Case 9 Flashcards
What molecules recognise a virus in the immediate innate immune response?
Defensins, Lactoferrin, Lysozyme
Preformed soluble effector molecules
What cells recognise a virus in the immediate innate immune response?
Macrophages, Mast cells, Conventional Dendritic Cells
Some memory T cells and NK cells
How does Influenza A target the mucus barrier to infection?
Cytolytic. Causes acute cell death of ciliated respiratory epithelial cells and removal of mucous secreting cells.
Blocks muco-ciliary escalator
Sentinel Cells
First line of defence.
Macrophages, Dendritic cells and a few NK cells.
PRRs recognises
PAMPs
Which Toll-like Receptors are found within endosomes?
TLR 3, 7, 8, 9
TLR3 detects…
dsRNA
TLR7 detects…
single stranded viral RNA
TLR8 detects…
single stranded viral RNA
TLR9 detects…
Unmethylated CpG-rich DNA
intracellular viral infection
Which Toll-like receptors detect viral glycoproteins?
TLR 1, 2, 4, 6
Which TLRs are found on the plasma membrane?
TLR1, 2, 4, 6
Genetic defect in TLR3 signalling pathway is associated with…
Recurrence of Herpes Simplex Encephalitis
How does TLR3 detect HSV-1 (a DNA virus)?
HSV-1 produces a dsRNA intermediate during transcription.
TLR3 detects ds RNA.
Epstein-Barr Virus infects what type of human cells?
B cells
Pyrogens released by macrophages on detection of a virus
IL-6,
TNF-alpha
IL-1 Beta
How do pyrogenic cytokines increase body temperature?
Act on hypothalamus to produce PGE2 (innervation of SNS, non-shivering thermogenesis and vasoconstriction)
Act on muscle to increase fat and protein utilisation,
TLR activation leads to….
Transcription of type 1 interferons (alpha and beta)
RIG-1
Interferon Stimulated Gene
Rig-like receptor involved in triggering interferon expression
MD-5
Interferon Stimulated Gene
Rig-like receptor involved in triggering interferon expression
IFITM3
Interferon Stimulated Gene
Prevents entry of enveloped viruses into cytoplasm by trapping them at plasma membrane.
Where are RLRs located?
cytosol
Interferon Response Factors
Activated by PRRs on detection of PAMPs
Enter nucleus and initiate transcription of type 1 interferons
Effect of Ebola on IFNs
Shuts off supply of interferons, preventing the antiviral state.
What do cytosolic RLRs detect?
Abnormal RNA
A majority of Interferon production in conducted by…
Plasmacytoid Dendritic Cells (pDCs)
Contain extensive rough endoplasmic reticulum.
Plasmacytoid Dentritic Cells are located…
Blood and lymphoid tissue
Plasmacytoid cells express TLRs…
7 and 9
Conventional Dendritic Cells - role…
Activation of naive T cells
Conventional dendritic cells are located (in the absence of infection)…
In peripheral tissues
Why are MMR vaccines not given singly and a week apart?
Interferon response to first vaccine would suppress replication of the second vaccine - diminished immune response.
Would need to be given 30 days apart (child is vulnerable to infection at this time)
NK cells release…
Perforins
Granzymes
IFN-g
Effect on macrophages of IFN-g release from NK cells
Makes macrophages more efficient at phagocytosis
Function of conventional dendritic cells
Transports antigen from site of infection to secondary lymphoid tissues
Cells which express MHC I
Found on surface of all nucleated cells.
MHC I display non-self proteins to…
Cytotoxic T lymphocytes
MHC II display non-self proteins to…
T Helper Cells
CD4
Glycoprotein expressed by T Helper Cells
Involved in detection of MHC II
CD8
Glycoprotein expressed by cytotoxic T cells.
Involved in detection of MHC I
Vaccination into deltoid will reach which secondary lymphoid tissue?
Axillary node
Vaccination into quadriceps will reach which secondary lymphoid tissue?
Inguinal node
Route of administration of influenza vaccine in children
Oral/Nasal
Route of administration of Rotavirus vaccination
Oral/Nasal
cDCs in Peyer’s Patches and Mesenteric Lymph Nodes of Intestines detect pathogen.
Immunoglobulin produced in adaptive immune response is?
IgA
cDCs in Axillary/Inguinal Lymph Nodes of Intestines detect pathogen.
Immunoglobulin produced in adaptive immune response is?
IgG
CCR7
Directs cDC to nearest draining lymph node
Lymph from upper body eventually reaches…
Right lymphatic duct
Lymph from lower body eventually reaches…
Thoracic duct
Intracellular antigens processed into peptides by
Proteasome
Extracellular antigens processed into peptides by…
Endosome used to bring antigen into cell
Why are live-attenuated vaccines the best way to achieve a CTL response?
Only live viruses can replicate intracellularly and be presented by MHC class I
CD4 and CD8 are examples of…
Co-receptors
Function of US6 protein in Human Cytomegalovirus
|nhibits peptide loading of MHC class I. Allows virus to evade recognition mechanisms.
2 Signals for full activation of CTLs by cDCs
- Binding of TCR with MHC:Peptide complex
2. Binding of C7 (upregulated by step 1) with C28 on surface of CTL
Swelling of lymph nodes occurs due to proliferation of which cells?
CD8 T cells/ Cytotoxic T Cells
Function of IL-2
Promotes proliferation and differentiation of T cells (into memory and effector cells)
On detecting virally infected target cells, CTLs release…
Perforins and Granzymes
TH1 cells
Migrate to infected tissues from lymph node to help macrophages
Function of Follicular Helper T cells
Stimulate somatic hypermutation of variable region of immunoglobulins on the surface of B cells.
Antibody on surface of B cells (prior to somatic hypermutation)
IgM
Activated Induced Cytidine Deaminase
Catalyses somatic hypermutation
Hyper IgM Syndrome
Mutation in gene which codes for AID.
B cells can only express IgM on their surface.
Linked Recognition
B cells and T cells must recognise epitopes of the same molecular complex in order to interact.
i.e. Both cells must recognise the antigen to interact.
Conjugate vaccines used for…
Encapsulated bacteria (covered in polysaccharide coat)
Conjugate vaccines consist of…
Protein and polysaccharide
What type of RNA is mRNA?
Positive, single stranded
Function of envelope of a virus
Syncytia formation - allows virus to utilise membranes of host cells.
Non-enveloped viruses are found…
In GI tract (since enveloped viruses cannot survive here)
DNA viruses mutate less frequently than RNA viruses because…
DNA polymerases have a proofreading function (RNA polymerases do not)
Treatment for Genotype 1 Hep C Infection
Sofosbuvir (nucleotide analogue)
Ledipasvir (inhibits viral infection)
Ribavirin (guanosine analogue, blocks RNA synthesis)
Interferons are not used for treatment of infection since…
They cause suicidal thoughts in patients
Pandemic
An epidemic that becomes very widespread, affecting a whole region/continent (may be worldwide).
High mortality.
Forms of Hepatitis spread by contaminated food and water..
A and E
HPV serotype causing cervical carcinoma
16 and 18
HPV vaccine protects against what percentage of cervical carcinomas?
70%
Inactivated polio vaccine protects against…
PV1, PV2 and PV3
Herpangina and Hand-Foot and Mouth Disease are caused by…
Cocksackie A Virus
Clinical Presentation of Cocksackie A virus
Sores in and around the mouth
Form of Hepatitis causing Hepatocarcinomas
Hep C
Clinical Presentation of Dengue Virus
Haemorrhagic Fever: Flushing of face and chest, Oedema, Bleeding, Samll red and purple spots (Petechiae)
Vaccination needed to go on a trip down the Amazon river
Yellow Fever
Major complications of pertussis infection
Weight loss (vomiting) Cerebral Hypoxia (Dyspnoea from cough) Bronchopneumonia
Pertussis infection lasts…
2-3 months
Effect of cytotoxin produced by B.Pertussis
Stops cilia from beating.
Unable to clear mucus from lungs.
Whole Cell Pertussis Vaccine
Reactogenic (seizures, high fever and brain damage)
Longer lived immunity
Acellular Pertussis
Non Reactogenic
Short lived immunity
Immunity resulting from whole Cell Pertussis vaccine is mediated by…
TH17 and TH1
Immunity resulting from Acellular Pertussis vaccine is mediated by…
TH2
Definition of an adjuvant
Substance which enhances immune response to antigens by bringing antigen into contact with immune system
Examples of adjuvants
Aluminium phosphate
Aluminium hydroxide
Molecule responsible for reactogenesis in Whole Cell Pertusis
Endotoxin
How does TH17 elicit immunity to B.Pertussis?
Releases IL-17 which recruits more neutrophils from bone marrow.
Neutrophils mop up extracellular bacteria.
Rubalavirus
Virus causing mumps
Spread of Mumps
Direct contact or droplet
Early symptoms of mumps
Fever Malaise Headache Anorexia Photophobia Earache
Late symptoms of mumps
Swelling of salivary/parotid glands (‘Hamster face’)
Hearing loss
Orchitis
Oophorytis (7%)
Complications of mumps
Encephalitis
Meningitis
Parotitis (Parotid glands)
Permanent Deafness
Diagnosis of mumps
Saliva (Mumps-specific IgM)
Urine
Observations
High serum amylase levels
Treatment of mumps
Treatment of symptoms e.g. Pyrexia using paracetamol
Genes coding for MHC are located on..
Chromosome 6
Why is herd immunity not effective against tetanus?
Tetanus is not transmitted from person to person
HPV strain causing genital warts
6 and 11
Spread of HPV
Skin-to-skin
Diagnosis of cervical cancer
Pap smear
Cervarix
2 in 1 HPV vaccine
Protects against HPV 16 and 18
Gardasil
4 in 1 HPV vaccine
Protects against HPV 6, 11, 16 and 18
Side effects of HPV Vaccine
Fever, Nausea, Rash, Itch, Headache, Dizziness
Structure of HPV Vaccine
L1 capsid protein of HPV
No viral DNA, non infectious
Neutralising antibodies
IgG and IgA
Block viral entry and uncoating
Antibody which transports across epithelium
IgA
Antibody which diffuses into extravascular sites
IgG
Antibodies which activate complement
IgM, IgG, IgA
Antibody which activates mast cells
IgE
Mechanism of neutralising action of IgA and IgG
Block attachment of virus
Block endocytosis of virus
Block uncoating of virus in endosome.
Why is intranasal administration of influenza vaccine more effective than injected?
Stimulates production of mucosal IgA antibodies.
Site of infuenza infection is mucosa.
Injection stimulates production of IgGs
Advantage of Live attenuated Sabin Poliovirus vaccine
Elicits a strong mucosal IgA response - intestinal immunity
Disadvantage of Injected Salk Poliovirus Vaccine
Does not produce intestinal immunity - less effective at preventing spread of poliovirus in a population.
Antibody involved in opsonisation
IgG
Phosphatidylserine
Membrane lipid found on surface of apoptotic cells.
Recognised by macrophages clearing debris from apoptosis.
Memory response (i.e. to an antigen the immune system has encountered before)
Faster
Longer duration
Greater quantity (by 100-1000x)
Higher affinity of Abs
Virulence of Hib
Encapsulated in polysaccharide coat.
Prevents fixation by alternative pathway.
Requires high affinity IgG to overcome this.
Main cause of meningitis in the UK
Haemophilus Influenza B
Early symptoms of meningitis
Fever
Irritability
Vomiting
Loss of appetite
Symptoms of meningitis in babies
High pitched, moaning cry Drowsy Stiff with jerky movements Pale and blotchy skin Turning blue Fever with cold hands and feet Non blanching rash
Transmission of Hib
Aerosol (coughing and sneezing)
Proteins usually used in conjugate vaccines
Tetanus or diphtheria toxoid proteins
Principle antibody of all bodily secretions
IgM
B cells exposed to IL-4
Isotype switching to IgE
End result of Hib vaccination
Secretion of high affinity, opsonising IgG
Examples of encapsulated bacteria:
Hib Steptococcus Pneumoniae Neiseria Meningitidis E. Coli Klebsiella Pneumoniae
Immunisations at 2 months
DTaP/IPV/Hib
PCV
Rotavirus
Immunisations at 3 months
DTaP/IPV/Hib
Men C
Rotavirus
Immunisations at 4 months
DTaP/IPV/Hib
PCV
Immunisations at 12-13 months
Hib/MenC
PCV
MMR
Immunisations at 40 months
DTaP/IPV
MMR
DTap/IPV/Hib immunisation given at
2, 3 and 4 months
Rotavirus immunisation given at
2 and 3 months
Route of administration of rotavirus vaccine
Oral
What type of vaccine is MMR?
Live attenuated
Purpose of Yellow Card Scheme (Vaccinations)
Reporting of all suspected reactions to vaccinations
Shingles vaccine is given to…
Patients over 70yrs
Course for Hep B Vaccination
3 dose = 0, 1, and 6 months
4 dose = 0, 1, 2 and 12 months
Single booster 5 years later
Immunisations for Health Care Workers
Influenza, BCG, Hep B, VZV MMR
Immunisations for patients over 65
Flu
PPV (Pneumococcal Infection)
Immunisations for patients over 70
Shingles
Immunisations for injecting drug users
Hep A and Hep B
Immunisations for MSM (Men who have Sex with men)
Hep A and Hep B
Immunisations for pregnant women
Influenza
Pertussis (aP)
HLA genes code for…
MHCs
Viral Envelope
Layer on the outside of a viral capsid, making the virus more fragile.
Makes it sensitive to drying out.
How are viruses able to grow in a short period of time? (Burst/Yield)
Grow by assembly of preformed components
mRNA is
Positive ssRNA
Enzymes used to generate cDNA in retroviruses
Reverse transcriptase and RNA-ase H
Plasma associated viraemia occurs in…
Polio (acute)
Cell-associated viraemia occurs in…
Epstein-Barr Virus (affects B cells)
HIV (affects T cells)
Human Cytomegalovirus (affects myeloid cells)
Influenza incubation period
1-2 days
Herpes simplex incubation period
5-8 days
Measles incubation period
9-12 days
Mumps incubation period
17-20 days
How does Herpes Virus become persistent?
Downregulates MHC expression - B cells do not recognise infected cells.
How does HIV become a persistent virus?
Rapid mutation enables it to evade CTLs.
Since T cells are generated for a specific virus, they cannot kill mutated HIV.
How are Hep B and Hep C similar?
Transmission via bodily fluids (semen, vaginal secretions, blood)
Viruses using the lung as primary tissue of replication:
Rhinovirus
Measles
Influenza
(Adenovirus, Coronavirusm Parainfluenza, Respiratory Syncytial virus)
Paramyxoviruses…
Measles
Respiratory syncytial virus and parainfluenza virus
Difference between Parainfluenza virus and Respiratory Syncytial Virus
PIV in children <3yrs
RSV in children >3yrs
Both are paramyxoviruses causing respiratory infection in immunocompetent children.
What is croup?
Barking cough
Stridor when breathing in
Surface proteins found in lipid envelope of Influenza Virus
Hemagglutinin
Neuraminidase
(M2 ion channel protein found additionally in Influenza A)
Complications of Influenza
Otitis Media
Pneumonia
Bronchitis
Myocarditis
Symptoms of influenza
Headache Shivers Myalgia Cough Fatigue
How does onset of common cold compare to influenza
Influenza = sudden onset
Common cold = Prolonged onset
Duration of severe symptoms of influenza
8-10 days
Epidemic caused by…
Antigenic Drift - progressive small changes in envelope proteins through mutation.
Antigenic Drift
Progressive small changes in envelope proteins through mutation
Leads to epidemic
Pandemic caused by..
Antigenic Shift - Sudden massive changes in envelope proteins through reassortment.
Antigenic Shift
Sudden massive changes in envelope protein through reassortment
Leads to pandemic
MOA of Amantadine
Inhibits M2 ion channel in viral envelope - preventing viral replication
Amantadine is used in treatment of
Influenza A
ADRs of Amantadine
GI disturbance, CNS effects
MOA of Feramivir/Oseltamavir
Neuraminidase inhibition.
Protein found in viral envelope which allows virus to bud from host cell.
Prevents viral replication.
ADRs of Feramivir/Oseltamavir
GI disturbance, Headache, Neuropsychiatric events
Feramivir/Oseltamavir used in the treatment of…
Influenza A and B
Contraindication for live attenuated vaccine
Immunosuppressed
Types of Influenza Vaccine:
Injection (Enzira, Fluzone)
Nasal Spray (Flumist) - USA
Influenza Vaccine recommended for:
People >65yo Chronic Respiratory Disease (e.g. Asthma) CVD Renal Disease Diabetes Mellitus Immunocompromised In residential long-stay accommodation
Symptoms of Measles
Enanthema/Koplik Spots - red spots in mouth
Makulopapulous Exanthema - red spots on skin
Tracheobronchitis
Laryngitis
Fever
Complication of Measles
Subacute Sclerosing Panencephalitis (delayed CNS disease, no cure)
Subacute Sclerosing Panencephalitis
Complication of persistent measles.
Elevated measles virus in CSF.
Satellite Virus to Hep B
Hep D
Symptoms of Viral Hepatitis
Icterus (yellowing of sclera and skin surrounding eyes)
Palmar Erythema
Ascites
Caput Medusae
Treatment of Hep B
Reverse Transcriptase Inhibitors - Tenofovir or Lamivudine
Hepadnavirus causes
Hepatitis B
Flavivirus causes
Hepatitis C
Features of Liver Cirrhosis
Gynaecomastia Testicular Atrophy Oedema Ascites Spider naevi Impaired immunity Splenomegaly
Why does liver cirrhosis cause gynaecomastia and testicular atrophy?
Impaired metabolism of oestrogen
Why does liver cirrhosis cause splenomegaly?
Portal Hypertension
Why does liver cirrhosis cause oedema and ascites?
Low albumin, increased hydrostatic pressure of blood.
Interferon alpha therapy is used for
Hepatitis B and C
ADRs of interferon therapy
Flu-like symptoms, anorexia, fatigue
Picorna Virus Causes
Hepatitis A
Transmission of Hepatitis A
Faeco-oral
Risk factor for Hep A
Poor sanitation
Travellers
Homosexual men
Hep E is caused by
Calicivirus
NANB (Hepatitis)
Non A and Non B
Dysfunctional cell in HIV
T cell
Pneumocystis Carinii
Opportunistic bacteria causing pneumonia in patients with HIV
Karposi’s Sarcoma
Lesions in skin, mucous membranes, nose, throat and lymph nodes.
Caused by poorly controlled HIV.
How does HIV lead to AIDS?
Depletion of CD4 T cells
Allowing opportunistic infection to occur e.g. thrush
First line treatment for HIV
2 x Nucleoside reverse transcriptase inhibitors
Plus
Non nucleoside RT inhibitor OR
Protease Inhibitor
Nucleoside Reverse Transcriptase Inhibitors (treatment of HIV)
Abacavir
Lamivudine
Tenofovir
Protease inhibitors (treatment of HIV)
Amprenavir
Darunavir
Fosamprenavir
Why does immunocompromise increased risk of cancer?
Immunocompromised patients are less likely to be able to control cancer growth.
MOA of Aciclovir
DNA polymerase inhibitor (guanosine analogue)
ADRs of Aciclovir
Abdominal pain
Diarrhoea
(topical) inflammation
Irritation
Contraindications of Aciclovir
Elderly (may cause adverse neurological reactions)
Indication of Aciclovir
HIV
VZV
MOA of Zidovudine
Reverse transcriptase inhibitor
Thymidine analogue
ADRs of Zidovudine
GI disturbance
Fatigue
Flu-like symptoms
Contraindications of Zidovudine
Haemopoietically Suppressed
i.e. Low Hb +/- low neutrophils
Indication for Zidovudine
HIV
Indication of Oseltamavir
Influenza
Contraindication of Oseltamavir
Pregnancy (BUT benefit:risk analysis may be carried out in pandemic situation)
ADRs of Oseltamavir
GI disturbance Abdominal Pain Dyspepsia Headache Nausea and Vomiting
MOA of Ribavirin
Nucleoside mimetic
Causes viral hypermutation during RNA synthesis
Indication of Ribavirin
Hep C
Contraindications of Ribavirin
Pregnancy (Terratogenic)
Cardiovascular Disease
Common ADR of Ribavirin
Depression
Serious ADR of Ribavirin
Haemolytic Anaemia
Symptoms of Rubella
Rash Fever Swollen lymph nodes Aching joints Cold-like symptoms
Treatment of Rubella
Paracetamol/Ibuprofen
Drinking water
Treat cold-like symptoms
Describe the rubella rash
Small red-pink spots.
Starts behind ears, spreads to head and neck, then trunk
Features of congenital rubella syndrome
Small head Eye defects Heart problems T1DM Over/Underactive thyroid
Ruth Griffiths Assessment
Formal assessment of development
Tonic Neck Reflex
“Fencing Reflex” seen in newborns (up to 1 month)
When the head is turned to one side, the arm and leg on that side are extended. The arm and leg on the other side are flexed.
Primitive reflexes seen in newborns:
Tonic neck reflex
Grip reflex
Step reflex
Crawl reflex
Average weight of newborn
3.5kg
Average length of newborn
50cm
Average OFC (Head circumference) of newborn
35cm
How many days after birth is weight gain seen?
10
When a 0-3 month old is supine…
Head is turned to one side
When a 0-3 month old is prone…
Props on forearms
Gross motor function in 0-3 month old:
Prone - props on forearms
Supine - head turned to one side
Minimal head lag when pulled to sit
In child development, when should a child begin to sit?
5-9 months
Gross motor function in 3-6 month old:
Rolls from prone to supine
Pushes up on extended arms when prone
Sitting (5-9 months)
When does stranger anxiety develop?
9 months
Protoimperative vs protodeclarative pointing
Protoimperative - point at something you want (9 months)
Protodeclarative - point at something to show interest (1 year)
Gross motor function at 1 year old
Walking (average 13 months)
Cruising (with support)
Crawls up stairs
Pincer grasp develops at…
1 year
Cognitive function in 1 year old:
Knows function for objects
i.e. comb for hair, hoover for floor
Gross motor function in 2 year old:
Running
Kicking
Stairs (2 feet/step)
Fine motor function in 2 year old:
Scribbling
Builds 2-3 cube tower
Turning of pages
Hand preference
Speech and language function in 2 year old:
50 words
some 2 word phrases