Lent Flashcards
(233 cards)
1
Q
What is a parasite?
A
An organism that lives and feeds on or in an organism of a different species and causes harm to its host
2
Q
What are parasitic diseases caused by?
A
Eukaryotic protozoans and helminths
3
Q
Give an example of a single-celled protozoa.
A
Plasmodium, Leishmania.
4
Q
What are metazoa?
A
Multicellular parasites, e.g., nematodes, cestodes.
5
Q
How is the diversity of parasites evidenced?
A
Evidenced by coprolites (fossilized faecal matter) and co-evolution with the host.
6
Q
What are the two types of life cycles in parasites, and what is the main difference between them?
A
Direct life cycle (requires only one host) Indirect life cycle (requires two or more hosts).
7
Q
Define definitive host.
A
The host in which the parasite reaches sexual maturity or undergoes sexual reproduction, e.g. mammals for Hookworms.
8
Q
What is an intermediate host?
A
Hosts required for development, where the parasite may undergo asexual reproduction but not sexual, e.g. mosquito Plasmodium
9
Q
How do protozoans evade the immune system?
A
Through antigenic variation (recombination of var genes coding for hypervariable surface proteins e.g. PfEMP1, instead of due to polymerase error causing mutation)
Hiding inside host cells (e.g., Plasmodium hiding in erythrocytes that don’t express MHC Class I)
10
Q
What is the immune evasion strategy of Trypanosomes?
A
They change their Variant Surface Glycoprotein (VSG).
11
Q
How do helminths modulate the immune system?
A
They dampen TH1 and TH2 pro-inflammatory responses, secrete anti-inflammatory proteins, and have systemic effects on the adaptive and innate immune systems.
12
Q
What are the secondary effects of worm secretions?
A
Suppression of tumor-suppressing genes, reduced immunity and response to vaccines, and reduced immunity to other infections.
13
Q
What are the positives of helminth infections?
A
They help in anti-inflammatory responses to allergies and other diseases.
14
Q
What is immunopathology?
A
It is the response to a pathogen causing damage to the host tissue, rather than the actual effect of the pathogen.
15
Q
What is crucial for preventing immunopathology?
A
A balanced response between anti-inflammatory and pro-inflammatory, with timing and size of the response being important.
16
Q
How many deaths does malaria cause annually, and what is its global impact?
A
627,000 deaths annually, with 500 million people experiencing a mild illness
17
Q
How do protozoans exhibit different forms of movement?
A
Amoeboid movement- Protozoans use cytoplasmic protrusions
Ciliary motion- Protozoans use hair-like projections
Flagellar movement- use a flagellum for navigation.
Gliding motility- through interactions between host and parasite, utilizing actin-myosin
18
Q
How does Toxoplasma achieve success, and what is its unique feature?
A
Toxoplasma’s success is attributed to oocyst resistance against the environment and the ability to change morphology under stress.
19
Q
Describe the replication process of Toxoplasma.
A
Toxoplasma undergoes sexual reproduction in the cat (definitive host)
1. Releases oocysts in faeces
2. Infects rats and develops into tachyzoites
3. Develop into bradyzoites for latent/chronic infection.
20
Q
What is the transmission method and pathology associated with Toxoplasma?
A
Transmission occurs through cat feces (oocysts) and eating undercooked meat (bradyzoite cysts).
Immunocompromised individuals can experience neurological issues.
21
Q
Outline the phases of Plasmodium’s life cycle
A
Plasmodium undergoes mosquito, liver, and blood phases in its life cycle.
22
Q
What is the detection method for Plasmodium species, and what is unique about its replication?
A
The rate of turnover in Plasmodium species differs, causing fever paroxysms. Parasite replicates in mosquitoes, liver cells, and red blood cells.
23
Q
What are the pathological effects of Plasmodium infection?
A
Plasmodium infection can lead to anemia (because they fed on RBC), respiratory distress, renal failure, and death.
24
Q
How does Plasmodium evade the immune system?
A
Plasmodium infects erythrocytes that don’t express MHC I and exports proteins to the surface to form knob-like structures in P.falciparum= Erythrocyte Membrane Protein 1 (PfEMP1)
Cause rosette formation, binding of RBC and potential blockage
25
What is the natural resistance to Plasmodium, and give an example?
Sickle cell anemia provides resistance to Plasmodium due to the modified shape of red blood cells.
26
How does Leishmania move, and what are the different life cycle stages?
Leishmania moves by flagellar mobility, and it has promastigote (flagellated) and amastigote (non-motile) stages.
27
Describe the life cycle of Leishmania and its survival strategies.
Leishmania has an indirect life cycle, replicating asexually between hosts and sandflies.
Its survival involves lipophosphoglycan (LPG) on the surface and transmission through various species of sandflies.
28
What are the different types of pathologies associated with Leishmania?
Cutaneous- located lesions
Diffuse cutaneous- Expanded lesions
Mucocutaneous- erosion of soft tissue
Visceral types- infect internal organs
Manifestations range from localized lesions to fatal infections.
29
What are the two main categories of multicellular organisms causing chronic infections?
Roundworms (Nematodes)
Flatworms= Cestodes (tapeworms) and Trematodes (flukes).
30
Describe the characteristics of Nematodes and examples.
Nematodes are non-segmented, have resilient eggs, and typically use a direct life cycle, relying on a single host.
Hookworm, Whipworm, Ascaris, Pinworm
31
What is the life cycle of the Hookworm (Ancylostoma), Whipworm and Ascaris?
Larvae penetrate the skin, migrate to the lungs, are coughed up and swallowed to access the gastrointestinal tract.
Hookworm= They use teeth to latch onto the intestinal wall and release eggs through the fecal route.
Whipworm= burrow tail in the large intestinal wall
Ascaris= don't attach to intestine but remain in gut
32
What is the pathology associated with Hookworm infections?
Hookworms secrete anticoagulants to feed on RBCs, causing anemia and malnutrition.
Symptoms may include a distended belly.
33
What is the pathology associated with Whipworm infections?
Feed on cellular secretion (not blood), and can cause anemia, due to effect of inflammation, tissue damage and toxic secretion (however don't directly feed on blood)
Symptoms like diarrhea and rectal swelling.
34
What is the pathology associated with Ascaris infections?
Heavy worm burden leads to allergic reactions to waste secretion, malnutrition due to anti-trypsin secretion.
35
Describe the life cycle of Pinworm (Enterobius vermicularis).
Pinworms spread through the fecal-oral route and are easily spread between children. Eggs become infectious quickly after secretion.
36
What are the characteristics of Tapeworms (Cestodes)?
They have a segmented structure, flatworm
Tapeworms are more complex life cycle, requiring two hosts (human as the definitive host, and pig/cow as the intermediate host).
37
Outline the life cycle of Tapeworms (Taenia).
Ingestion by pig/cow leads to cyst formation, ingestion of undercooked meat leads to the ingestion of cysts, larvae are released and develop into adult worms in the intestine.
38
What is Cysticercosis, and how is it caused by Tapeworms?
Cysticercosis is caused by the ingestion of eggs/proglottids, making humans intermediate hosts (instead of definitive), leading to cyst formation in the CNS.
39
Describe the life cycle of Trematodes (Schistosoma cercariae).
1. Trematodes hatch in water
2. Develop into Miracidia
3. Infect a snail (intermediate host)
4. Hatch as Cercariae
5. Infect humans (definitive host) by burrowing through the skin
6. Lose the tail to become Schistosomulae
7. Develop into adults in the liver/bladder.
40
What is the pathology associated with Schistosomiasis?
Schistosomiasis can lead to bladder or liver fibrosis, calcification, cancer, and morbidity due to egg deposition, initiating a Th2 response.
41
What is the size comparison among different helminths?
Schistosome eggs are much larger than the nematode eggs (hookworm, tapeworm etc.)
42
What is eradication in the context of disease control?
Eradication refers to the permanent elimination of a pathogen and the associated disease, where intervention measures are no longer necessary
43
Define elimination in the context of disease control.
Elimination involves reducing the incidence of a disease to zero within a defined geographical area. Unlike eradication, intervention measures may still be required to maintain this reduced incidence and prevent the re-emergence of the disease.
44
What is the concept of control in disease management?
Control refers to the active efforts to reduce the incidence and morbidity of a disease. Unlike elimination and eradication, control measures need to be continuously implemented
45
Outline some challenges in disease control efforts
-Development of resistance by parasites
-Diverse morphologies
- Immune evasion
- Limited resources and funding
- Existence of potential reservoirs
- Availability of diagnostic tools to monitor changes in disease prevalence
46
What are the challenges associated with creating vaccines for parasitic diseases?
- Ability of parasites to manipulate and evade host defenses
- Presence of multiple developmental stages
- Occupation of different niches in various life cycle stages
- Various permissive geographical locations
- Inability to grow certain parasites in a lab.
47
Provide examples of successfully eliminated parasitic diseases and the strategies employed.
Schistosoma japonicum: The elimination program began in the 1940s and successfully eradicated the disease in Japan in 1996. Strategies included cementing irrigation systems and using drugs to reduce snail populations.
48
What vaccines are there for malaria?
RTS,S
- targets pre-erythrocytic phase and prevents infection of hepatocytes.
- Action by presenting P.falciparum RTS protein, as a VLP vaccine (lipids and saponin)
- efficacy below 50%, and protection diminishes significantly over time.
R21
- similar efficacy
- uses saponin based adjuvant
- efficacy of around 75% Nikita et al., 2023
49
What are some challenges associated with drug development for parasitic diseases?
- Different morphologies within the parasite's life cycle
- Lack of effective drugs
- Development of drug resistance
- Co-infections complicating treatment
- Inadequate dissemination of drugs to those who need them.
50
Provide an example of vector control against parasitic diseases.
DDT (insecticide) against mosquitoes. In the 1950s, its targeted use in North America and Europe.
In Africa- Pyrethroid bednets, containing insecticides, also serve as a form of vector control
51
What are the key characteristics of apicomplexans?
Apicoplast- vestigial plasmid
Apical complex
Secretion of enzymes and form parasitophorus vesicle (protect from acidification and destruction)
E.g. plasmodium, toxoplasma
52
What is the general pathology associated with filarial worm infections?
Filarial worm death induces inflammation, often characterized by an overreaction, typically involving a Th2 immune response.
This immunopathology is irreversible and chronic.
53
Name the three types of filarial worm infections based on their classification.
Lymphatic filariasis: Infects the lymphatics.
Subcutaneous filariasis: Infection of subcutaneous tissue.
Serous Cavity filariasis: Infects the serous cavity of the abdomen, e.g., Dog heartworm.
54
What is the life cycle of filarial worms, and what morphologies do they exist as in humans?
Filarial worms have an indirect life cycle, requiring two hosts: a human and an insect.
They exist as adults and microfilariae in humans.
Unlike many parasites, filarial worms do not lay eggs; instead, they shed microfilariae.
55
Explain the immunomodulation strategies employed by filarial worms.
1. Inhibiting cell proliferation
2. Secreting peptides signaling immune cell apoptosis
3. Block translocation of MHC and antigen presenting molecules to the surface
4. Block antibody formation, modulating response of B cells and T cells
5. Phosphorylcholine-Modulate expansion of immune cells, block B cells but allow Treg cells
6. Modulate through chemokines and cytokines
56
Provide information on Wuchereria bancrofti, including transmission, prevalence, and development duration.
W. bancrofti causes lymphatic filariasis
Transmitted through mosquitoes. Approximately 863 million people are at risk, with 120 million infected.
The mosquitoes that transmit W. bancrofti exhibit diurnal behavior, moving to peripheral areas at night when mosquito bites are more likely.
The development from infection to an adult can take up to a year.
57
What is the pathology associated with W. bancrofti infection, and what are the treatment options?
Dead W. bancrofti worms release antigens, causing an inflammatory response.
This infection leads to lymphedema, with pulmonary eosinophilia in the lungs and elephantiasis in the legs.
Treatment involves using DEC, which kills microfilariae but not adults, blocking the transmission of the helminth.
58
Describe the pathology and treatment options for Onchocerca volvulus
O. volvulus causes subcutaneous filariasis.
The pathology includes river blindness, leading to inflammation and corneal hardening.
Dermatitis with skin thickening is also observed.
Treatment involves Ivermectin, which decreases microfilarial load but not adults, requiring repeated administration.
59
What are the characteristics of Loa loa, and what pathology and treatment options are associated with it?
Loa loa causes subcutaneous filariasis, transmitted by deerflies.
It migrates to the bloodstream with diurnal periodicity.
Pathology includes Calabar swelling due to IL-5 release.
Endemic individuals show tolerance, while visitors may experience greater pathology. (Clinical immunity)
DEC is used for treatment but may lead to encephalopathy if not administered repeatedly.
60
What are the challenges associated with treatment options for filarial worm infections?
Co-infections can complicate treatment. For example, DEC used against Onchocerca volvulus may lead to the Mazzotti reaction. Ivermectin against Loa loa can cause allergic encephalopathy.
61
What is the role of Wolbachia in filarial worms, and how is it targeted for treatment?
Wolbachia is a bacterial endosymbiont with a mutualistic relationship with filarial worms (except L. loa).
It is essential for worm fertility and viability.
Doxycycline (DOX) kills Wolbachia and is effective against O. volvulus and W. bancrofti.
However, DOX has challenges, requiring long treatment and repeated doses, and cannot be safely used in pregnant women and children.
62
What immune responses are triggered when Wolbachia is released during worm death, and what complications can arise?
When Wolbachia is released during worm death, it can cause an immune response. In the eyes, it may result in corneal haze, while in the skin, it can lead to dermatitis.
63
What is the action of Ivermectin on parasites?
1. Binds to glutamate-activated chloride channels
2. Causes hyperpolarization, by increasing permeability of chloride ion
3. Paralyses the parasite to death
64
Who developed the pasteurization technique and what did it involve?
Louis Pasteur
Using a swan neck shaped flask to avoid air coming in and bacteria developing
Involves heating a liquid to a specific temperature to kill or inactivate potential pathogens, followed by rapid cooling, making the medium sterile.
65
What are Koch's postulates, and what is their purpose in bacteriology?
Developed by Robert Koch to establish the association between a specific bacterium and a particular disease
Requirements
1. The bacterium must be present in every case of the disease.
2. The bacterium must be isolated and grown in pure culture.
3. The cultured bacterium should cause the disease when introduced into a healthy host.
4. The bacterium must be recovered from the newly infected individual.
The purpose is to prove the causative relationship between a bacterium and a disease.
66
What are some uses of bacteria in scientific research and technology?
- Fundamental Genetics: Bacteria are used to study gene regulation, operons, transcription, and translation.
- Insights into Host Biology: Bacterial studies provide insights into intracellular trafficking, innate immunity, and signal transduction.
- Genetic Manipulation: Bacteria are essential for studying genetic manipulation, involving restriction enzymes, plasmids, and polymerases (e.g., Taq for PCR).
- Genetic Editing: The CRISPR/Cas9 system, used for genetic editing, has been derived from bacterial systems.
67
What are the three types of disease outbreaks, and how do they differ?
- Point Source Outbreaks: These arise from a single origin and can include instances like Legionnaire's Disease originating from contaminated water in AC systems or food poisoning.
- Continuous Source Outbreaks: These occur when the source is not eradicated, allowing the disease to spread continuously. Examples include carriers of diseases like typhoid.
- Propagated Outbreaks: These involve host-to-host transmission and various modes of transmission. Examples include whooping cough, tuberculosis, gonorrhea, cholera
68
What are the characteristics of an endemic, epidemic, and pandemic disease?
- Endemic: Occurs regularly at a low or moderate frequency in a specific population or geographic area (e.g., Streptococcus mutans causing tooth cavities).
- Epidemic: Sudden appearance or increase in disease cases above the endemic level, typically affecting a specific region (e.g., pre-WWII Diptheria epidemic in Europe).
- Pandemic: A global epidemic affecting a large population across multiple countries or continents (e.g., cholera).
69
Describe the size range of bacterial cells.
Bacterial cells typically have a size ranging from 0.5 to 3 micrometers.
This small size allows them to remain unicellular and undergo binary fission for replication.
70
What is the role of MreB in bacterial cells, and how does it contribute to their structure? What other factors regulate the bacterial cytoskeleton?
MreB is an actin homologue in bacterial cells. It plays a crucial role in maintaining the rod-like structure of bacteria. MreB filaments align along the cell's long axis, directing the synthesis of peptidoglycan and influencing cell shape.
FtsZ a tubulin homologue - for division
Crescentin an intermediate filament homologue, for curved structure
71
Why do bacteria produce endospores, and what conditions do endospores help them survive?
In response to harsh environmental conditions.
Endospores can withstand desiccation, radiation, heat, starvation, and exposure to disinfectants, allowing bacteria to endure unfavorable circumstances.
72
What is the primary component of bacterial cell walls, and how is it structured?
Bacterial cell walls is peptidoglycan. It is a mesh-like structure formed from alternating sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), vertically and horizontally cross-linked by oligopeptides.
73
Explain the Gram staining technique and its significance in bacterial classification.
Differentiates bacteria into Gram-positive and Gram-negative based on cell wall characteristics.
Gram-positive bacteria have a thick peptidoglycan wall, retaining the crystal violet stain, while Gram-negative bacteria, contain an outer membrane and don't retain the crystal violet. Only retains the counter stain safronin
74
What is the role of the periplasm in gram negative bacteria?
-Space for reactions
-Compartmentalization of Enzymes:
- Detoxification, improve antibiotic resistance
75
Describe the structure of LPS found on the outer membrane of gram-ve bacteria?
Lipopolysaccharides
Composed of 3 sections
LipidA- attaches to membrane, is recognised by TLR4
Core polysaccharide- constant region
O-antigen- variable, aiding with evasion from the immune system
76
Elaborate on the role of bacterial capsules and how they are detected.
Bacterial capsules serve to prevent desiccation and protect against host defenses.
They are detected through (acid) staining, where the background is stained with an acidic stain, and the cell is stained with a basic stain, resulting in a visible halo around the cell due to lack of capsule staining.
77
How do bacteria achieve motility, and what role do flagella play in this process?
Rotation of flagella.
Require an electrochemical (pH) gradient and proton gradient
Tumble (clockwise rotation)
Swimming (anti-clockwise rotation)
78
How do bacteria secrete proteins?
Various secretion systems
Sec- unfolded and Tat- folded
BAM- Integration of protein into membrane
Type III and IV- used needle like for direct secretion into host
Flagellin structure from inner membrane is detected by TLR5 formation is from sequential addition of units
79
Explain the process of chemotaxis in bacterial cells.
1. Sense chemical signals and move towards them. Bacteria detect gradients of chemicals
2. Transducing the signal via phosphorelay systems
3. Directed movement toward more favorable conditions.
80
Describe the phases in bacterial growth
Lag- adaptation to media
Log- rapid binary fission
Stationary- exhaustion of nutrients
Death- secretion or build up of toxic waste
81
What is quorum sensing, and how does it influence bacterial behavior?
Quorum sensing is a communication system in bacteria where they alter their behavior in response to changes in population density.
As bacterial populations increase, they release signaling molecules, coordinating activities like biofilm formation and other collective behaviors.
e.g. Production of AHL by LuxI, reach threshold binds to LuxR to activate LuxAB and LuxI
82
How are bacteria able to adapt rapidly?
Transcription and translation compound are linked
Signalling changes by Histadine-aspartate phosphorelay (HAP) pathway
83
What genetic changes can incur in bacteria?
Horizontal transfer
- Conjugation - plasmid and pili
- Transformation- take up from env
- Transduction - transfer by phage
- Transposition- movement of transponse elements from acquired plasmids etc.
84
What is Polycistronic?
Many proteins encoded within the gene
85
What are the key events in bacterial pathogenesis?
1.Colonization:
- Adhesion is crucial, and if bacteria remain extracellular, multiplication occurs.
2. Invasion:
- Bacteria are either uptaken or forcefully enter the host for replication.
3. Replication
4. Damage:
- Can be direct (caused by bacteria, e.g., toxin secretion) or indirect (caused by the host response to infection).
5. Transmission
86
What are virulence genes, and how are they commonly spread?
Genes that contribute to the ability of a microorganism to cause disease in a host e.g. toxins, adhesins and invasion proteins
Virulence genes are not always expressed and are horizontally spread between bacteria.
They are often carried on extrachromosomal plasmids and bacteriophages.
87
What are pathogenicity islands, and how do they evolve (3)?
Pathogenicity islands are groups of pathogenic genes (e.g., adhesins, invasion proteins, toxins) that evolved through the integration of transposons, bacteriophages, and horizontal plasmid transfer.
They have a G+C content that differs from the rest of the genome.
88
What is swarming motility, and how is it characterized?
Swarming motility is a community movement of bacteria effective in colonizing surfaces, often with a radial outwards trajectory.
89
Where are cell surface adhesins commonly found, and what is an example?
Found on the end of pili and are used for attachment to glycoproteins on the surface of host cells. An example is the P-pilus adhesin in uropathogenic E.coli (UPEC), which binds to kidney receptors.
90
Describe the process of pili formation.
1. Chaperone proteins bind to adhesin and transport it to the Usher protein.
2. Pilus subunits are transported to the Usher protein, where they polymerize to form a structure.
3. Aggregation occurs when the pilus is long enough.
91
What are the steps involved in recurrent infections?
1. Lumenal replication
2. Invasion of bacteria into the epithelium
3. Intracellular replication
4. Exfoliation and lysis of the cell (action of inflammasome)
5. Tissue repair (burying some pathogens in the layer below)
6. Resurgence (when immunocompromised, infection recurs)
92
Explain the process of pedestal formation in bacterial pathogenesis. And where this is located
Located in the intestines
By enteropathogenic E.coli (EPEC) and enterohaemorrhagic E.coli (EHEC) through the Type III secretion of Translocated Intimin Receptor (Tir).
1. Secrete the effector that acts as a receptor
2. Bind by intimin on the bacteria surface
3. Binding causes actin polymerisation
93
What is a biofilm, and why is it difficult to eradicate?
A biofilm is a community of bacteria encased in a self-produced extracellular matrix.
- e.g. alginate polysaccharide from P.aeruginosa
It is difficult to eradicate due to the protective nature of the matrix and communication through quorum sensing.
94
How does bacterial invasion of the host occur through the zipper mechanism?
1. Invasins on the bacterial surface mimic a eukaryotic ligand.
2. Invasins bind to adhesin molecules on the host membrane.
3. Multiple points of contact are formed, changing the cytoskeleton.
4. Internalization of the bacteria occurs.
e.g. Listeria and UPEC
95
How does bacterial invasion occur by the trigger mechanism?
1. Secretion of effector proteins into the host by Type III secretion system
2. Effectors (e.g. SipA and SipC) act as actin binding proteins
3. Cause rearrangment of actin- leading to ruffled surface
4. Encapsulates bacteria leading to invasion
e.g. Salmonella
96
Describe the life cycle of Listeria
1. Lyse membrane - secretion of listeriolysin O and phospholipase 1
2. Intracellular movement- actin comet (1µm/s) caused by the presence of ActA on the surface, to avoid immune system
3. Spread- form protrusion between cells, which is pinched off by phospholipase 2
97
Describe the lifestyle of salmonella in a cell
Secrete effectors using T3SS, causing membrane ruffling
- Effectors prevent fusion with lysosymes and down-regulate antigen presentation
- Their capsule (e.g. Vi in S.typhi) can prevent ubiquitination
S.typhi can also survive within macrophages and avoid degradation
98
Describe the life style of Chlamydia
Obligate intracellular bacteria
- Can cause trachoma (infectious blindness, due to inversion of eye lids damaging the corneal surface)
Also cause STD
1. Forms elementary body (EB), highly infectious
2. Secretes Tarp, facilitating its uptake (cytoskeletal rearrangement)
3. Differentiates into reticulate bodies (RB), less infectious but metabolically active
4. Forms an inclusion that then transform to EB and lyse = spread
99
How do bacteria survive hostile host environments such as low Iron and acidic pH?
Low iron- secrete siderophores that increase uptake of iron as they bind with great affinity e.g. equibactin in S.equi
Acidic pH- present H transporters on their membrane pumping out H+, or secrete urease to increase pH. Shigella and H.pylori
100
How do bacteria survive macrophage action?
1. Paralyse and prevent macrophage action
- Yersinia injects YopT (affects GTPase and alters cytoskeleton) and YopP triggering apoptosis
2. Inhibition of chemotaxis
- inhibiting C5a signalling
3. Resisting phagocytosis
- Capsulated bacteria acts as a physical block
4. Secretion of cytolysins
- pore forming enzymes that breakdown cell e.g. Streptolysin O from S.pyogenes
101
How do bacteria resist complement action?
Presentation of LPS- O antigen, creates a barrier that prevents complement from reaching the surface of the bacteria and binding
102
How do bacteria evade antibodies?
1. Mimic the host, present sialic acid on the surface e.g. Neisseria gonorrhoea
2. Switch expression of antigens
- Create genetic variation on surface antigens, e.g. switch from flagellin 1 to flagellin 2
3. Genetic recombination
- Express different proteins on the surface
4. Inactivate the antibody
- Cleave secretory IgA, separating Fab and Fc region e.g. N.gonorrhoea and S. pneumoniae
103
What are the key effectors and pathology associated with Streptococcus pyogenes
- Streptolysin O - pore forming
- Hyaluronidase- breaks down tissue
- Pyogenic toxins - cause Toxic shock
- Surface M proteins - binds to complement factor H
=> type III hypersensitive response due to accumulation of
104
What are endotoxins, exotoxins and toxoids?
Endotoxins- Toxins in pathogen, that aren't secreted
Exotoxins - toxins that are secreted
Toxoid- inert toxin, commonly used to generate vaccines
105
What are two key groups of exotoxins that cause damage to the cell?
1. Cytolysins - disrupt cell structure
2. Intracellular toxins- disturb metabolism and intracellular mechanisms
106
Describe the role of cytolysins
Enzymatic degradation- damage membrane but don't perforate e.g. phospholipases and this can result in the release of DAMPs and immune response
Pore forming toxins- disrupt the osmotic potential across the membrane, commonly resulting in lysis e.g. Streptolysin O (S.pyogenes) and Haemolysin (E.coli)
107
What are the two different structure AB toxins can take shape?
Single polypeptide- long chain that has been cleaved, then rejoined together using S-S bonds e.g. tetanus and diphtheria
Multimeric- multiple B componenets surrounding an A component e.g. anthrax and cholera
108
What are some actions of AB toxins?
1. ADP-ribosylating- add ribose (CTX)
2. Adenylate cyclase - produce cAMP (Anthrax)
3. Genotoxins- cleave DNA
4. Neurotoxins- target nerve and signal transduction (TeNT, BoNT)
109
Describe the action of the cholera toxin
1. AB5 structure binds to GM1 receptor
2. CTX is internalised and retrograde transported to the ER
3. Disassembled into A and B components
4. A is secreted out and binds to Gs which activates an adenylate cyclase increasing cAMP
5. cAMP increases Cl- movement out of CFTR and inhibits uptake of Na+
6. Water moves out, seen as water diarrhoea
110
Describe the action of the diphtheria toxin
1. B attaches to the heparin- binding epidermal growth factor (HB- EGF)
2. Furin in endosome nicks polypeptide and exposes structure
3. Endosome acidifies
4. S-S is reduced and A is translocated out into cytoplasm
ADP-ribosylating toxin adds ADP-ribose to Elongation factor 2 (EF2), which is a transcription factor and INHIBITS it
- found in corynebacterium diphtheriae
111
Describe the action of Botulinum neurotoxin and Tetanus neurotoxin
Tetanus causes spastic paralysis, targets SNARE proteins in inhibitory nervous system. Requires retrograde transport
Botulinum causes flaccid paralysis, also targets SNARE, but on peripheral nerves
112
What are superantigens?
Effectors secreted by bacteria that attach to TCR and MHC, causing a cytokine storm and indirect damage
- Causes activation even when antigen is not present
e.g. causes toxic shock syndrome
113
What are examples of acute inflammation causing immunopathology (bacteriology)?
Triggered by lipid A in LPS, which is detected by TLR4
- Causes cytokine storm and inflammatory damage
- Causes meningitis e.g. by Neisseria meningitidis
114
What are examples of bacteria that can cause chronic inflammation? (4)
1. Chlamydia- can cause low level chronic inflammation that can result in infertility
2. H.pylori- causes formation of gastric ulcers and is linked to gastric cancer
3. M. tuberculosis- forms a granuloma, and resurgence can occur when immunocompromised
4. Lyme disease- caused by ticks, triggering a type III hypersensitive response due to build up of antigen-antibody complexes, can cause arthritis and meningitis
115
Describe the formation of platelets.
Platelets are formed through cytoplasmic fragmentation of megakaryocytes, resulting in anuclear discs that have a lifespan of around 7 days.
116
What is the role of von Willebrand factor (vWF) in platelet adhesion?
Mediates platelet adhesion by forming a bridge between exposed collagen and glycoprotein IB on platelets.
117
What are the structural and secretory changes that occur during platelet activation?
Structural changes
- Shape change
- Conformational changes in glycoproteins
Secretory changes
- release of thromboxane A2 (TxA2) and 5HT.
118
Describe the coagulation cascade
1. Release of tissue factor
2. Involves the activation of extrinsic factors
3. Activation of factor X -> Xa
4. Thrombin production and fibrin formation.
119
What are the roles of thrombin in haemostasis? (3)
1. Thrombin acts as a protease
- Cleaves fibrinogen to fibrin
2. Activates factor XIII
3. Activates coagulation factors XI, V, and VIII. = Positive feedback loop
120
What are the dual roles of endothelial cells in haemostasis?
In normal healthy vessels (anti-coagulation)
1. Tissue Factor Pathway Inhibitor (TFPI)
2. Thrombomodulin - binds thrombin prevent coagulation
3. Antithrombin and Heparin like molecules
4. Produces NO and prostacyclin, inhibiting platelet aggregation and vasodilation
5. Produce tissue plasminogen activator (tPA) activating fibrinolysis
In damaged vessels (pro-coagulation)
1. Releases vWF, collagen and Tissue factor
2. Promote pro- haemostatic molecules
121
Describe anti-haemostatic compounds and pro-haemostatic compunds
Anti - promote the activation of plasmin, which breaks down clots
- Plasmin (fibrinolytic protease)
- tPa, uPA and Streptokinase
Pro - prevents formation of anti (that'll form plasmin)
- Plasminogen activator inhibitor 1 (PAI-1)
122
What is a thrombus?
Mass formed from blood constituents, composed of fibrin, platelets, WBC and RBC
123
What are the predisposing factors (Virchow's triad)?
1. Changes to vessel wall
- Ischaemia
- Infection
- Physical and chemical damage
2. Changes to blood flow
- Disruption to laminar flow
- Arteries - narrowing of vessels can occur
- Veins - stasis of blood and formation of clots
3. Changes to the constituents of blood
- Increase in LDL etc.
124
How do the appearance of thrombi in veins and arteries compare?
Arteries
- Compact mass
- Contain laminations (lines of Zahn)
-- Contain darker and lighter layers
Veins
- Pale headed with a long tail towards the arteries
- Little to no laminations
125
What are the various fates of thrombi? (6)
1. Lysis
2. Propagation
3. Stenosis or occlusion
4. Organisation
- Recanalisation, where new channels form
- Repair due to secretion of collagen
- Inflammation
5. Infection
6. Embolism
- Spread
126
What is an embolus and embolisation?
Embolus- Intravascular mass that is carried around to a distant site, can be liquid, gas or solid
Embolisation causes
- occlusion or stenosis of vessels
- Ischaemia/ infarction
Location
- RSH -> moves into pulmonary vasculature
- LSH -> moves into the systemic circulation
NOTE: it's possible that a clot moves through the septum by moving through an unsealed foramen ovale
127
What is a blood clot and how is formed?
Collection of blood constituents
Formed by stenosis of blood
128
What are the three main layers of an artery?
Tunica intima - Endothelial cell lining, helps regulate blood pressure
Tunica media - Muscular or elastic depending on ratio
Tunica adventitia - Connective tissue with lyphatic and vaso vasorum
129
What are some acquired risk factors for atherosclerosis?
Dyslipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus.
130
What are some constitutive (non-modifiable) risk factors for atherosclerosis?
Genetics (polygenic or single gene disorders)
Aging
Male gender
131
What are low-density lipoproteins (LDL) and high-density lipoproteins (HDL), and what are their functions?
1. LDL delivers cholesterol to peripheral tissues
2. While HDL transports cholesterol to the liver for excretion in bile.
3. LDL is often referred to as "bad" cholesterol, while HDL is considered "good" cholesterol.
132
What are the two pathways involved in the removal of LDL?
1. Native LDL pathway present in hepatocytes
- Transcription of the receptor is regulated by cholesterol levels
2. Scavenger receptor pathway used by macrophages.
- Forms foam cells, uncontrolled phagocytosis of LDL
133
What are some changes in the vessel wall associated with atherosclerosis?
1. Endothelial cell injury and dysfunction
- Caused by haemodynamic changes
2. Monocyte migration into plaques
- Recruited by chemotactic factors
- Phagocytosis
3. Smooth muscle cell activation
- induced by PDGF and FGF
4. Lipoprotein infiltration
- act as chemoattractants
- stimulate release of cytokines
5. T-lymphocyte migration
- Activate immune response
6. Platelet adhesion
- early and advanced lesions, forming plaques
134
What are the different types of atherosclerotic plaques, and what are their structures?
1. Fatty streaks
2. Fibro-fatty atherosclerotic plaques
- Fibro-fatty atherosclerotic plaques consist of a fibrous cap, lipid core, and shoulder region
3. Complicated plaques
- complicated plaques can become calcified and lead to thrombosis, embolisation, or aneurysms.
135
What is atherogenesis and its causes?
Pathogenesis associated with atheromas
Caused by:
- Chronic inflammation
-- Rupture of plaques and endothelial dysfunction
- Tissue destruction
- Presence of monocytes
- Collagen deposition
136
What is ischaemia, and what is infarction?
Ischaemia refers to inadequate blood supply
Infarction is necrosis due to ischaemia.
137
What are some causes of ischaemia?
External or internal narrowing or occlusion of vessel
Vessel spasms
Capillary blockage
Shock.
138
What are the types of shock, and what are their causes?
- Cardiogenic (failure of the heart),
- Hypovolaemic (loss of blood volume),
- Septic (caused by pathogens)
- Anaphylactic (Type 1 hypersensitive response).
139
What are the cellular consequences of ischaemia?
Hypoxia,
Poor nutrient supply
Failure to remove waste products
Damage to mitochondria and membranes
Cytoskeleton, DNA, and protein damage
140
What are the reversible and irreversible damages caused by ischaemia?
Reversible damage includes cell swelling and plasma membrane blebs
Irreversible damage includes denaturation of proteins, digestion due to lysosomal rupture, and changes in the nucleus such as karyolysis, karyorrhexis, and pyknosis.
141
What is coagulative necrosis, and what are its characteristics?
Form of necrosis where the tissue retains its structure due to degradation but not digestion.
It appears as a pale area in solid organs and involves the formation of wedge or cone-shaped infarcts.
142
What factors affect the outcome or effect of ischaemia?
1. Susceptibility of cells and organs
2. Size and degree of blockage, the tissue's demand
3. Speed of onset
4. Persistence of blockage.
143
What is ischaemic reperfusion injury?
Occurs when blood supply is restored to cells, leading to irreversible damage due to the generation of reactive oxygen species (ROS) and inflammation caused by the delivery of cells such as neutrophils.
144
What are the microscopic and macroscopic appearances of infarcts?
Microscopically, infarcts show coagulative necrosis, acute inflammation, and eventual scar tissue formation.
Macroscopically, infarcts can appear as pale or red, depending on the organ affected, and may develop into septic or cystic infarcts.
145
What distinguishes pale infarcts from red infarcts?
Pale infarcts are characterized by a white or pale centre due to a lack of blood flow, often with a red rim from haemorrhage.
Red infarcts, on the other hand, have haemorrhage in the centre and may occur in hollow organs.
146
What is anaemia, and what is its primary consequence?
Anaemia is a reduction in the total circulating RBC mass, leading to a decrease in oxygen-carrying capacity.
Its primary consequence is hypoxic damage.
147
What are the stages of erythropoiesis?
Erythropoiesis involves hematopoietic stem cells, erythroid progenitors, erythroblasts, reticulocytes, and finally, mature erythrocytes, which have a lifespan of about 120 days.
148
What are some consequences of anaemia?
- Pale and thin skin
- Hypoxic damage resulting in symptoms like angina and weakness
2. Compensatory changes
- increased cardiac output
- increased bone marrow activity
- hyperplasia.
149
What are the common causes of anaemia?
Blood loss (hemorrhage)
Impaired generation of RBCs (dyserythropoiesis)
Increased RBC destruction (hemolysis).
150
What are the characteristics and causes of megaloblastic anaemia?
Megaloblastic anaemia is characterized by enlarged RBC precursors due to deficiencies in
-vitamin B12 or folic acid, leading to reduced thymidine synthesis.
151
What are the causes and consequences of iron deficiency anaemia?
Iron deficiency anaemia, the most common form, can result from impaired absorption, increased demand, chronic blood loss, or low dietary intake.
It leads to smaller RBCs and reduced oxygen-carrying capacity.
152
What are the two main types of haemoglobinopathies, and what are their effects?
1. Structural abnormalities in globin chains, such as sickle cell disease
2. Reduced production of globins, such as thalassaemias.
They can cause various effects including haemolysis, tissue hypoxia, and chronic anaemia.
153
What distinguishes extravascular from intravascular haemolysis?
Extravascular haemolysis occurs within macrophages, typically in the spleen
Intravascular haemolysis involves the direct lysis of RBCs in the bloodstream.
154
What are some causes of haemolytic anaemias?
Intrinsic abnormalities like hereditary conditions or enzyme defects
- e.g. spherocytosis, pyruvate kinase
Extrinsic factors
- physical damage
- chemical exposure
- immune reactions
- infections like malaria.
155
What is the response of the body to haemolytic anaemias?
Increases erythropoiesis, leading to higher numbers of circulating reticulocytes and bone marrow expansion.
156
What is the nomenclature for benign, malginant epithelial and malignant mesenchyme tumours?
Benign - 'oma'
Malignant epithelial - 'carcinoma'
Malignant mesenchyme - 'sarcoma'
157
What are the causes of cancer?
Step-wise accumulation of mutations
- Failure of 3D growth control
- Deranged tissue architecture (loss of polarity in cells)
158
What are benign, malignant and metastases tumours?
Benign - haven't invaded past the basement membrane
Malignant - tumuors that have invaded cells
Metastases- secondary tumours forming after metastasis of the primary tumour
159
How are invasive tumours identified?
Tumours that have breached the muscularis mucosae
- No clear epithelium
160
What are the stages of cancer development from a polyp to a tumour?
Polyp - small outgrowth on a stalk
Benign tumour - develop into a larger structure
Malignant - invade the basement membrane
161
How do benign tumours cause death?
- Build up of pressure (e.g. intracranial pressure)
- Pituitary adenomas secrete hormones that disrupt a patient's physiology
- Obstruction of blood flow
- Block secretion of enzymes
- Cachexia (wasting away)
162
What are the incidence rates of cancer in the UK?
300, 000 new cases each year
20% of deaths associated with lung cancer specifically
163
What are the methods of screening for cancer?
1. Cervical screening
- Targets ectocervix where HPV commonly affects, cells are squamous epithelial
2. Colorectal screening
- requires endoscopy
3. Mammogram
- breast screening, however has high false positive rates
164
What are the key environmental and genetic causes of cancer?
Environmental
- Chemical carcinogens
- UV light
- Infectious agents
- Diet
- Asbestos
- Agent orange (dioxins)
Genetic
- Predisposition (BRCA mutations)
- Mutations in cell cycle checkpoints
165
What chemicals in smoke cause cancer?
Benzo[a]pyrene (BAP) binds to ARNT
Causes transcription of CYP1A, generating oxidative stress
Beta naphthylamine
166
How do infectious agents cause cancer?
- Viruses can integrate oncogenes e.g. p53 by E6 and E7 in HPV
- H.pylori is linked to gastric adenocarcinoma
- Herpes virus (HHV8) causes Kaposi's sarcoma in immunosuppressed individuals
- Epstein-Barr virus linked to Burkitt lymphoma
167
How can diet cause cancer?
Indirectly increase the risk of cancer, by exacerbating other health risks
- Aflatoxin B1 produced by fungus Aspergillus flavus found on peanuts that are stored in humid conditions
168
How can asbestos cause cancer?
Causes mesothelioma
1. Penetration of small fibres
2. Chronic inflammation
3. Rapid turnover of cells
4. Increased risk of cancer
Acts as a promoter instead of an initiator
169
What are examples of promoters and initiators of cancer?
Promoters
- Substances that promote the development of cancer, commonly by promoting inflammation
e.g. asbestos
Initiators
- cause the cancer e.g. UV, industrial chemicals, viral infections (HPV)
170
How does the risk of cancer vary with the age of development?
High risk during mammary gland development
- Increase risk if first pregnancy is later in life
171
How does Rous Sarcoma virus cause cancer?
Virus carries proto-oncogenes
e.g. raf, abl, erbB and Ras
- Causes changes in cell morphology
172
How does the morphology of cancer cells change? And what are the hallmarks of cancer (6)
- Change in shape
- Loss of contact inhibition
- High-density growth
- Immortality (telomerase)
- Growth- factor independence
- Resistance to stop signals (Bcl2 anti, Bax reduces)
173
What are the different forms of genetic changes in cancer cells?
- Point mutations
- Translocations
- Deletions/ Insertions
- Amplifications
- Viral gene insertions
174
What are oncogenes? Give some examples
Mutations that result in increase proliferation of cells.
Commonly dominant and only require mutation in one gene
e.g. BRAF (melanoma), EGFR (lung cancer) and KRAS (colorectal cancer)
175
What are tumour suppressor genes?
Loss of gene function that would normally control cell cycle
- Recessive so requires mutations in both e.g. BRCA
176
What is the role of retinoblastoma?
Rb = inhibits the progression of the cell cycle from G1/S, by inhibiting DNA replication
CDK4 and 6 can phosphorylate and inhibit this, this is promoted by Cyclin D
p16 and p21 inhibit the formation of cyclin D
- So mutations are commonly in CDK (constantly active), or Rb, or p16 and p21
177
How important is the type of mutation in cancer?
Point mutations can be worse in proteins that form complexes e.g. p53 forms a tetramer complex
Mutation in one copy of genes leads to infection of the whole pool of proteins
However, deletion would lead to no faulty proteins, just less but no clear different would be seen
178
What are the two types of genetic instability?
Sequence
- small mutations in specific bases, commonly due to mismatch repair
Chromosomal
- greater degree of mutations, due to difference in mitosis
179
What causes sequence instability?
1. Mismatch repair
- MLH1 or MSH2 mutations (by methylation of promoter)
2. Double stranded break
- Homologous recombination (HR) more faithful uses sister chromatid as template, contain BRCA1 and 2
- Non-homologous end joining (NHEJ) use ends as templates
180
What causes chromosomal instability?
1. DNA synthesis
- mutation in the ε subunit in the DNA polymerase for proof-reading
2. Mitosis
- mutations in the formation of spindle fibres
- result in aneuploidy
181
What is the Vogelstein model for colorectal cancer?
1. Mutation in APC or β-catenin gene
APC regulates spindle and polarises cell
β-catenin causes cell adhesion
2. Second mutation causes genetic instability
3. Suppression of tumour suppressor
- development of an adenoma (TGF-β)
4. Suppression of other tumour suppressors
- development into a carcinoma e.g. p53
182
What is hereditary predisposition to cancer? Give examples
Mutations in tumour suppressor genes such as BRCA
- Increases risk from 13% to 50-80%
1. Adenomatous polyposis
- polyps in the colon, due to APC mutation
2. Lynch syndrome
- mutation in MLH1
3. Retinoblastoma
- mutation in RB1 gene
4. Breast cancer
183
How is it shown that genetic instability is not required for malignancy?
Curing and recovery of BRCA gene still leads to the development of the tumour
- once other mutations have occurred then other forces are at play
184
What mutations occur in signalling pathways that lead to cancer?
1. In EGF-Receptor
- RAS leads to MAPK signalling
- PIP3 formation, AKT signalling
2. Wnt receptor
- Lack of Wnt ligand causes the formation of a β-catenin degradation complex, presence causes β-catenin to move from TCF4
3. Inhibitory TGF-β pathway
- Mutations in SMAD, causing constant activation
185
What is the differentiation block?
Block can occur at the stem cell stage, leads to the build up of progenitor cells
- Seen as lack of polarisation of cells
- Due to mutation in APC
186
What is the difference between chronic and acute leukaemias?
Acute - Proliferation of progenitor cells that then differentiate
Chronic- Proliferate but remain in undifferentiated state
187
How is resistance to apoptosis generated?
Anti-apoptotic - Bcl2 (promoted)
Pro-apoptotic - Bax (inhibited)
p53 is pro-apoptotic, mutations can arise and prevent that
= Lack of formation of the Mitochondrial Outer Membrane Permeabilization (MOMP)
188
How is immortality in cancer cells generated?
Lack of telomere shortening, due to the upregulation of telomerases
- Normal shortening leads to the Hayflick limit, lack of senescence
- TERT (promoter) mutation
or TERT promoter rearrangement
189
How does p53 coordinate stress?
p53 causes cell cycle arrest and leads to senescence when mutation and damage is detected
190
What metabolic changes occur in cancer cells?
1. Warburg effect
- Aerobic glycolysis with high levels of lactate
- Production of ROS
2. Metabolic remodelling
- High levels of succinate and fumurate
- Gain function (IDH1 and IDH2), produce onco-metabolites due to mutation in genes encoding enzymes
191
How do cancer cells cause angiogenesis?
- Tumours secrete angiogenic factors
- Angiogenic switch to pro-angiogenic factors
- Growth requires more blood (Folkman postulate)
Commonly occurs when hypoxic conditions are present in inflammation
192
How do cancers commonly metastasise?
Spread via lymphatics and venous circulation
- 0.02% of tumour cells develop into a metastases
Carcinomas- via lymphatics
Sarcomas - via the blood
If in the gut, spleen and pancreas goes straight to the liver
- Tests by detecting the presence of cytokeratin
193
What factors affect metastasis?
Mechanical factors
- circulation
- number of cells delivered
Cancer and compatibility
- Organ may support or suppress growth
194
What is clonal evolution?
Natural selection of cells that selects for favourable traits
- For competition of resources
- Give rise to progeny that also have that mutation
195
What is the evidence for clonal selection?
GFP staining of APC in WT and mutated.
In WT cells die and proliferate at a normal rate
Mutated cells
196
What is the hierarchical approach of cancer development?
- Mutations occur in the stem cell stage and are passed down
- So their stemness is passed down
197
What is the stochastic model for tumour development?
- Random mutations cause tumour growth, with every cell having an equal chance of acquiring mutations
198
What is the evidence for the cancer stem cell model?
Leukaemias
- Expression of CD34 confers stem cell identity
- Expression of CD38 confers differentiated state
=> Injection of CD34+ led to tumour development however CD38+ didn't
Intestinal cells
- Lgr5 confers stem cell identity
- Mutations in the crypts (where stem cell located) causes adenomas
- Mutations in the transit amplifying cells causes microadenomas
199
How is the niche environment important for cancer stem cell development?
Wnt signalling
- Wnt produced from Paneth cells lead to retention of stemness
Location
- Certain areas more prone to cancer e.g. eye lids that receive a lot of UV, or mesothelia by asbestos
200
In what cases might environment not be the cause but the promoter of cancer?
Lung cancer in people that don't smoke
- Mutations in KRAS and EGFR are common, and solely not sufficient to cause cancer
- However pollution can cause development into adenomas by secretion of Nf-kB conferring stem cell identity
201
How does chronic inflammation cause cancer?
- Rapid turnover of cells increases risk of mutations
- Release of IL-1β triggering cancer in EGFR mutants
= Injection of anti-IL-1β meant cancer didn't develop
202
What do tumour cells also require for establishment and development?
- Tumour stroma
Transplant without stroma meant cells unable to establish themselves
203
What are the 2 mechanisms to investigate cancer?
1. Single cell sequencing
- similar mutations suggesting link can be generate to create a hierarchical
2. Spatial transcriptomics
- look at transcriptomes to locate different cell types
204
What are the 5 main methods for treating cancer?
1. Surgery
2. Cytotoxic agents
3. Exploiting cancer cell properties
4. Targeted agents
5. Exploiting the immune system
205
How is surgical removal of a tumour carried out?
1. Debulking by using cytotoxic agents
2. Surgical removal, easier if benign
206
By what mechanism do cytotoxic drugs help kill cancer? And what are the problems with using them?
- Cause DNA damage to signal apoptosis
- Inhibit topoisomerases and mitotic spindle fibres
Cyclophosphamide - alkylating agent, Cisplatin - DNA cross linker
Problems
- side-effects unknown
- resistance can be developed (flippases)
- can lead to systemic toxicity
207
How can cancer cell properties be targeted and exploited?
1. Exploiting cell cycle checkpoints
- e.g. p21 that control G1/S checkpoint, tested in the Waldman experiment in which radiation led to apoptosis in mutants, but arrest in WT
- e.g. p53 causing arrest, infection with modified adenovirus means only cancer cells are lysed due to replication of virus, normal cells are able to stop replication
2. Targeting genetic instability
- PARP inhibitor, means single stranded repair by PARP doesn't occur, use other forms e.g. NHEJ, however in cancer cells these may be mutated (BRCA), and cause build up of mutations and cell death
208
What are examples of targeted cancer therapy?
1. Targeting ATP binding site of kinases
- e.g. Crizotinib and Vemurafenib (a BRAF inhibitor)
- inhibition of kinase prevents downstream MAP kinase signalling
e.g. ALK inhibitors to prevent NPM- ALK which is a constantly active kinase receptor that is no longer transmembrane and always dimerised
2. Monoclonal antibodies
- bind to receptors and compete with proper ligand
- Cetuximab binds to EGFR
- Herceptin binds to HER2 receptors
- Rituximab binds to CD20 on B cells
3. Armed clonal antibodies
- Brentuximab delivers MMAE toxin when endocytosed
209
How can the immune system be exploited to fight cancer?
1. Re-awaken exhausted T cells
- Inhibition of CTLA4 or PD-1 or PD-L1
- e.g. Ipilumumab is anti-CTLA4
2. Bispecific T cells Engagers (BiTEs)
- Recognise CD3 on T cells and CD19 on B cell lymphoma, bringing them together
3. Chimeric antigen Receptor T cells (CAR Ts)
- T cells are extracted and modified, and re-introduced to provide resistance. However is expensive, can cause cytokine storm by IL-6 and has to be unique to each person
210
What are the 3 strategies carried out by viruses to avoid the immune system?
1. Hiding
2. Change
3. Suppress
211
What are examples of hiding strategies carried out by viruses?
1. Latency
- Hide in neurones or immunologically privileged sites
- EBV hides in B cells
2. Leaving DNA in a cell
- As an episome (HSV and Varicella)
3. Genome integration
- HIV, integrate proviral DNA into the host genome
4. Hiding during spread
- cause cells to form syncytia, spread between and prevent apoptosis
212
How do viruses change their surface proteins to evade the host immune system?
Antigenic variation
-Antigenic shift - re-assortment of RNA segments following co-infections e.g. Influenza A
- Antigenic drift - mutations over time cause significant enough change
- Recombination- Cross over events, e.g. in Influenza with 8 segments
213
What are the ways in which viruses suppress the immune system?(5)
1. Disrupt innate immune system by immunomodulators
- Inhibit PRR signalling pathways, inhibiting RIG-I, which reduces Nf-kB,
-By cleaving receptors for example enterovirus E71 secretes 3C protein that cleaves a protein causing less IL-1β release
2. Decoys
3. Apoptosis inhibition
4. Degradation - by E3 ubiquitin ligase
5. Preventing MHC presentation
214
How does Influenza evade the immune system?
Producing NS1
- Multifunctional protein that targets IFN production, inflammasome production and apoptosis
215
How can MHC presentation be targeted by viruses?
Kaposi's sarcoma-associated herpesvirus (HHV-8)
- produce K3 which ubiquitinates MHC I, results in endocytosis and degradation
Cowpox
- CPX203 - stops transfer from golgi to membrane
- CP012- prevents TAP from loading antigen onto receptor
HPV
- E5 reduces expresison
- E6 prevents presentation
216
What are atheromatous diseases?
Diseases caused by the presence of atheromas, plaques and their rupture
- Heart attack
- Stroke
- Endothelial dysfunction
217
What occurs in endothelial dysfunction?
- Presentation of adhesion molecule VCAM-1 and ICAM-1
- Inflammatory response
- Macrophages, neutrophils
- Impaired vasodilation, reduced production of NO
- Increased vascular permeability
- Increase in prothrombotic factors
- Oxidative stress, production of ROS promoting inflammation
218
What is endothelial dysfunction?
Impairment of normal epithelial function
- Changes in permeability
- Promoting adhesion of molecules
Factors causing
- Oxidative stress
- Dyslipidemia
- Hypertension
- Shear stress
219
How is multidrug resistance generated in pathogens? (4)
1. Efflux pumps
- Actively pumps drugs out of cell
2. Alter drug targets
- By variation can alter the binding affinity of drugs
3. Enzymatic modification
- Produce enzymes that modify the drugs
4. Biofilm formation
220
What is the role of Nf-kB?
TF that regulates immune system and inflammation
- Promotes anti-apoptosis via Bcl-2
- Regulates proliferation and differentiation of B and T cells
- Responds to stress signals e.g. oxidative
221
How does TB survive in granulomas and spread?
- Mycolic acid resistant to degradation
- Secretes factors that prevent phago-lysosyme fusion
SPREAD
- ESAT6 facilitates lysis and spread
- Inhibits IL12 which initiates Type I response
222
What carcinogenic chemicals are released from tobacco smoke?
1. Benzo[a]pyrene (BAP)
- increases CYP1A1, generating oxidative stress
2. β-naphthylamine
- hydroxylated in the liver and causes damage
223
How is a granuloma formed?
1. Infection of epithelioid macrophages by TB
2. Formation of Langerhans giant cell
3. Lymphocytes support attack + macrophages
4. Contain bacteria within a granuloma
224
What are common genes that are mutated in lung cancer?
KRAS and EGFR
KRAS- in 25% of patients with non–small cell lung cancers (NSCL). Arbour et al., 2018
225
What mutations can occur to cause changes in the shape of normal cells in cancer cells?
1. actin genes (e.g., ACTG1, ACTB)
2. Mutations in myosin genes (e.g., MYH9, MYH10)
226
What is the role of KRAS?
Signalling- mutation leads to activation of Nf-kB conferring stem cell identity
227
What type of cancer is agent orange associated with?
Non-hodgkin lymphoma and sarcomas and other lymphomas
- Exposure in Vietnam war
- Frumkin 2003
228
How do mutations in BRCA1/2 cause cancer? What is its normal function?
- associates with DNA recombinase Rad51, for HR (Scully et al, 1997)
- associates with MSH2, for mismatch repair (Wang et al, 2001)
229
How do bacteria target macrophages?
1. Paralyse the macrophage
- Yersinia secretes YopT and YopP
2. Kill macrophages
- Strep. pyogenes secretes streptolysin O, as a cytolysin
3. Resist macrophage
- Capsule acts a block, TB,
230
Paper suggesting mutations in colorectal cancer
APC, KRAS, SMAD4 and p53 mutations as suggested in Fodde, 2002
231
How does H.pylori cause gastric cancer?
Polk and Peek, 2010
- CagA causes release of β-catenin from it being bound to membrane by E-caherin
- CagA and APC mutations found in 50% of gastric cancers
- Increase in inflammation via Nf-kB and cytokines (both CagA and VacA)
232
How do parasites evade the host immune system?
1. Hide
- P.falciparum in RBC, Toxo in cysts in the intestine
2. Mimicry
- Schistosomes present MHC or blood group proteins
3. Immunomodulation
- Schistosomes, present receptors that bind to complement
- Secrete cytokines that interfere
4. Treg upregulation
233
What evidence is there for molecular mimicry and immune evasion by schistosomes?
Mimicry - presentation of MHC and blood antigens
Evasion - receptors that bind to complement, mainly C3 that inhibit the response. McGuiness and Kemp 1981
