches on sets of genes to try and stops the virus
- At the same time the virus coevolves with the host to have a set of it's own genes, which counteract what the host is trying to do

25

What causes a skewing of the immune response?

- Many viruses modulate the immune response, presumably to increase their own replication and transmission
- This can result in inadvertant pathology
- The effects of IFN can vary from protective to immunopathologic. This may depend on how much IFN is made (100 times more IFN is requires for IL-6 induction than Mx)

26

What is a cytokine storm? What infections is this common with? What does it cause?

Innate immunopathology of virus infections
- Virus replicates, induces high IFN accompanied by massive TNFα and other cytokines
- Differences in clinical outcome may reflect vigour of innate immune system, which may vary with age
- This is typical of Dengue haemorrhagic fever, severe influenza infections and Ebola

If viral load is greater than IFN production the virus will go on to infect more cells, which hugely increases IFN production
Cytokine storm will lead to pulmonary fibrosis, caused by accumulation of immune cells in the lung spaces

27

What is the use of viruses that lack the ability to control IFN?

New generation of live attenuated viruses
- Viruses deficient in control of IFN are attenuated in IFN competent cells
- The high IFN levels they induce induce can also recruit useful immune cells, IFN acting as an 'adjuvant'
- Cells naturally or engineered to be deficient in IFN response can be used to grow these attenuated virus strains

28

Why can IFN not be used as a broad spectrum antiviral?

- Unpleasant side effects
- Stimulates production of several cytokines (e.g. TNFα and IL-6)
- Was used to treat Hep C- as a combination of pegylated IFN with ribavirin

29

Why could IFNλ be used as an influenza therapeutic?

- Active on receptors present on epithelial surfaces
- Cannot signal through receptors present on immune cells (therefore no immunopathology/side effects)
- Could induce an antiviral state in target cells

30

How could oncolytic viruses be used to treat cancer?

Would take advantage of the IFN deficient cancer cells
- would uniquely replicate inside cancer cells and kill them
- cancer cells are deficient in their ability to mount a proper immune response
- virus that is unable to overcome IFN response would be unable to replicate in healthy cells but will replicate in cancer cells
- could be injected into the tumour and kill the cells

31

Which answer is not true?
Viruses that can't control the innate immune system well might...
1. be useful as oncolytic agents
2. be difficult to grow in standard cell culture systems
3. be restricted at crossing the host range barrier and unlikely to spark outbreaks in other species
4. be useful as live-attenuated vaccines
5. be highly adapted to their host species

5. be highly adapted to their host species

32

Viruses counteract activation of the innate immune system by:
1. varying their coat protein sequence
2. encoding proteins that cleave or target host immune factors for degradation
3. preventing the loading of peptides by TAP
4. inducing a cytokine storm
5. encoding MHC homologues

2. encoding proteins that cleave or target host immune factors for degradation

33

What are common Staphylococcus aureus skin infections?

Gram positive coccus
- Most common skin infection (including post-surgery)
- Commensal (in normal flora)
- MRSA
- Bone, joint, lung infection
- Sepsis

34

What toxins are produced by S. aureus and what is their action?

Panton Valentine Leuocidin
- Virulence factor
- Makes infections more aggressive
Exfoliative toxin
- Cleavage of epidermis
- Produces blisters
TSST-1 (Toxic Shock Syndrome Toxin-1)
- Causes toxic shock syndrome
- Drop in BP, malaise
- Same as retained tampon TSS
Enterotoxin
- Skin infection gets into food
- Food ingested and causes gastritis
- Diarrhoea and vomiting

35

What are the different manifestations of S. aureus skin infection?

Impetigo: infection of subcorneal layer or epidermis
Ecthyma: infection of full thickness of epidermis
Folliculitis: infection of mouth of hair follicle
Boil: abscess of hair follicle
Carbuncle: abscess of several adjacent hair follicles

36

What is the presentation of impetigo?

Superficial infection of subcorneal layer of epidermis
- Problem in children
- Usually around mouth and nose
- Crusted erosions
S. aureus = golden colour

37

What is Bullous impetigo?

S. aureus infection of the subcorneal layer of the epidermis
- producing exfoliative toxin causing blistering and cleavage of the epidermis

38

What is Staphylococcal scalded skin syndrome? How is it treated?

S. aureus infection in the body spreads to the skin and causes it to slough off
Normally occurs in children
Admitted to hospital; IV antibiotics (if not can die)

39

What is Treponema pallidum?

- Gram negative spirochete
- Cause of syphilis
- STD
- 12 million cases per year worldwide
- Increases transmission of HIV

40

What is the development of a syphilis infection?

Primary (3-8 weeks)
- painless chancre (ulcer) at inoculation site (genital or oral)
Secondary (6-12 weeks)
- disseminated infection
- generalised rash and lymphadenopathy
Latent syphilis (no clinical signs)
Tertiary syphilis
- skin, neurological and vascular manifestations

Congential
- acquired perinatally
- early and late manifestations
- miscarriage
- still birth
- prematurity
- rashes
- brain and neurological problems
- bone disease

41

How is syphilis diagnosed

Using dark field microscopy

42

What causes chickenpox and shingles?

HHV-3 (Varicella Zoster Virus)

43

What causes oro-genital herpes? Which type typically affects the mouth and which affects the genitals?

Herpes simplex virus HHV-1 and HHV-2
Type 1- oral herpes
Type 2- genital herpes
(can be the other way around)

44

What is the clinical presentation of Herpes simplex virus? How is it transmitted? What causes a flare up?

- Vesicular rash - 2 weeks (starts as a blister then crusts over)
- Eczema herpeticum
- Herpes encephalitis
Transmitted through skin to skin contact anywhere on the body
Flare up from:
- being run down
- sunlight
- infection

45

What is the differential diagnosis for Herpes simplex virus?

Steven Johnsons syndrome

46

What is Eczema herpeticum?

Ezcema which becomes infected with herpes simplex virus which disseminates and can infect organs and brain
- 3-4mm lesions

47

What is the site of active lesions and site of viral latency of herpes simplex virus 1&2 and varicella zoster?

Site of active lesion: on the lip
Site of viral latency: Trigeminal nerve ganglion

48

What is Dermatophytes? Where do infections present?

Type of mould
e.g. Trichophyton rubrum
Grows on keratin
Long hyphae, grow from the tip
Infects skin, hair and nails

49

What kind of infections are caused by yeasts?

e.g. Candida
Grow on warm, wet surfaces
Single cell and bud

50

What is Tinea unguium? Where does it occur and how is it diagnosed?

Tinea: skin
Dermatophyte infection of nails
Yellow, crumbly nails
Otherwise asymptomatic
Send off clipping for diagnosis

51

What is Tinea capitis? How is it diagnosed and treated?

Infection of the scalp
Pretty much only affects children
Pluck off hairs and send off scales for diagnosis
Has to be treated with a systemic antifungal

52

What is a kerion?

Small mass of Tinea capitis
Looks a bit like an abscess

53

Where does Tinea manuum occur?

Infection on the hand

54

Where does Tinea pedis occur?

On the foot

55

Where does Tinea cruris occur?

In the groin

56

Where does Tinea facei occur?

On the face

57

What is Candida intertrigo?

A Candida infection of skin folds causing irritation
Treated with antifungals

58

What is Sarcoptes scabei? Where does it occur? How is it diagnosed? How is it treated?

Scabies
The female burrows under the epidermis
Transmitted through skin-skin contact
- Normally patient will get infection, but takes 4 weeks to develop an immune response (itching)
- Presents with intense itching, worse at night
- Must look for burrows (no burrows = not scabies), with black dot (head of mite) at one end
Treatment
- Topical cream on for 12 hours then washed off, repeat 5 days later- will kill scabies
- Topical steroid to treat the itching

59

What is the importance of the stratum corneum? What do defects cause?

Very important for the barrier function of the skin
- Defects lead to eczema
- Filagrin gene mutation common in eczema

60

What is atopic eczema?

Atopy- tendency to develop hypersensitivity
- common, relapsing and remitting

61

What is the atopic march?

Onset of atopic condition
Eczema (1-2 years)
Food allergy (1-2 years)
Asthma (~5 years)
Rhinitis (~9 years)

62

What is the pathogenesis of atopic eczema? What intrinsic and extrinsic factors affect it? What occurs in acute and chronic atopic dermatitis?

Extrinsic factors- penetration of exogenous agents
- Allergens (e.g. house dust mite)
- Irritants (e.g. detergents in soaps)
- Pathogens (e.g. staphylococcus)
Intrinsic factors
leading to defects in the epidermal skin barrier (e.g. filaggrin gene mutations)
Mast cell degranulation releasing histamine

Acute Atopic Dermatitis
- Activation of CD4⁺ lymphocytes and the Th2 immune response
Chronic Atopic Dermatitis
- Activation of CD4⁺ and CD8⁺ lymphocytes and the Th1 immune response

63

What sign on the hand would indicate a filagrin gene mutation?

Palmar hyperlinearity (intrinsically dry and flaky skin)

64

How does infantile atopic eczema contribute to development of food allergy?

In infants eczema is common particularly around the mouth (and elbows and knees). This decreases the effectiveness of the skin as an external barrier. Allows entry of food allergens which causes sensitisation and contributes to allergy

65

What are the common sites for eczema outbreaks in children and adults?

Children:
- Head (top and back of head)
- Cheeks
- Neck
- Forearms
- Hands
- Feet
- Backs of legs

Adults:
- Face
- Neck
- Inner elbow
- Hands
- Wrist
- Arms
- Can also occur on torso, thighs and legs

66

What is eczema with lichenification?

Eczema with chronic scratching- skin thickens

67

What are the different types of eczema? Describe them

- Atopic eczema: occurs in those who have a tendency to develop hypersensitivity
- Seborrhoeic eczema: overgrowth of yeast, skin reacts to the yeast. Usually occurs around breasts, eyebrows, cheeks. Not as itchy
- Allergic contact dermatitis: occurs in contact with a chemical (e.g. Nickel, cosmetics). Patients with atopic eczema are more likely to to get this, but can occur without
- Discoid eczema: from over washing and dry climates (Discoid = discs)

68

Why do Henna tattoos cause allergy?

Contains black dye (PPD), which is also in hair dye.
Henna tattoos will cause sensitisation which will result in permanent hair dye allergy

69

What is psoriasis? What is the cause and histology?

Very common inflammatory dermatitis
Skin lesions- dry, scaly, well defined, salmon pink
Caused by over proliferation of keratinocytes
Underlying genetic susceptibility and environmental triggers (e.g. stress)
Hyperkeratosis: Over proliferation of keratinocytes
Parakeratosis: Retention of nuclei in the stratum corneum
Acanthosis: Thickening of the skin
Inflammation
Dilated blood vessels

70

What are the common locations of psoriasis?

Face, scalp, armpit, elbows, trunk, buttocks, groin and genitals, knees, nails

71

What abnormalities occur in nail psoriasis?

- Subungual hyperkeratosis
- Dystophic nail and loss of cuticle
- Onycholysis
- Pitting

72

What is guttate psoriasis?

- Affects teenagers
- Triggered by strep. throat
- Within a week get an outbreak of psoriasis
- Appearance like rain drops

73

What is palmoplantar pustulosis

Psoriasis on the hands and feet
Presents with formation of pustules

74

What is the presentation of generalised pustular psoriasis? How is it treated?

- Pink scaly skin
- Very inflammed with pustules
Treated: Admission to hospital and treated with immunosuppressants

75

What is acne?

Inflammatory disease of hair follicles
- White head formation from accumulation of dead cells and sebum
- Androgenic drive increases sebum production
- Bacteria proliferate
- Rupture of follicle then further inflammation

76

What are the clinical features of acne?

- Scars
- Blackheads (open comedones)
- Whiteheads (closed comedones)
- Papules
- Pustules
- Nodules
- Typically affects the face, chest, back and genitals

77

What causes bullous pemphigoid? Who does it present in? What are the complications and how is it treated?

Caused by autoantibodies
Epidermis is derived from endoderm
Dermis is derived from mesoderm
Lots of proteins present in the basement membrane zone- body makes antibodies to proteins BPAg1 and BPAg2 causing the epidermis to split from the dermis
- Forms blisters, blisters can start with a rash
- Common in elderly and western, european origin
- Common skin infections
- Can die from sepsis
- Easily treated with oral and topical steroids

78

What causes epidermolysis bullosa?

Defect in proteins in the basement membrane zone.
- Can be mild and not present till adulthood
- Layer of the skin shear off and takes a long time to heal (with scarring)

79

What causes pempigus vulgaris? How does it present; who is commonly affected?

Autoantibodies directed to components of the epidermis
Leads to splitting of keratinocytes away from each other
- Don't see blisters; just see eroded skin
- Common in middle-aged people (40-60) and middle easter, asian people
- Without treatment ~90% mortality

80

What is the process of MHC presentation of viral peptides?

- MHC is coded for by DNA and translated in the endoplasmic reticulum
- Viral peptides are chopped up by the proteasome and enter the ER through TAP where they are loaded onto MHC (class I) via tapasin
- MHC migrates to the cell surface where is is presented to T cells

81

How does EBV regulate MHC class I antigen presentation?

EBV EBNA1 has lots of glycine and alanine repeats which prevent it from being processed by the proteasome
If it cannot be processed by the proteasome it cannot be presented on MHC

82

How does HSV regulate MHC class I antigen presentation?

HSV ICP47 blocks access of the processed peptide to TAP so it cannot enter the ER and be presented on MHC

83

How does CMV regulate MHC class I antigen presentation?

CMV US6 stops ATP binding to TAP which prevents its translocation to the endoplasmic reticulum so it cannot be presented on MHC
CMV US3 binds tapasin and prevents peptide being loaded to MHC

84

How does Adenovirus regulate MHC class I antigen presentation?

Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum

85

How does Kaposi's Sarcoma interfere with MHC presentation at the cell surface?

KSHV kK3 protein induces polyubiquitinylation and internalisation of MHC. From the internalised endosome, MHC is passed to lysosomes where it is degraded

86

What happens if a cell does not display MHC at it's surface? How do viruses avoid this mechanism? Give an example of a virus which uses this mechanism.

Cells that don't display MHC are detected and killed by NK cells, so viruses that disrupt MHC presentation would end up being killed by MHC
Viruses encode for (fake) MHC analogues (e.g. CMV gpUL40) or upregulate MHC
- this is non-functional so T cells are not activated

This is how people have life long viral infections

87

What problem does HCMV cause in transplant patients?

Human cytomegalovirus infects 60-90% of people but is only a problem in immunocompromised
It is usually seen in the first 30 days after a transplant
The virus needs to be eliminated from bone marrow cells of a transplant recipient before transplantation otherwise it will reactivate

88

What change in the cell surface of HCMV latently infected cells could lead to a new therapeutic approach to the virus?

- MRP-1 is a transporter which moves toxic substances out of a cell from the infected cell surface
- HCMV makes UL138 which causes loss of MRP-1
- Loss of MRP-1 transporter leads to accumulation of certain molecules inside the infected cells
- This includes toxic drug vincristine which could be used to treat donors prior to transplantation to eliminate HCMV

89

What is antigenic drift? Give an example of a virus which this frequently occurs in?

Continued rapid evolution driven by antigenic pressures from the host resulting in accumulation of mutation. Even a 3 amino acid mutation would change the protein which requires a new antibody and therefore a new vaccine
Occurs in influenza

90

What is a quasispecies? Give an example of a virus this occurs in?

A cloud of related genotypes that exist with a high mutation rate in a patient, where more mutations will be accumulated. Results in a large variations of antigen in one patient
Occurs in HIV

91

What is antigenic shift? Give an example of a virus which this frequently occurs in?

Two or more different viruses (or different strains of a virus) combine to form a new subtype having a mixture of the surface antigens of the original strains
Occurs in influenza

92

What viruses have different serotypes in circulation?

Rhinovirus: >120 of serotypes
Poliovirus: 3 serotypes
Dengue fever: 4 serotypes

93

What type of vaccine is the seasonal influenza vaccine? How is it changed every year?

Trivalent or quadrivalent
Every component of the vaccine has to be updated every year

94

What is the theory behind a universal influenza vaccine?

Influenza virus is made up of HA1 (variable region) and HA2 (conserved region)
HA2 region does not drift like the HA1 region so antibodies to this region would be more effective

95

How does HIV resist neutralisation?

HIV envelope spike GP120 resists neutralisation because:
- Large space between spikes prevents antibody cross-linking
- Extensive glycosylation masks antibody epitopes
- Functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant amino acids are visible to B cell receptor and antibodies

Antibodies that can cross react with many HIV strains do exist alongside virus in people who control the infection

96

What is the role of BNab in HIV?

BNabs produced as biological therapeutics can control viral load- but escape mutants to appear

97

Describe the poliovirus

There are 3 serotypes of poliovirus so it requires a trivalent vaccine
The live attenuated Sabin vaccine administered all 3 at once but had virus interference and poor response to one component
One poliovirus serotype has been eradicated from the world

98

What is Dengue haemorrhagic fever?

- Responsible for 500,000 hospitalisations each year with 5% fatalities
- Leakage of blood plasma from capillaries
- Detected by increase in red cell count and decrease in protein level in blood
- Tendency to severe bruising, and bleeding. Patient deteriorates even after fever drops; shock
- Treat with IV fluid replacement

99

What is antibody dependent enhancement of Dengue fever?

Dengue virus exists as 4 different serotypes
- Antibody generated against a previous infection can bind but not neutralise, and lead to ADE, causing Dengue Haemorrhagic Fever

ADE (antibody dependent enhancement)
- Heterotypic antibody from previous infection binds virus
- Presents to monocyte
- Virus replicates inside the monocyte
- Increases viral load inside monocyte causing diseases

100

How does Ebola evade antibody response?

- Soluble GP is the default coding for the GP gene. Full length GP is made by polymerase stuttering
- sGP is an antibody decoy
- sGP is immunosuppressive, inhibits neutrophils
- Reston virus version only suppressive in macaques

101

What effect does measles virus have on the immune system?

- Measles virus infects CD150 positive cells, including memory lymphocytes and erases immunological memory
- Measles virus results in a 2-3 year decreases in immunological memory that leads to morbidity and mortality from other diseases

102

Viruses counteract activation of the innate immune system by:
1. Varying their coat protein sequences
2. Encoding proteins that cleave or target host immune factors for degradation
3. Preventing the loading of peptides by TAP
4. Inducing a cytokine storm
5. Encoding MHC homologues

2. Encoding proteins that cleave or target host immune factors for degradation

103

RNA viruses are more likely than DNA viruses to
1. Code for proteins that interfere with innate immunity
2. Code for proteins that interfere with cellular immunity
3. Have error prone polymerases that promote antigenic variation
4. Use lipid envelopes to protect their genomes that also contain host proteins that control complement activation
5. Activate interferon induction pathway through cGAS and STING

3. Have error prone polymerases that promote antigenic variation

104

Which is NOT true?
Hepatitis C virus evades our immune systems in the following ways:
1. Its E2 protein varies by more than 30% so antibodies only bind a tiny fraction of the viral quasispecies
2. T cell epitopes vary so that the virus is not cleared in the early stage of infection and this determines chronicity
3. NS3/4A protease cleaves MAVS and prevents activation of interferon
4. It encodes a protein called vif that counteracts the interferon stimulated gene APOBEC and prevents if from inducing hypermutation of the viral genome
5. A genetic polymorphism in IL28b results in non-responsiveness to interferon treatment

4. It encodes a protein called vif that counteracts the interferon stimulated gene APOBEC and prevents if from inducing hypermutation of the viral genome

105

What are the common virulence factors bacteria can have?

- Diverse secretion systems
- Flagella (movement, attachment)
- Pili (important adherence factors)
- Capsule (protect against phagocytosis)
- Endospores (metabolically dormant forms of bacteria)
heat, cold, desiccation and chemical resistant
- Biofilms (organised aggregates of bacteria embedded in polysaccharide matrix - antibiotic resistant)
- Exotoxins
- Endotoxins

106

Give an example of a bacteria that has a capsule.

Streptococcus pneumoniae

107

Give examples of bacteria that have endospores.

Bacillus spp.
Clostridium spp.

108

Give examples of bacteria that have biofilms.

Pseudomonas aeruginosa
Staphylococcus epidermidis

109

What are different types of exotoxin? Give examples of the bacteria they are present in.

1. Neurotoxins (act on nerves or motor endplate)
i.e Tetanus or Botulinum toxins
2. Enterotoxins (act on the GI tract)
- Infectious diarrhoea
i.e. Vibrio cholera, Escherichia coli, Shigella dysenteriae and Campylobacter jejuni
- Food poisoning
i.e. Bacillus cereus or Staphylococcus aureus
3. Pyrogenic exotoxins (stimulate release of sytokines)
i.e. Staphylococcus aureus or Streptococcus pyogenes
4. Tissue invasive exotoxin (allow bacteria to destroy and tunnel through tissue - enzymes that destory DNA, collagen, fibrin, NAD, red or white blood cells)
i.e. Staphylococcus aureus, Streptococcus pyogenes, Clostridium perfringens)
5. Miscellaneous exotoxin (specific to a certain bacterium and/or function not well understood)
i.e. Bacillus anthracis and Carynebacterium diptheriae

110

What type of bacteria produces endotoxins?

Only Gram negative bacteria

111

What are endotoxins? What is the problem that occurs with treating a bacteria that produce this?

- Not a protein but the lipid A moiety of LPS
- Shed in steady amounts from living bacteria
- Treating a patient who has a Gram-negative infection with antibiotics can sometimes worsen the condition
- When bacteria lyse they release large quantities of LPS/Endotoxin causing Septic shock

112

How are outbreak strains detected?

Using PCR
- Isolates can be screened by multiplex PCR for characteristic features of the outbreak strain

113

What was the difference between Enteroaggregative E. coli (EAEC) and the 2011 German E. coli outbreak?

The outbreak strain contained most of the EAEC genome plus the Shiga toxin from enterohaemorrhagic E. coli

114

What does the Shiga toxin do?

Shiga toxin family members have an AB5 subunit composition
- StxA is non-covalently associated with a pentamer of protein B (StxB)
- StxA is enzymatically active domain
- StxB pentamer is responsible for binding to host cell receptors
- StxA is an enzyme that cleaves the 28S ribosomal RNA in eukaryotic cells - leads to inhibition of proteins synthesis
- Bacterial ribosomes are also a substrate for StxA and this will result in decreased proliferation of susceptible bacteria - might affect the commensal bacteria in the gut

Shiga toxin not only blocks protein synthesis in eukaryotic calls but also affects several other cellular processes

115

How does Shiga toxin move from one strain of E. coli to another?

- It is encoded onto a bacteriophage
- Highly mobile genetic elements and contributes to horizontal gene transfer
- Toxins are highly expressed when the lytic cycle of the phage is activated

116

What is the virulence factor produced by EAEC?

Enteroaggregative E. coli: AAF (aggregative adherence fimbriae)
- genes encoding for AAF are on a plasmid
- mobilised between strains
- AAF required for adhesion to enterocytes
- AAF stimulate a strong IL-8 response
- Allows biofilm formation
- Additional virulence factors lead to the disruption of actin cytoskeleton → exfoliations

117

What is an outbreak?

An outbreak is a greater-than-normal or greater-than-expected number of individuals infected or diagnosed with a particular infection in a given period of time, or a particular place, or both

118

How is an outbreak identified?

Surveillance provides an opportunity to identify outbreaks
Good and timely reporting systems are instrumental to identify outbreaks

119

What are the different groups of communicable diseases in Europe?

1. Respiratory tract infections
2. Sexually transmitted infections, including HIV and blood-borne viruses
3. Food- and waterborne diseases and zoonoses
4. Emerging and vector-borne diseases
5. Vaccine-preventable diseases
6. Antimicrobial resistance and healthcare-associated infections

120

What are the different respiratory tract infections in Europe? Which of these are bacterial?

- Influenza
- Animal influenzas, including avian influenza
- SARS (severe acute respiratory syndrome)
- Legionnaire's disease (Legionellosis)*
Legionella pneumophilia (Gram -ve)
- Tuberculosis*
Mycobacterium tuberculosis (Gram +ve)

*bacterial

121

What is Legionella pneumophila? Describe the infection

- Gram-negative bacterium
- Lives in amoeba in ponds, lakes, air conditioning units, whirlpools
- Infection route: inhalation of contaminated aerosols (droplet inhalation)
- In humans L. pneumophilia will infect and grow in alveolar macrophages
- Human infection is "dead end" for bacteria
- Important virulence factor type IV secretion system - Secretion of effector proteins by the type IV secretion system allow Legionella to replicate in a Legionella containing vacuole (LCV)

122

What is Mycobacterium tuberculosis? Describe the infection

- Groups with Gram-positive bacteria
- Very different cell wall - extra lipid layer makes treatment more difficult
- M. tuberculosis can enter a dormant state (Latent TB- immunological tests show infection but no signs or symptoms)
- Around 70,000 cases reported in EU in 2011
- Treatment of infections: with antibiotics BUT takes at leat 6 months
- 77% success rate of treatment of new cases
- 54% success rate for second infection
- Multi-drug resistant treatment success rate is 32%

123

What are the different sexually transmitted infections in Europe? Which ones are bacterial?

- Chlamydia trachomatis infection*
- Gonorrhoea*
Neisseria gonorrhooeae
- Hepatitis B virus infection
- Hepatitis C virus infection
- HIV/AIDs
- Syphilis*
Treponema pallidum

*bacterial

124

What is Chlamydia trachomatis? Describe the infection.

- Obligate intracellular pathogen - cannot culture it outside of host cell
- Most frequent STI in Europe → 350,000 cases per year
- Infection likely higher due to underreporting
- Other parts of the world → Eye infection: 84 million people infected and about 8 million people visually impaired
- It is responsible for more than 3% of the worlds blindness

125

What is Neisseria gonorrhoeae? Describe the infection.

- Gram-negative diplococcus
- Establishes infection in the urogenital tract by interacting with non-ciliated epithelial cells
Important virulence factors:
- pili and antigenic variation escape detection and clearance by the immune system

126

What are the different food- and water-borne diseases and zoonoses in Europe?

- Anthrax
(Gram +ve Bacillus anthracis - hoofed animals, but humans that come into contact with infected animals can get sick)
- Botulism (Gram +ve Clostridium botulinium - through wounds, canned/preserved food)
- Brucellosis (Gram -ve Brucella spp - caused by ingestion of unsterilised milk or meat)
- Campylobacteriosis (Campylobacter spp. mostly C. jejuni)
- Cholera (Gram -ve Vibro cholera)
- Infection with Vero/shiga toxin-producing Escherichia coli (Gram -ve)
- Leptospirosis (Gram -ve Leptospira spp.)
- Listeriosis (Gram +ve Listeria monocytogenes)
- Salmonellosis (Gram -ve Salmonella spp.)
- Shigellosis (Gram -ve Shigella spp.)
- Tularaemia (Gram -ve Francisella tularensis)
- Typhoid/paratyphoid fever (Gram -ve Salmonella typhi and S. Paratyphi)
- Yersiniosis (Gram -ve Yersinia enterocolitica

127

What is Campylobacter spp. Describe the infection.

- Most commonly reported infectious GI disease in the EU
- Usually sporadic cases and not outbreaks
- Small children 0-4 years - highest risk group
- Infection most likely through undercooked poultry
- Virulence factor:
Adhesion and invasion factors. Flagella motility, Type IV secretion system, Toxin

128

What is Salmonella spp? Describe the infection.

- One of the most common GI infections in the EU
- Undercooked poultry
- Outbreaks
- Highest infection rate in small children (0-4 years)
- Important virulence determinant
Type III secretion systems encoded on pathogenicity islands (SPI)

129

What virulence factors are produced by Salmonella enterica?

Type III secretion system (encoded on pathogenicity islands)
SPI1: is required for invasion
SPI2: intracellular accumulation

130

What is Vibrio cholerae? Describe the infection.

- Cholera is an acute, severe diarrheal disease
- Without prompt rehydration, death can occur within hours of the onset of symtpoms
- Latest epidemic in Haiti (October 2010-ongoing, as of Jan 2013 > 600,000 cases with 8000 deaths)
Important virulence factors:
- Type IV fimbria
- Cholera toxin
- Carried on phages

131

What is Listeria monocytogenes? Who is particularly at risk?

- Risk group is immunocompromised, elderly, pregnant and their fetus
- Listeria can enter non-phagocytic cells and cross their tight barriers

132

What are the different emerging and vector-borne diseases? Which ones are bacterial

- Malaria
- Plague*
(Gram -ve Yersinia pestis)
- Q fever*
(Gram -ve Coxiella burnetti)
- Severe acute respiratory syndrome (SARS)
- Smallpox
(Eradicated in 1980 due to successful vaccine programme)
- Viral haemorrhagic fevers (VHF)
- West Nile Fever
- Yellow Fever

*bacterial

133

What are the different vaccine preventable diseases? Which ones are bacterial?

- Diphtheria*
(Gram +ve Clostridium diphtheriae)
- Invasive haemophilus influenza disease*
(Gram -ve Haemophilus influenzae)
- Invasive pneumococcal disease (IPD)*
(Gram +ve Streptococcus pneumoniae)
- Measles
- Mumps
- Pertussis*
(Gram -ve Bordetella pertussis)
- Polio
- Rabies
- Rubella
- Tetanus
(Gram +ve Clostridium tetani)

134

What does antimicrobial mean?

Interferes with growth and reproduction of a 'microbe'

135

What does antibacterial mean?

Commonly used to describe agents to reduce or eliminate harmful bacteria

136

What are healthcare associated infections?

Infections that occur after exposure to healthcare
- infection starts >48 hours after admission to the hospital

137

What are the most common healthcare associated infections?

- surgical site infections
- urinary tract infections
- pneumonia
- bloodstream infections
- gastrointestinal infections

138

What interventions make patients vulnerable to infection?

- Lines (intravenous, central, arterial, CVP/pulmonary artery)
- Catheterisation
- Intubation
- Chemotherapy
- Prophylactic antibiotics
- Inappropriate prescribing
- Prosthetic material

139

What are the main bacteria that cause healthcare associated infections? What antibiotics are they resistant to?

ESCAPE
Enterococcus faecium (vancomycin resistant)
Staphylococcus aureus (Methicillin resistant- MRSA)
Clostridium difficile (because of previous antibiotic treatment)
Acinetobacter baumanii (highly drug resistant)
Psuedomonas aeruginosa (multidrug resistant; i.e. fluoroquinolone resistant)
Enterobacteriaceae
- E. coli (multidrug resistant)
- Klebsiella pneumoniae (multidrug resistant)
- Enterobacter sp. (multidrug resistant)

140

What is the most frequent cause of community and hospital acquired UTIs and bacteraemia?

Pathogenic E. coli
- Increase in multidrug resistant strains
- Occurrence of resistance to to 3rd generation cephalosporins as high as 20% in some countries
- Cephalosporin resistant isolates express the extended spectrum beta lactamase
- Still sensitive to carbapenems

141

What are cephalosporins? What is their target? How is bacteria resistant to it?

A class of β-lactam antibiotics
Target pathway: inhibit peptidoglycan synthesis
Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
Resistance: Extended spectrum β-lactamase encoded on plasmid cleave cephalosporin

142

What are carbapenems? What is their target? How is bacteria resistant to it?

A class of β-lactam antibiotics
Target pathway: inhibit peptidoglycan synthesis
Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
Resistance: Carbapenemase enzyme bla^(kpc) encoded on a transposon mobile genetic element cleaves carbapenem

143

What is Klebsialla pneumoniae? Who is particularly at risk? What antibiotics is it resistant to?

Important cause of UTI and respiratory tract infections
Risk group: immunocompromised
High proportion of resistance to 3rd generation cephalosporins, fluquinolones and aminoglycosides
Carbapenem-resistant Klebsiella pneumoniae is the most common in the US

144

What is Pseudomonas aeruginosa? Who is particularly at risk? What antibiotics is it resistant to?

Important cause of infection in immunocompromised
High proportion of strains are resistant to several antimicrobials

145

What is the most important cause of antimicrobial resistant infection in the world?

Methicillin resistant S. aureus (MRSA)

146

What are carbapenems? What is their target? How is MRSA resistant to it?

It is a β-lactam antibiotics
Target pathway: inhibit peptidoglycan synthesis
Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
Resistance: Expression of additional penicillin binding protein (PBP2A) which has a low affinity for methicillin and can still function in the presence of the antibiotic
MRSA strains can synthesise peptidoglycan and survive in the presence of methicillin

147

What is Enterococcus faecium? What antibiotic is it resistant to?

Third most frequently identified cause of nosocomial blood streat infections (BSI) in the US
Vancomycin resistance it around 60%

148

What is vancomycin's target? How is enterococcus faecium resistant to it?

Target pathway: inhibit peptidoglycan synthesis
Target protein: Binds to peptidoglycan precursor
Resistance: Multiple proteins; genes encoded on plasmid or transposon. Results in synthesis of a different peptidoglycan precursor

149

What are the major antifungal immune effector cells

- Opsonization by pentraxin 3 and mannor-binding lectin
- Phagocytes are a critical first line of defense
- NK cells provide early IFNγ
- A failure of innate immunity leads to adaptive responses
- Dendritic cells influence T cell differentiation
- Th1 and Th17 play a role

150

What is an endoparasite? Give examples.

An organism that lives in the host and is dependent on it for nutrition- causing damage
Protozoa: amoeba, coccidiae, ciliate, flagellates
Metazoa: roundworms, flatworms, flukes

151

What are ectoparasites?

An organism that lives on the host and is dependent on it for nutrition, causing damage

152

What are Protozoa?

Single celled organisms
- Eukaryotes (genome within a nucleus, complex organelles in cytoplasm)
- Pathogenesis varied
- Some have insect vectors (e.g. malaria)
- No eosiniphilia

153

What are metazoa?

Multicellular organisms (helminths/worms)
- Free living, intermediate hosts and vectors
- Some just inhabit gut (geohelminths), others invade tissues
- Eosinophilia- if invade blood

154

What are the different types of protozoa? Give examples

Amoeba
- Entamoeba histolytica
- Entamoeba dispar
Coccidia
- Plasmodium spp.
- Toxoplasma
- Crytpsporidium
Ciliates
- Balantidum coli
Flagellates
- Trichomonas
- Giardia
- Trypanosoma
- Leishmania

155

How do you acquire an amoeba infection?

By ingestion of mature cysts in food or water, or on hands contaminated by faeces

156

What are the symptoms of a E. histolytica infection?

The cysts of E. histolytica enter the SI and release active amoebic parasites (trophozoites), which invade the epithelial cells of the large intestines, causing flask whated ulcers. Infection can then spread from the intestine to other organs (e.g. liver, lungs and brain) via the venous system

Asymptomatic carriers can pass cysts in faeces and the asymptomatic phase can persist indefinitely. Cysts remain viable for up to 2 months

Invasive amoebiasis most often causes an amoebic liver abscess, but may affect the lung, heart, brain, urinary tract and skin

157

What much E. histolytica be differentiated from? Why?

Must be differentiated from Entamoebe dispar, which is a normal commensal of the GI tract

158

Give three examples of Coccidia organisms. What disease is caused by them?

1. Plasmodium spp. (Malaria)
2. Toxoplasma (Toxoplasmosis)
3. Crytosporidium (Diarrhoea)

159

What are the symptoms of malaria?

Can appear as early as 7 days but the time between exposure and signs of illness can be as long as one year
- Fever, headache, chills, vomiting, muscle pain
- Paroxysm (cycle in 4-8 hours)

Complications of malaria
- Severe anaemia (due to destruction of red cells)
- Cerebral malaria (swelling of the brain, seizures, coma)

- liver failure
- shock
- pulmonary oedema
- abnormally low blood sugar
- kidney failure
- swelling and rupturing of the spleen

160

What are the symptoms of Toxoplasma?

Mild disease
In immunocompromised patients:
- Central nervous system disease
- Brain lesions
- Pneumonitis
- Retinochoroiditis
- Fever
- Swollen lymoh nodes
- Headaches
- Sore throat

In pregnancy poses serious danger for the foetus

161

What are the symptoms of Cryptosporidium?

Causes diarrhoea, fever, nausea, vomiting. Very common in HIV +ve patients presenting with diarrhoea
In immunocompromised patients the parasites can cause serious pathological changes

162

Give an example of a Ciliate organism. What are the symptoms?

Balantidium coli
Most people infected have no symptoms
Immunocompromised patients may experience more severe signs and symptoms:
- persistent diarrhoea
- dysentery
- abdominal pain
- weight loss
- nausea
- vomiting
- if left untreated can result in performation of the colon

163

What are the different types of flagellate organisms?

1. Giardia lamblia
2. Trichomonas
3. Leishmania

164

What are the symptoms of Giardiasis?

Acute symptoms:
- Diarrhoea
- Greasy stools that tend to float
- Stomach or abdominal cramps
- Upset stomach or nausea/vomiting
- Dehydration

165

What are the symptoms of Trichomonas?

Females:
- 10-50% are asymptomatic
- Vaginal discharge, vulval itching, dysuria or offensive odour but these are non-specific
- Occasionally the presenting complain is of low abdominal discomfort or vulval ulceration

Males:
15-50% are asymptomatic
- Discharge and/or dysuria

Complications
Detrimental outcome on pregnancy and is associated with preterm delivery and low birth weight

HIV
Trichomonas infection may enhance HIV transmission and there may be an increased risk of tricomonas in those that are HIV +ve

166

What are the different types of Helminths?

Roundworms (Nematodes):
- Ascaris
- Hookworm
- Filaria
- Strongyloides

Flatworm (Cestodes):
- Taenia (tapeworms)

Flukes (Trematodes):
- Schistosoma

167

What are the symptoms of Ascariasis?

Roundworm
Often causes no symptoms
Infections with large numbers of worms may cause:
- Abdominal pain
- Intestinal obstruction

Can cause:
- Malnourishment
- Localised reactions in various organs
- Loeffler's pneumonia (penetration of larvae from capillaries into lungs)

168

Give examples of species of Hookworm. What symptoms do they cause?

Ancylostoma duodenale
Symptoms:
- Iron deficiency anaemia (most common)
- Cardiac complications
- Gastrointestinal and nutritional/metabolic symptoms
- Local skin manifestations ('ground itch')
- Respiratory symptoms

Whip worm
Symptoms:
- Can cause no symptoms
If you have hundreds of worms:
- Bloody diarrhoea
- Anaemia (due to severe vitamin and iron loss)
- Inflammation of intestine wall (due to open wounds)
- Rectal prolapse

169

Give examples of Filaria species. What symptoms do they cause?

Brugia malayi
Wucheria bancrofti
- Causes lymphatic obstruction (especially in the legs) can progress to elephatiasis - can also occur in the arm, breast, scrotum

Loa loa (Loaiasis)
- Can cause blindness

170

Give examples of different taenia spp. What symptoms do they cause?

T. solium ∼3m
- Commonest acquired cause of epilepsy worldwide
T. asiatica ∼3m
T. saginata (causes more symptoms) <10m
Symptoms:
- Most people have no symptoms or mild symptoms
- Abdominal pain
- Loss of appetite
- Weight loss
- Upset stomach

171

Give an example of a fluke organism. What symptoms does it cause?

Schistosomiasis
Within days:
- Possible rash or itchy dkin
Within 1-2 months:
- Fever
- Chills
- Cough
- Muscle aches
- (most people have no symptoms at this phase)
When adult worms are present:
- Eggs travel to intestine, liver or bladder, causing inflammation or scarring

Children who are repeatedly infected:
- Anaemia
- Malnutrition

After years of infection can damage:
- Liver
- Intestine
- Lungs
- Bladder

172

Give an example of ectoparasite organisms.

Sarcoptes scabiei (scabies)
Pediculus humanus capitis (head louse)
Pediculus humanus corporis (body louse, clothes louse)
Pthirus pubis (pubic louse, 'crab' louse)

173

What organism causes scabies? What are the symptoms and how is it diagnosed?

Sarcoptes scabiei
Diagnosed:
- Appearance of rash
- Presence of burrows

Symptoms:
- Rash
- Itching

174

What are the different types of Leishmania? How is it transmitted?

- Promastigote
- Amastigote

Transmitted within sand fly vector

175

What are the different types of malaria? What is the vector?

Plasmodium
- P. falciparum
- P. malariae
- P. ovale
- P. vivax
- P. knowlesi

Transmitted by female Anopheles mosquito

176

What are the symptoms of visceral leishmaniasis?

(Kala azar = black fever)
Most severe form. Fatal if left untreated
- irregular fever
- weight loss
- swelling of liver and spleen
- anaemia

Post Kala-azar Dermal Leishmaniasis
- Lesions start on face, usually around mouth
- Lesions become nodular
- PKDL can spread to the trunk and limbs

177

What are the symptoms of (localised) cutaneous leishmaniasis?

- Skin lesions on exposed body parts, often self-healing
- Can create serious disability and scars
- Immunity to reinfection
- Large irregular ulcers; surrounded by papular and crusted lesions which all contain parasites

178

What are the symptoms of diffuse cutaneous leishmaniasis?

- Disseminated lesions
- Resembles leprosy (difficult to treat)
- No spontaneous healing
- Frequent relapses
- Multiple, nodular, non-ulcerating lesions

179

What are the symptoms of mucocutaneous leishmaniasis?

- Disfiguring
- Destroys mucous membranes