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3s2: Infection and Immunity > Week 8 > Flashcards

Week 8 Flashcards

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1
Q

What is an overview of mycobacteria?

A

Mycobacteria are Actinobacteria (Gram positive) that belong to the suborder of Corynebacterineae
Corynebacterineae are very common in the environment

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2
Q

What are examples of mycobacteria?

A

Mycobacterium tuberculosis (M-TB) (tuberculosis- TB)
Mycobacterium leprae (leprosy)
Mycobacterium bovis (bovine tuberculosis)

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3
Q

What is an overview of mycobacterial cell wall?

A

Mycobacteria have very different cell walls to Gram positives
Most components - essential for cell survival or pathogenicity

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4
Q

What constitutes mycobacterial cell wall?

A

Thin peptidogycan layer
Arbibo-glycan layer
Mycolic acid
Glycolipids (50 to 60 layers in Tuberculosis)
Capsule with free lipids and carbohydrates, often the thickest layer

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5
Q

What is an overview Mycobacterium tuberculosis has had on history?

A

One of the biggest killers in recorded history
In the early 1900s, TB killed one out of every seven people living in the United States and Europe.
Nespaheran priest of Amun - Egpytian mummy from 21st dynasty 1000 BC
Killed George Orwell
No cure pre-1950

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6
Q

How many people died of Tuberculosis in 2022?

A

1,300,000

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7
Q

What is an overview of TB infection?

A

M-TB is a very slow growing species (doubling time of 12 -24 hours)
Inhaled in aerosols coughed out by an infected person

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8
Q

What is an overview of the lifecycle of TB?

A

90-95% can be contained in granulomas
Granulomes can become a latent infection
5-10% are active disease
When active disease can transmit

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9
Q

What can cause TB to reactivate?

A

Due to HIV, malnutrition, stress, smoking, other infectious diseases

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10
Q

How does TB infect people?

A

M-TB divides within macrophages
Granulomas form when the immune cells surround infected macrophages though Tb may stimylate this to protect from immunity
M-TB is spread if the granuloma becomes necrotic
Necrotic granulomas accumulate within the lungs, leading to death

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11
Q

What is an overview of macrophages role?

A

The role of macrophages is to engulf and destroy foreign material, including microbes
Normally, cells become trapped in the phagolysosome and are killed through acidity induced via a recruited ATPase pump, reactive oxygen species and specialised enzymes

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12
Q

How can TB protect against macrophage phagolysome death?

A

Various cell wall components and secreted proteins prevent phagolysosome formation and protect M-TB against reactive oxygen species and free radicals

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13
Q

What are TB molecules used to protect against macrophages?

A

Cell-wall glycolipids = Inhibitd PI3P deposition (I3P is involved in endocytosis and vesicular trafficking toward the lysosome)
Glutathione - Scavenges free radicals
Protein Kinase G - Inhibits phagosome lysosome fusion
PhoP - Two-component system associated with pathogenesis

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14
Q

What is the pathogenesis of active TB?

A

Gradual loss of lung function
Leads to fevers, chills, weight loss (consumption)
Chest fills up with liquid leading to death

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15
Q

What is an overview of TB stages?

A

Infection of apical alveoli, modulate macrophages and disrupt surfactant
Bronchial obstruction stasis
Post obstructive lipid pneumonia
Broncial spread of infection
Rapid development of caseaos pneumonia with symptoms of community acquired pneumonia

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16
Q

What can happen after rapid development of caseaos pneumonia?

A

Softening and fragmentation to cough out pieces of lung or
Caseation becomes dry and firm

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17
Q

What happens after Softening and fragmentation form from TB?

A

Thin walled cavity –> MTB gorw as surface pellicle to be coughed out (holes in lung TB can spread around body)
Thin wall are form granulomas around caseation

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18
Q

What happens after caseation becomes dry and firm from TB?

A

Granulomas form around caseation
Fibrocaseous tuberculosis
Granulomas around caseation can from thin wall

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19
Q

How many people do you think have latent TB?

A

About 30% of the world’s population

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20
Q

How common is TB?

A

1/3 of global population are infected TB
10% will go on to form active TB

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21
Q

How does latent TB survives in cells?

A

Cells stay dormant either inside macrophages or granulomas
Protect DNA
Ensure cell integrity (cell wall plays a role)
Lower metabolic activity and cells likely generate energy via a very low rate of respiration
Dormant cells are resistant to many TB drugs

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22
Q

How can latent TB be confirmed?

A

Person is infected with M-TB but does not have TB
Very big area of research
Can be detected with the Mantoux tuberculin skin test

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23
Q

What is an overview of first TB vaccine?

A

The Bacillus Calmette-Guerin vaccine was first used in 1921
An attenuated Mycobacterium bovis that was subcultured 239 times over 13 years
Shows clear protection in children
May protect against other respiratory illnesses in children
20-80% protective effect against leprosy

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24
Q

What is are problems with Bacillus Calmette-Guerin vaccine?

A

Efficacy in adults is debated
Differences between substrains
Genetic variation in populations
Exposure to environmental mycobacteria
Requires refrigeration

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25
What is an overview of new TB vaccines?
No new vaccine approved Many candidate vaccines in pipeline (phase3): MTBVAC - Biofabri (Attenuated TB) VPM1002 - SIIPL (Recombinant BCG) Phase 2b - MVA85A - Oxford Uni (Viral vector-based TB)
26
What was the first effective drug treatment for TB?
First effective drug developed for TB was streptomycin Isolated from Streptomyces griseus in 1943 Blocks the ribosome First successful treatment in 1946
27
What is an overview of Isoniazid?
Targets mycolic acid biosynthesis, specifically InhA, the enoyl-acyl carrier Must be activated by KatG
28
What is an overview of Pyrazinamide?
Converted by the M-TB enzyme pyrazinamidase to the active form Inhibits coenzyme A biosynthesis
29
What is an overview of Ethambutol?
Targets enzymes involved in arabinogalactan and lipoarabinomannan biosynthesis
30
What is an overview of Rifampicin?
Inhibits RNA ploymerase
31
What is an overview of most TB antibotics?
ALL DRUGS HAVE SERIOUS SIDE EFFECTS Isoniazid and Rifampicin are effective against latent TB Most antibiotics only work against TB not other GP and GN bacteria and vice versa
32
Why do beta-lactams not work on TB?
Diffusion of beta lactam antibiotics (e.g. penicillin) are hundreds of fold slower than the penetration in E. coli and therefore are not effective
33
Why are M-TB resistant to macrolides?
M-TB are naturally resistant to macrolides (e.g. erythromycin) and lincosamides (e.g. lincomycin) A protein called Erm7 limits affinity of these drugs to their targets in the ribosome
34
What other ways are M-TB resistant to antibiotics?
Chemical modification of drugs Enzymatic degradation of drugs, e.g. Beta-lactamases Drug export by efflux pumps
35
What is the typical treatment for TB using antibiotics?
The typical drug treatment is 2 antibiotics (isoniazid and rifampicin) for 6 months with 2 additional antibiotics (pyrazinamide and ethambutol) for the first 2 months of the 6-month treatment period (NHS)
36
What are the problems with the current treatment?
Due to side effects and people feeling better after a few weeks many patients do not take the full 6-month treatment Leads to high levels of drug resistance (detected by PCR)
37
What is an overview of multi and extensively drug resistant TB?
Multidrug resistant TB is resistant to isoniazid and rifampicin Very few treatment options which are less effective, more expensive and have more side effects
38
What is an overview of how TB are drug resistant?
Extensively drug resistant TB (XDR-TB) that is resistant to isoniazid and rifampicin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)
39
What new drugs have been developed to target TB?
Bedaquiline Linezolid Pretomanid Delamanid
40
What is an overview of Bedaquiline?
Targets ATP synthase Cost for a 6 month treatment is US$900, US$3,000 and US$30,000 in low, middle, high income countries respectively Only used for multidrug resistant TB
41
What is an overview of Linezolid?
Targets the ribosome
42
What is an overview of Pretomanid?
Only used in combination with bedaquiline and linezolid Inhibits cell wall synthesis (mycolic acids) Active against latent TB
43
What is an overview of Delamanid?
Targets biosynthesis of certain mycolic acids
44
What are examples of phase 2 an 3 TB antibiotics?
P3 - Sudapyridine P2 - Telacebec, Alpibectir and BTZ-043 Though used to be more indevelopment such as 2 phase 3 lots not effective or moved back in phase
45
What is an overview of the impact leprosy has had on history?
One of the most feared diseases in history Baldwin IV of Jerusalem Jesus healing the 10 lepers (11th century manuscript)
46
What is an overview of Leprosy?
Caused by Mycobacterium leprae Obligate pathogen with a reduced genome (only 1614 genes compared to ~4000 genes in M-TB)
47
What is an overview of the leprosy disease process?
Thought to be spread via aerosol transmission (not through casual contact or sex) Very slow growing bacterium (doubling time of 14 days) Can only be cultured in armadillos and certain mice M. leprae causes demyelination of Schwann cells Exact process of pathogenesis still controversial
48
How does Leprosy demyelinate Schwann cells?
Invades Schwann cells via PGL-1 and α-dystroglycan/ laminin interaction Macrophages are attracted to the invasion site M. leprae then infects these macrophages PGL-1 stimulates nitric oxide production damaging axons This stimulates an immune response Cells die releasing the bacterium which infects new cells
49
What is an overview of leprosy symptoms?
Leads to lesions, paralysis of hands and feet, loss of toes, fingers and noses, blindness
50
What is an overview of leprosy prevalence?
Still about 200,000 cases reported each year (WHO) No vaccine (that is better than BCG) or diagnostic test available (biopsies currently used) Easily treatable with rifampicin, dapsone (targets folate biosynthesis) and clofazimine (binds to guanine in DNA)
51
What is an overview of mycobacterium bovis?
Mycobacterium bovis primarily infects cattle but can infect humans where it causes TB symptoms (about 1-2% of TB) Typically, infection comes from eating or drinking contaminated, unpasteurized dairy products
52
What is an overview of mycobacterium bovis cases?
Estimated 143,000 human cases and 12,300 deaths in 2018 Cost the cattle industry billions (most with TB are culled) Found in some wildlife
53
What is a summary of mycobacterium?
TB has killed about 180 people in the last hour TB cases and deaths are going down year by year The cell wall is key to pathogenesis and drug resistance but also a potential Achilles Heel Leprosy should not exist but the lack of a diagnostic test makes it difficult to identify carriers Mycobacterial diseases are still major agricultural issues
54
What are prions?
Proteinaceous Infective particles Different from all other known infectious agent: lack of nucleic acids
55
What is an overview of prions?
Discovered in 1982 by Stanley Prusiner (Noble prize in 1997) (but John Griffith first proposed the idea of a protein infectious agent) Controversial viral particles vs infectious proteins Violate(?) the “universal” rule of protein synthesis (production) – translated mRNA which itself is transcribed from DNA.
56
Why are prions controverisal?
Dont fullfil one of Koch's postulates 'That pathogen must be isolated and grown in pure culture'
57
What do prions compose of?
Prions are composed of a single protein (usually found in lymphocytes and CNS neurons): functions controversial - receptor for b-amyloid peptide, involved in neuroprotection, stem cell renewal, memory mechanisms
58
How common are prion orignal genes?
All mammals contain gene that codes for amino acids in PrP (possibly all plants and animals, some unicellular yeasts and filamentous fungi)
59
What is the difference between normal and prion protein?
Protein can fold into at least two stable tertiary structures: normal, functional structure, with several a helices but disease-causing form, with b-pleated sheets (same amino acid sequence) Normal PrPC refolds to prion PrPSc when in contact with prion PrPSc Different prion protein conformations and glycosylation patterns exist as well
60
What is the consequence of having beta-pleated sheets rather than alpha helixes?
They form multimeric complex within cytoplasm of cell prodcing fibres
61
What is the difference in PrPC and PrPSc solubility?
PrPC - soluble PrPSc - nonsoluble
62
What is the difference in PrPC and PrPSc structure?
PrPC - predominantly alpha-helical PrPSc - Predominantly beta-sheeted
63
What is the difference in PrPC and PrPSc state?
PrPC - Monomeric PrPSc - Mutimeric (aggregates)
64
What is the difference in PrPC and PrPSc infectivity?
PrPC - Non-infectious PrPSc - Infectious
65
What is the difference in PrPC and PrPSc resistants?
PrPC - Broken down by protease and temperature PrPSc - Resist protease and temperature
66
What is an overview of prion protein conversion?
Unfolded PrPC --(folding)--> PrPSc --(folding)--> Native PrPC Native PrPC --(unfolding)--> Native PrPC
67
What is an overview of PrPSc fibril formation?
PrPSc then stick together, stack up to form fibrils (or fibres)
68
What is the consequence of PrPSc fibrils?
These are toxic to cells and kill off neurons Astrocytes migrate to area of brain and remove dead cells, leaving the holes or vacuoles in the brain
69
What is an overview of prion disease?
Fatal neurological degeneration Depositions of fibrils in the brain Loss of brain matter which results in vacuoles
70
What are examples of prion diseases?
Bovine spongiforme encephalopathy (BSE mad cow disease) Scrapie (sheep) Creutzfeldt-Jakob disease (CJD in humans) vCJD (in humans – a result of eating infected beef)
71
How are prion disease transmitted?
Ingestion of infected tissue, contact with mucous membranes, or skin abrasions of infected tissue
72
What is a key feature of prions disease?
Spongy’ brains Confirmation requires post-mortem histopathology and/or PrPSc detection
73
What is an overview of scrapie?
The oldest known prion disease, was described 1759 (Leopold) and is characterized by the abnormal walk and scratching of infected sheep and goats The scrapie agent was adapted to mice and hamster, which are used as model systems in basic research
74
What is an overview of CJD?
Most common form of human prion diseases Estimated incidence of 1 case / 1 million pop / per year Mean age of onset is ~ 60-65 years Mean illness duration is ~7-8 month Death occurs < 12 months in 85-90 % of cases
75
What is an overview of the symptoms of CJD?
Usual symptoms are rapid dementia, visual abnormalities, cerebellar dysfunctions (lack of coordination, gait, speech abnormalities) and EEG tracing shows characteristic signals
76
What is the cause of CJD?
85 % of all CJD cases are sporadic ~ 10-15 % are caused by mutations (genetic)
77
What are other prion diseases?
Gerstmann-Straussler-Scheinker (GSS) Fatal Familiar Insomnia (FFI) = other genetic prion diseases. Dominant transmission.
78
How can mutations impact prion diseases?
~20 different mutations in prion protein gene are associated with human prion diseases. Cu2+ binding important
79
How can infectious diseases impact prions?
< 1 % of all CJD cases are caused by infection Infection caused by medical treatment: neurosurgery, transplantations (contaminated corneas) or human growth hormone, (blood transfusions?)
80
What is an overview of Bovine spongiform encephalopathy?
Since 1985 prion diseases brought to attention by the BSE epidemic in UK Offal of scrapie infected sheep responsible?
81
Why did bovine spongiform encephalopathy appear suddenly?
1970s the process of meat and bone meal (MBM) production altered and scrapie agent not inactivated anymore Since feed-ban in 1988 the BSE epidemic reached maximum in 1992 with more than 37,000 cases (2023 = last known case in UK)
82
What is an overview of CJD varients?
1996 prion diseases attracted public attention again because a new variant of CJD reported in UK vCJD distinguished from CJD by unusual young age at onset (mean: 28 years) and prolonged duration (mean: 14 month) most patients show psychiatric symptoms first; no EEG characteristics all (bar one) cases of vCJD: individuals methionine homozygous at codon 129
83
How does the immune system help spread prions to brain when ingested?
Specialized epithelial cells of the mucosal immune system (M cells) in the Peyer's patch sample luminal contents and pass them to innate immune cells. M cells can transport prions to antigen presenting cells (APCs) waiting in the lamina propria. Where they can go via vascular system, spleen and lymph nodes through the nervous sustem
84
Why do prions fail to activate an immune response?
Prion proteins can be recognised by antibodies but arent taken up and presented by MHCs so no immune response Likewise with T cells So immune system isnt aware
85
What is an overview of therapeutic treatment in prions?
No cure for prion diseases No treatment has been found to be completely effective once symptoms appear
86
What are potential treatments for prions?
Quinacrine has shown promise in slowing the progression of disease in patients with vCJD (inhibits formation of PrPSc) Pentosan polysulphate (PPS) appears to prevent conversion to PrPSc and the PrPSc forming clumps
87
What are approaches to prevent prions?
Prion gene knockdown (though it was a normal function so problem their) Antibodies to prevent prion conversion Antibodies prevent prion aggregation Compounds to interfere with neurotoxicity Stabilisie prion fibrils Antibodies or compounds to clear protein
88
What is the similar with neurodegenerative diseases and prions?
Role for prions in neurodegenerative conditions Maybe overlap but maybe seperate so not confident in extraperlating

3s2: Infection and Immunity (12 decks)

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