Microbiology Flashcards
1
Q
What is the most common cause of sporadic encephalitis in the Western world?
A
Herpes Simplex Encephalitis
2
Q
What does innate immunity comprise of?
A
1) Barriers
2) Interferon response
3
Q
How do epithelial surfaces act as barriers to viruses?
A
They are covered with protective secretions that contain mucous and collectins which can act as decoy receptors
4
Q
How done influenza virus neuraminidase gain access into the host?
A
Can enzymatically remove the decoy receptors from mucous, allowing the virus to gain access to the ‘real’ receptor at the cell surface
5
Q
What are interforns?
A
Soluble cytokines that are secreted when the cell detects a foreign pattern
6
Q
What are the different types of interferon?
A
Type I (IFN alpha and IFN beta ) IFN gamma (type II) IFN lambda (type III
7
Q
What types of interferons are produced by all cell types
A
Type I (IFN alpha and beta)
8
Q
What type of cell produce Type II interferons (IFN gamma)?
A
Produced by activated T cells and NK cells
9
Q
What type of cells produce IFN lambda? (type III)
A
Produce by all cells but only acts at epithelial cells
10
Q
What are the three major functions of type I interferons?
A
They are polypeptides secreted from infected cells
1) Induce antimicrobial state in infected and neighbouring cells
2) Modulate innate response to promote Ag presentation and NK but inhibit proinflammation
3) Activate the adaptive immune response
11
Q
What triggers IFN beta induction?
A
IRF-3
12
Q
What are plasmacytoid dendritic cells?
A
Specialist IFN alpha secreting cells. They express high levels of IRF-7 constitutuvely.
13
Q
What do type II interferons signal through?
A
Different receptor- IFNGR
14
Q
What receptors do type III interferons signal through?
A
IL28R and IL10B
- Mainly present on epithelial surfaces
15
Q
How is self differentiated from non-self?
A
PAMPs are detected by PRRs
16
Q
What are PAMPs?
A
Pathogen associated molecular patterns
17
Q
What are PRRs?
A
Pattern recognition receptors
- Often sense foreign nucleic acid
18
Q
Where do PRRs reside?
A
- Cytoplasm: RIG-I-like receptors (RLRs) and nucleotide oligmerisation domain receptors (NLRs)
- Endosome: Endosomal toll like receptors (TLRs)
19
Q
What is interferon?
A
A soluble cytokine that is newly transcribed and translated as a result of PAMP recognition
- It is secreted from the infected cells and binds to specific receptors and signal activation of de novo transcription of hundred of Interferon Stimulated Genes (ISGs). These have various anti-viral effects
20
Q
What does interferon induction involve?
A
Activation of the promotor of the IFN-beta gene in the nucleus of the infected cell.
21
Q
What is the function of interferon?
A
- Is a ‘master regulator’ of the immune response
- Direct anti-viral effects: IFN beta binds to receptor, causing phosphorylation of the intracellular proteins, STAT-1, STAT 2
- These then form a heterodimer, translocate to the nucleus and via promotor binding activate transcription oF ISG
22
Q
What are interferon stimulated genes?
A
They are synthesised in response to interferon and all have anti-viral effects
23
Q
Give examples of interferon stimulated genes
A
- PKR
- 2’5’OAS
- Mx
- ISG15, ISG54, ISG56
- PML bodies
- APOBECs and TRIMs
- ADAR
- Serprine
- Viperin
- miRNAs
- Apoptosis
- Cell cycle arrest
24
Q
What is Mx?
A
An interferon stimulated gene
- Is a GTPase with homology to dynamin
- Can form multimers which wrap around the nucleocaspids of incoming viruses
25
What does Mx1 inhibit?
Influenza
26
What does Mx2 inhibit?
HIV
27
What are the effects of PKR (protein kinase R)?
Is an antiviral mediatory
1) Phosphorylates the alpha subunit of eIF2 and therefore prevents translation
2) Activates IKKBeta leading to release of NFκB.
- NFκB is a very important transcription factor for antiviral response
28
Why does the antiviral state not last?
- IFN response may only be maintains for several hours
- Therefore the ability to respond to IFN is lost due to negative regulation
- SOCS suppressor of cytokine signalling genes turn off the response
29
How do viruses evade the IFN response?
Avoid detection by hiding the PAMP.
- Interfere globally with host cell gene expression and/or protein synthesis
- 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
30
How does Hepatitis C virus antagonise the IFN response?
Encodes a protease that targets and destroys MAVS, a key protein in the detection pathway that leads to IFN synthesis
31
How does influenza virus antagonise the IFN response?
Has an NS1 protein that acts as an antagonist to interferon induction by binding to RIG-I/TRIM25/RNA complex and preventing the activation of the signalling pathway.
Also prevents nuclear processing of newly induced genes
32
How do pox viruses antagonise the IFN response?
Prevent the signal from getting through
- Pox viruses and herpes viruses are large DNA viruses
- More that half the pox virus genome is comprised of accessory gees that modify immune response
- Pox viruses encode soluble cytokine receptors (vaccina virus B18) that mop up IFN and stop it from reaching its own receptor
33
How does HIV deal with restriction factors?
Using accessory genes
- Vif targets APOBEC
- Vpu targets tetherin
34
What may account for the emergence of HIV in humans?
The acquisition of ability to overcome restriction factors using accessory genes
35
What is APOBEC3G
| (Apoliporotein B mRNA-editing enzyme catalytic polypeptide like 3G)?
An interferon stimulated gene.
- Human host cell protein involved in innate immune resistance to retroviruses and hepdnaviruses
- Deaminates dC to dU in negative strand viral cDNA during reverse transcription
- Results in G to A hypermutation
36
What is targets Tetherin?
HIV Vpu, Env, Nef
37
What are the consequences of innate immunity?
- A combination of damage of infected cells by virus and
| - damage of infected and bystander cells by the immune response
38
What is the cytokine storm?
Sometimes, the virus is resistant to the ISG meaning that despite production, more viruses are made which triggers a larger cytokine response. - cytokine storm. Possibly fatal
39
What viruses can see a cytokine storm?
Dengue haemorrhagic fever
Severe influenca infections
Ebola
40
How can viruses that don't have good control of IFN be used?
Make a live attenuated virus for vaccine.
- Exposure to the virus will result in PAMP recognition and immune response, however poor control of IFN results in quick suppression of the virus quickly to prevent the host getting sick
41
How can IFN be used as a treatments?
Pegylated IFN is often used with ribavirin as a treatment for Hepatitis C virus
42
Why is IFN as a treatment associated with unpleasant side effects?
Interferon stimulates so many aspects of a cytokine and chemokine response that it is associated with side effects like fever and aching
43
How can infected cells be recognised and destroyed?
By antigen specific T cells when viral peptides are processed and presented by MHC Class I.
To avoid this many viruses encode products that intervene with MHC processing and presentation
44
How do viruses prevent the loading of antigens onto the transporter protein complex TAP?
- EBV EBNA1 cannot be processed by the proteasome
- Herpes simplex- HSV ICP47 blocks the access of the processed peptide to TAP
- CMV US6 stops ATP binding to TAP preventing translocation
45
How does human cytomegalovirus prevent MHC transport?
CMV US3 binds tapasin and prevents peptides being loaded to MHC
46
How does adenovirus prevent MHC transport?
Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum
47
How does Kaposi's sarcoma-associated herpesvirus interfere with MHV presentation at the cell surface?
KSHV kK3 protein induced polyubiquitinylation and internalisation of MHC
From the internalised endosome, MHC is passed to lysosomes where it is degraded
48
How do viruses avoid NK killing by the missing self mechanisms?
- Normal healthy cells display MHC at their surface
- Cells that don't display MHC are detected by NK cells and kills
- Viruses that disrupt MHC presentation would end up being killed by NK cells
- Viruses encode MHC analogues (CMV gpUL40) or up-regulate MHC
49
How does destruction of T cells lead to virus pathology?
- HIV targets CD4 positive cells and depletes the ability to support an immune response
- Ebola virus infection also results in destruction of target dendritic cells and macrophages by direct infection and of T cells by a bystander response
50
Why does human cytomegalovirus need to be eliminated from bone marrow cells before transplantation?
Otherwise will reactivate in transplant recipient
| - it infects 60-90% of people and is only a problem in immunocompromised
51
What is antigenic variation?
Influenza antigenic drift: Continued rapid evolution driven by antigenic pressure from host
Influenza antigenic shift: introduction of new subtypes from animal source
52
What is the antigenic variation in human rhinovirus?
- Human rhinovuruses cause the common cold
- They exist as more than 120 antigenically distinct serotypes that co-circulate
- Impossible to make a vaccine against them all
53
What are the consequences of antigenic variation of Dengue virus?
- Dengue haemorrhagic fever
- 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 after fever drops- shock. Treat with IV fluid replacement
54
What is the mechanism of antibody dependent enhancement of Dengue virus?
- The virus exists as 4 different serotypes. Once infected, the host is protected against the same serotype
- The antibodies generated against previous infection do not neutralise different serotypes, they merely bind and signal for more immune cells to come.
This effectively delivers the viral load to the immune cells, as the viruses are still completely active
- Results in effect similar to cytokine storm and may lead to ADE, causing Dengue haemorrhagic fever
55
How do viruses evade the antibody response?
- Some viruses have glycoprotein antigens that are so heavily glycosylated (mucin like) that antibodu access is hindered e.g. HIV and Ebola
- Ebola virus particle membranes have a high content of phosphatidyl serine lipids, making them look like apoptotic bodies that are rapidly taken up by macropinocytosis, away from antibody surveillance
- Viral filaments might be harder for antibodies to neutralise as GP inaccessible in folded pockets (EBOV)
56
What is the role of soluble glycoprotein (SGP) in ebola evasion antibody?
- sGP is the default coding for the GP gene. Full length GP is made by polymerase stuttering
- sGP is an antibody decoy
- sGP is immunosuppressive and inhibits neutrophils
- GP2 and GPs have an immunosuppressive peptide.
57
How does the measles vaccination target measles?
- The vaccination infects CD150 positive cells including memory lymphocytes and erases immunological memory
- Measles virus infection results in a 2-3 decrease in immunological memory that leads to morbidity and mortality from other diseases
58
What is the definition of infection?
Invasion by and growth of pathogenic microorganisms
59
What is the definition of disease?
A disordered or incorrectly functioning organ, part, structure or system of the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional deficiency or imbalance, toxicity, or unfavourable environmental factors, illness, sickness, ailment
60
What is a parasite?
Organism living in or on the host and dependent on it for nutrition- causing damage
61
What are the types of endoparasites?
Protozoa: amoeba, coccidiae, ciliae, flagellates
Metazoa: roundworms, flatworms, flukes
62
What are protozoa?
- Single cell organisms
- Eukaryotes (genome within a nucleus, complex organelles in cytoplasm
- Varied pathogenesis
- Some have insect vectors (malaria)
- No eosinophilia
63
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
64
How does infection with amoebae occur?
By ingestion of mature cysts in food or water, or on hands contaminated by faeces
65
What is E histolytica?
- Responsible fro amaeobiasis
- Often asymptomatic but can cause a bloody form of diarrhoea when it infects the colon and can also lead to abscess in the liver
- Cysts release active trophozoites which invade the epithelial cels of the large intestines, causing ulcers. This infection can spread via the venous system
- Must be differentiated from Entamoeba dispar, which is a normal commensal of the GI tract
66
How are amebiasis treated?
Nitroimidazole derivatives (act on trophozoite but not on cysts) and parmomycine or diloxanide furoate
67
Give examples of coccidial infections and the diseases they cause
1) Plasmodium species- malaria
2) Toxoplasma- Toxoplasmosis
3) Cryptosporidum- diarrhoea
68
What is the life cycle of malaria?
- Different types of plasmodium- P.falciparum, P.malariae, P.ovale, P. vivax, P knowlesi
- 2 types of host: humans and female Anopheles mosquitoes
- 2 stages in human: liver and blood stages
69
What are the symptoms of malaria?
- Can appear as early as 7 days but the time between exposure and signs of illness can be up to 1 year
- 9 to 14 days- Plasmodium falciparum
- 12 to 18 days- P malariae
- 18 to 14 days- P.malariae
- 11 to 12 days- P. knowlesi
- Fever, headache, chills, vomiting, muscle pain,
Paroxysm (cycle in 4-8 hours)
70
What are the complications of malaria?
- Severe anaemia (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
71
What are the treatments for malaria?
Uncomplicated malaria:
Chloroquine, atovaquone, Artemether-lumefantrine, quinine sulfate plus one of the following- Doxycycline, tetracycline or clindamycin quinine sulfate, mefloquine
Severe malaria:
Artemisinin-based combination therapy (ACT) is recommended for the treatment of P.falciparum malaria
72
How can humans become infected with toxoplasma gondii?
- Eating undercooked meat of animals harbouring tissue cysts
- Consuming food or water contaminated with cat faeces
- By contaminated environmental samples
- Blood transfusion
- Organ transplantation
- Transplacentally from mother to foetus
- Immunocompromised patients may develop central nervous system disease, brain lesions, pneumotis or retinochoroiditis among other risks
73
What does cryptosporidum cause?
Diarrhoea in humans, very common in HIV+ patients presenting with diarrhoea
Diagnosis: stool examination
Treatment: fluid rehydration
74
What is balantium coli?
A ciliate causing balantidiasis
Reservoir hosts: pigs, rodents, primates
- Most people infected will experience no symptoms
- Immunocompromised patients may experience more severe signs- persistent diarrhoea, dysentry, abdominal pain, weight loss, nausea and vomiting. If left untreated, can lead to perforation of the colon
Diagnosis: Stool examination
75
What is Giarda?
A flagellate
- Giardasis
- Flagellated trophozoites attach by their suckers to the surface of the duodenal or jejunal mucosa
- Life cycle consists of 2 stages: cyst and trophozoite
- Ovoid cysts are able to survive standard chlorination procedures, filtration is required to exclude them from drinking water
76
What are the acute symptoms of giardiasis?
```
Diarrhoea
Greasy stools that tend to float
Stomach or abdominal cramps
Upset stomach or nausea/vomiting
Dehydration
```
77
How is Giardiasis diagnosed and treated?
Diagnosis: Stool examination
Treatment: Metronidazole/Tnidazole
78
What is Trichomonas?
- Sexually transmitted flagellate
- In women, the organism is found in the vagina, urethra and paraurethral glands, in men infection is usually of the urethra
79
What are the symptoms of trichomoniasis?
Females:
- 10-50% asymptomatic
- Vaginal discharge, vulval itching, dysuria, or offensive colour
- Occasionally the presenting complaint is of low abdominal discomfort or vulval ulceration
Males:
15-50% of men are asymptomatic
- Discharge and/or dysuria
Complications- detrimental outcome on pregnancy and is associated with preterm delivery and low birth weight
80
How is trichomoniasis diagnosed and treated?
Diagnosis: Microscopy, detection of motile trichomonads in swab/urine
- Trichomonas rapid test
Treatment: Metronidazole
81
What are helminths?
- Metazoa
- Cycles may involve insect vectors and intermediate hosts
- For most, humans are the definitive host, few are zoonoses (acquired from animals)
- Adult worms cannot multiply in man- number of adults related to infection
- Lay eggs, microfilaria, larvae
82
What are the different roundworms?
Ascaris
Hookworm
Filaria
Strongyloides
83
What can ascaris cause?
Ascariasis in the bowel.
Worms can cause obstruction especially of the bile duct or if sufficient numbers, the bowel
- Often causes no symptoms
- Penetration of the larvae from capillaries into the lungs can lead to Loeffler's pneumonia in which pools of blood and dead epithelial cells clog air spaces in the lungs
84
How is ascariasis diagnosed and treated?
Diagnosis: stool examination
Treatmet: albendazole and mebendazole
85
What are hookworms?
- Anyclostoma duodenale
- Around 1cm long and curved. They are attached by their buccal capsules to the villi of the small intestine
- Larvae are carried through the blood vessels to the heart and then to the lungs. They penetrate into the pulmonary alveoli, ascend the bronchial tree to the pharynx and are swallowed.
86
What are the symptoms of hookworms?
- Iron deficiency anaemia: caused by blood loss at the site of intestinal attachment of the adult worms. Can be accompanies by cardiac complications
- Gastrointestinal and nutritional/metabolic symptoms
- Local skin manifestations can occur during penetration by the filariform larvae
- Respiratory symptoms during pulmonary migration of the larvae
87
How are hookworms diagnosed and treated?
Diagnosis: Stool examination
Treatment: Albendazole and mebendazole
88
What is trichuris trichiura?
- Whipworm (hookworm)
- The eggs hatch in the small intestine and release larvae that mature and establish themselves as adults in the colon. The adult worms live in the caecum and ascending colon. The adult worms are fixed in that location
- With hundreds of worms there may be blood diarrhoea and anaemia due to severe vitamin and iron loss. The worms leave open wound which cause inflammation of the intestinal wall. May develop rectal prolapse
89
How is trichuris trichiura diagnosed and treated?
Diagnosis: Stool examination
Treatment: Albendazole and mebendazole
- Whipworm is used in helminthic therapy to help against allergic and autoimmune diseases
90
What diseases can filaria cause?
- Lymphatic filariasis (elephantiasis). Transmitted by Aedes mosquitoes.
- Cutaneous filariasis (onchocerciasis) leading to river blindness. Transmitted be blackflies.
- Ioaiasis (eye worm). Transmitted by mango flies.
91
How do tapeworms cause problems?
Taenia solium- from pork
Taenia sagnita- from beef
- Cause abdominal discomfort, diarrhoea and weight loss
- Tapeworms attach to the small intestine and can be 3m long in adulthood
92
How are tapeworms diagnosed and treated?
Diagnosis: Segment ins tool or identification of eggs in stool
Treatment: Praziquantel
93
What is Schistosoma?
An example of a fluke
- Eggs in water hatch into miracidiae which penetrate suitable snails. There they develop into sprocysts which are released and become fork-tailed cerariae. These penetrate the skin of a human in the water where they shed their tail and become schistosomulae.
- They migrate via the portal venous system and liver to the rectum where they lay eggs.
- S. haematobium settles in bladder so its eggs are expelled in the urine instead of the faeces.
- Eggs laid in the liver cause cirrhosis.
- Leads to portal hypertension, oesophageal varices and haematemesis
- Treated with praziquantel
94
What are ectoparasites?
They are external
- Scabies (Sarcoptes scabiei)- mites whose females burrow into the epidermis to lay their eggs
- Lice, including head lice (pediculis capitis) and public live (Pthirus pubis)
95
What is leishmanias caused by?
Leishmania- a flagellate
- It's vector is a sandfly where Leishmania develops into promastigotes. These move using flagella.
Promastigotes are injected into humans when the infected sand fly bites.
Once the parasite has infected the human cells, it retracts its flagella becoming an immobile amastigote
- Promastigote and amastigote are the two forms of leishmania
96
What are the four major forms of leishmaniasis?
- Visceral leishmaniasis
- Localised cutaneous leishmaniasis
- Diffuse cutaneus leishmaniasis
- Mucocutaneous/mucosal leishmaniasis
97
Which leishmania feed on blood?
Females- to supply nutrients for their eggs
98
What are the properties of visceral leishmaniasis?
'kala azar'
- Fatal if untreated
- Risk factors: malnutrition and immunosuppression.
- Can be caused by L. donovani
- Symptoms: irregular fever, weight loss, hepatomegaly, splenomegaly, anaemia
99
How is visceral leishmaniasis treated?
IM or IV sodium stibogluconate (SSG) or meglumin antagimoniate
100
What is Post-Kala-azar Dermal Lishmaniasis (PKDL)?
- Common during of after treatment of a sub-clinical infection
- Lesions start on face, usually around mouth
- Lesions become nodular
- PKDL can spread to the trunk and limbs
101
What are the properties of localised cutaneous leishmaniasis (LCL)?
- Causes skin lesions on exposed body parts which can be ulcerating
- Often self-healing and lead to immunity against re-infection but can create serious disability and scars
- Species causing cutaneous leishmaniasis include L.major (multiple crusted lesions) and L. tropica (crusted ulcer)
102
What are the properties of diffuse cutaneous leishmaniasis (DCL)?
- Causes multiple, nodular, non-ulcerating skin lesions often on the face and hands
- Once species that causes it is L.aethopica
103
What are the properities of mucocutaneous leishmaniasis (MCL)
Caused by L. braziliensis
- Affects skin around the mouth causing disfigurement
- MUCOSAL leishmaniasis destroys the mouth and lips themselves (mucous membranes). Caused by L.infantum, L.major, L. tropica and L. aethopica
104
How do cells provide immunity to fungal infection?
- Opsonisation by pentraxin 3 and mannose-binding lectin
- Phagocytes are a critical first line of defence
- NK cells provide early interferon-gamma
- A failure of innate immunity leads to adaptive responses
- Dendritic cells influence T cell differentiation
- Th1 and Th17 play a role
105
How do fungal morphisms of opportunistic pathogens cause virulence?
- Candidal dipmorphism (yeast/hyphal forms) allows tissue invasion
- Crytpococcus forms a capsule to evade phagocytosis
- Aspergillus species (sporulating fungi) inhaled as conidia, invade the tissues as hyphae
106
Why is Toll important in Drosophila?
Toll is an innate pattern recognition receptor in Drosophila required for fungal immunity
107
What are the opportunistic pathogens?
- They require some sort of immunocompromised host in order to establish infection
- Aspergillus species
- Candida species
- Cytococcus species
108
What are the major antifungal effector cells?
1) Neutrophils- phagocytosis of fungi, oxidative and non-oxidative fungal killing (and cytokine production)
2) Macrophage- phagocytosis of fungi, pro-inflammatory cytokine production, killing of fungi, granuloma formation , maintenance of latency
3) Dendritic cells- antigen presentation, Th1/2 polarisation
109
How do innate immune responses protect against airborne fungal pathogens?
- Ciliary clearance and pulmonary polymorphonuclear leukocytes (encountered in alveolar space) protect against infection
- Aspergillus species are major components of the airborne microflora
- In the absence of a competient immune response, aspergillus species will germinate and go on to produce a lesion in lung
110
How are infectious fungal cells cleared?
- During phagocytosis, the NADPH oxidase complex consumes oxygen which generates the superoxide anion 02 and hydrogen peroxide H202
- These metabolites give rise to other oxygen species that are anti-microbial but can also cause tissue damage and apoptosis
- Mutations of NADPH oxidase enzyme leads to the inability to produce the respiratory burst. Results in chronic granulomatous disorder (CGD)- suffered are highly susceptible to aspergillus and candida infections
111
What is the NADPH oxidase enzyme complex?
Multi-subunit complex which mediates the respiratory burst of superoxide oxygen
112
Describe the neutrophil-mediated killing of Aspergillus
NETs (neutrophil extracellular traps) are extracellular fibres, derived from chromatin and coated with granule proteins that produced as a final act of defence by dying neutrophils
- NET production requires reactive oxygen intermiediate-mediated signalling cascade
113
How are fungal pathogens recognised?
- Via cell wall components with PAMPs that act through several pattern recognition receptors
114
What is the fungal cell wall composed of?
- Predominantly of glucans and chitin (offfering physical protection) and PAMPs
115
What are the different shapes of bacteria?
Cocci: coccus, diplococci, streptococci, staphylococci, sarcina, tetrad
Bacilli: coccobacilus, bacillus, diplobacilli, streptobacilli, palisades
Budding and appendages: hypha, stalk
116
What are common virulence factors in bacteria?
1) Diverse secretion systems
2) Flagella (movement attachment)
3) Pili (important adherence factors)
4) Capsule (protect against phagocytosis) i.e. streptococcus pneumoniae
5) Endospores
6) Biofilms
7) Exotoxins
8) Endotoxin
117
What are endospores?
Metabolically dormant forms of bacteria
- Become resistant to heat, cold, desiccation and are chemical resistant
- E.g. Bacillus sp and Clostridum sp.
118
What are biofilms?
Organised aggregates of bacteria embedded in polysaccharide matrix
- Antibiotic resistant
i. e. Pseuomonas aeuginosa
i. e. Staphylococcus epidermidis
119
What are exotoxins and the various types?
They are secreted by bacteria and act on host cells
- Neurotoxins
- Enterotoxins
- Pyrogenic entotoxins
- Tissue invasive exotoxin
- Miscellaneous exotoxin
120
What are neurotoxin?
Exotoxins that act on the nerve or motor endplates to cause paralysis
i.e. Tetanus toxin or Botulinum toxins
121
What are Enterotoxins?
Exotoxins which act on the GI tract to cause Diarrhoea.
Enterotoxins inhibit NaCl resorption, activate NaCl secretion or kill intestinal epithelial cells
- Commune end result is the osmotic pull of fluid into the intestine which causes diarrhoea
1) Infectious diarrhoea e.g. Vibrio cholera Escherichia coli, Shigella dysenteriae, Campylobacter jejuni
2) Food poisoning e.g. Bacillus cereus or Staphylococcus aureis
122
What are pyrogenic exotoxins?
- Stimulate the release of cytokines and can cause rash, fever and toxic shock syndrome
- E.g. Staphylococcus aureus or streptococcus pyogenes
123
What are tissue invasive exotoxins?
- Allow bacteria to destroy and tunnel through tissue
- Enzymes that destroy DNA collagen, fibrin, NAD, red or white blood cells
- Staphylococcus aureus, Streptococcus pyogenes, Clostridium perfringens
124
What are miscellaneous exotoxins?
- Specific to a certain bacterium
| - Bacillus antracis and Corynebacterium diptheriae
125
What are endotoxins?
- Produced by Gram negative bacteria
- The lipid A part of LPS
- Shed in steady amount from living bacteria
- Treating a patient with a Gram-negative infection with antibiotics can sometimes worsen the condition
- When bacteria lyse they release large quantities of LPS/Endotoxin leading to septic shock
126
What is septic shock/.
- Sepsis that results in dangerous drops in blood pressure and organ dysfunction
- Referred to as endotoxin shock as endotoxin triggers the immune response that results in sepsis and shock
127
What is an outbreak?
- 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.
128
How is an outbreak defined?
Need to know the cause, characteristics, scale, time-frame, source, illness, involvement of different strains, symptoms to look for
129
What is used to detect outbreak strain?
PCR
130
What is the composition of Shiga toxin family members?
AB5 subunit composition
131
What is the structure of the shiga toxin?
- Subunit a (StxA) is non-covalently associated with a pentamer of protein B (StxB)
- StxA is the enzymatically active domain
- StxB pentamer is responsible for binding to host cell receptors
- Shiga toxin blocks protein synthesis in eukaryotic cells and affects other cellular processes
132
What is StxA?
An enzyme in the Shiga toxin which cleaves the 28S ribosomal RNA in eukaryotic cells
- Leads to the inhibition of protein synthesis
- Bacterial ribosomes are a substrate for StxA resulting in decreased proliferation of susceptible bacteria
133
Why can Shiga toxin affect commensal microflora in the gut?
Bacterial ribosomes are also a substrate for StxA and this will result in decreased proliferation of susceptible bacteria
134
What occurs as a result of Shiga toxins being encoded on a bacteriophage?
Bacteriophages are highly mobile genetic elements and contribute to horizontal gene transfer
- The toxins are high expressed when the lytic cycle of the phage is activated
135
What can enteroaggregrative E.coli (EAEC) colonise?
The small and large bowels
136
What can neonatal meningitis E coli colonise?
Brain
137
What forms of E.coli can colonise the bloodstream?
Uropathogenic E. coli (UPEC)
| Neonatal meningitis E.coli (NMEC)
138
What forms of E.coli can colonise the large bowel?
Enterohaemorrhagic E coli (EHEC)
Enteroinvasive E. coli (EIEC)
Enteraggregrative E.coli (EAEC)
139
What forms of E.coli colonise the small bowel?
Enteraggregrative E.coli (EAEC)
Enteropathogenic E.coli (EPEC)
Enterotoxigenic E coli (ETEC)
Diffusely adherent E.coli (DAEC)
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What form of E.coli colonises the bladder?
Uropathogenic E. coli (UPEC)
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What is the virulence factor in the EAEC strain?
Aggregative adherance fimbriae (AAF)
- Genes coding for AAF are on a plasmid
- Required for adhesion to enterocytes
- Stimulates a strong IL-8 response
- Allows biofilm formation
- Allows additional virulence factors
- Results in disruption of actin cytoskeleton leading to exfoliations
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How can an outbreak be identified?
- Surveillance provides an opportunity to identify outbreaks
- Good and timely reporting systems are instrumental to identify outbreaks
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What are some communicable disease 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-born diseases
5) Vaccine-preventable disease
6) Antimicrobial resistance and healthcare-associated infections
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What are some respiratory tract infections?
- Influenza
- Animal influenzas, including avian influenza
- SARS: Severe acute respiratory syndrome
- Legionnaire's disease (legionellosis)
- Tuberculosis
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What is the bacteria in Legionnaire's disease?
Legionella pneumophila
| Gram -
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What is the bacteria in tuberculosis?
Myobacterium tuberculosis
| Gram +
147
What is Legionella pneumophila?
- Gram -
- Lives in amoeba in ponds, lakes, air conditioning units
- Infection route: inhalation of contaminated aerosols
- In humans the bacteria will infect and grow in alveolar macrophages
- Human infection is 'dead end' for bacteria
- Important virulence factor type IV secretion system
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How does the type IV secretion system aid L. pneumophila?
Allows the bacteria to infect and replicate in human macrophages
- It allows fro the secretion of effector proteins into the cytoplasm of host cells
- Legionella can replicate in a Legionella containing vacuole (LCV)
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What is Mycobacterium tuberculosis?
- Gram +
- Very different cell wall. Extra lipid layer makes treatment more difficult
- Can enter a dormant state: Latent TB. There is evidence of infection by immunological tests but no clinical signs and symptoms of active disease
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What are different sexually transmitted infections?
- Chlamidiya trachomatis infection
- Gonorrheoa
- Hepatitis B virus infection
- Hepatitis C virus infection
- HIV/AIDS
- Syphilis (Treponema pallidum- Gram negative)
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What is Chlamydia trachomatis?
- Gram negative
- Obligate intracellular pathogen that cannot culture outside host cell
- Most frequent STI in Europe
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What is Neisseria gonorrhoeae?
- Gram negative diplococcus
- Establishes infection in urogenital tract by interacting with non-ciliated epithelial cells
- Important virulence factors: pili
- Antigenic variation allows the bacterium to escape detection and clearance by the immune system
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Give example of food and waterborne disease and zonoses
- Campylobacter sp.
- Samonella sp.
- Bacillus anthracis
- Vibrio cholera
- Listeria monocytogenes
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What is Campylobacter sp.?
Mostly C.jejuni
- Campylobacteriosis is most commonly reported infectious GI disease in EU
- Infection most likely through undercooked poultry
- Virulence factor: adhesion and invasion factors, flagella motility, type IV secretion system, toxin
- Sporadic cases not outbreaks
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What is Salmonella sp.?
- Highest infection in small children
- Important virulence determinant: Type III secretion systems encoded on pathogenicity islands (SPI)
SPI1- for invasion
SPI2- intracellular accumulation
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What is Vibrio cholerae?
- Cholera is an acute, severe, diarrheal disease
- Death can occur within hours without prompt rehydration
- Important virulence factor: Type IV fimbria, cholera toxin,
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What is the action of the cholera toxin?
Makes the cell produce cyclic AMP, activating transporters leading to the efflux of chloride ions with water movement following
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What is Listeria monocytogenes
- Risk group are immuno-compromised, elderly, pregnant and their foetus
- Listeria can enter non-phagocytic cells and cross three tight barriers (intestinal, BBB, materno/foetal barrier)
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What are some emerging and vector borne disease?
- Plague (yersinia pestis, gram negative)
- Q fever (coxiella burnetti, gram negative)
- Smallpox (eradicated)
160
What are some vaccine preventable diseases?
- Diptheria
- Invasive Haemophilius influenza
- Invasive meningococcal disease
- Invasive pneumococcal disease (IPD)
- Pertussis
- Tetanus
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What is an antimicrobial?
Interferes with growth and reproduction of a microbe
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How do hospital interventions act as a source of infection
- Lines: intravenous, central, arterial, CVP/Pulmonary artery
- Cathetirisation
- Intubation
- Chemotherapy
- Prophylactic antibiotics, inappropriate prescribing
- Prosthetic material
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How do hospitals act as a source of infection by dissemination?
Via hospital staff e.g. stethoscopes, use of computer keyboards
164
How do hospitals act as a source of infection by concentration?
There are high density of infection and patients within a hospital
165
What hospital acquired pathogens are major problems?
```
'ESCAPE'
Gram +:
- Enterococcus faecium
- Staphylococcus aureus
- Clostridium difficile
Gram -:
- Acinetobacter baumanii
- Pseudomonas aeruginosa
- Enterobacteriaceae
```
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Why is Enterococcus faecium a problem?
Vancomycin resistance
167
Why is Staphylococcus aureus a problem?
Methicillin resistant- MRSA
168
Why is Clostridium difficile a problem?
Can establish infection because of previous antibiotic treatment
169
Why is Acinetobacter baumanii a problem?
High drug resistant
170
Why is Pseudomonas aeruginosa a problem?
Multi drug resistant i.e. fluoroquinolone-resistant
171
Why is Enterobacteriaceae- pathogenic E. coli a problem?
Multi drug resistant
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Why is Klebsiella pneumoniae a problem?
Multi drug resistant
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Why is enterobacter sp. a problem?
Multi drug resistant
174
What drug is used for ESCAPE pathogens?
Colistin
| - Previously discarded drug as therapeutic options are limited
175
Why is pathogenic E.coli a problem in hospitals?
- Most frequent cause of bacteraemia by Gram- bacteria
- Most frequent cause of community and hospital acquired UTI
- Increase in multi-drug resistant strains
- Most isolates that are resistant to cephalosporin express the extended spectrum beta lactamase (ESBL)
- Still sensitive to carbapenems
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What are cephalosporins?
- Class of beta-lactam anitbiotics
- Target pathway: inhibit peptidoglycan synthesis
Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
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What are the properties of bacteria resistant to cephalosprins?
They have extended spectrum beta-lactamase (ESBL) encoded on a mobile plasmid, this enzyme cleaves the cephalosporin
178
What are carbapenems?
- Class of beta-lactam antibiotics
- Target pathway: inhibit peptidoglycan synthesis
- Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
179
What are the properties of bacteria resistant to carbapenems?
- Resistant bacteria have a carbapenemase enzyme encoded on a transposon mobile genetic element
- This enzyme cleaves the antibiotic
180
Why is Klebsiella pneumoniae a problem in hospitals?
- Important cause of UTI and respiratory tract infections
Risk group: immunocompromised
- High proportion of resistance to 3rd gen ephalosporins, fluroquinolones and aminoglycosides
181
Why is Pseudomonas aeruginosa a problem in hospitals?
- Important cause of infection in immuno-compromised
| - High proportions of strains are resistant to several antimicrobials
182
What is methicillin?
- Beta-lactam antibiotic
Target pathway: Inhibit peptidoglycan synthesis
Target protein: Inhibit the activity of penicillin binding proteins (PBPs)
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How is resistance to methicillin achieved?
- Expression of additional penicillin binding protein (PBP2A0
- PBP2A has 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
184
Why is Vancomycin resistant Entercoccus faecium (VRE) a problem in hospital?
- Third most frequently identified cause of nosocomial blood stream infections (BSI
- Vancomycin resistance is around 60%
185
What is Vancomycin?
Target pathway: inhibits peptidoglycan synthesis
| Target: binds to peptidoglycan precursor
186
How is resistance to vancomycin achieved?
- Multiple proteins genes encoded on plasmid or transposon
| - Results in the synthesis of a different peptidoglycan precursor
