W9L11 - Infectious Disease Flashcards
Innate Immune System - First Line of Defence
Non-specific defence Includes: 1. Mechanical barriers - intact mucous membrane - intact skin 2. Normal flora - competition 3. Secretions - mechanical removal and germicidal action - sebum (oil) pH 5 - antimicrobial peptides - acid in gastric juice - spermine and zinc in semen
Innate Immune System - Second Line of Defence
Serum
- complement, a series of 20 proteins, adhere, initiate inflammation, membrane lesions, opsinisation
- other anti-microbial peptides (e.g.) interferon, acute phase proteins)
Cells
- polymorphonuclear cells (neutrophils, eosinophils and basophils etc.)
- monocytes/macrophages/dendritic cells (phagocytic - present
antigen)
- natural killer cells (NK), type of lymphocyte, (recognise viral
infected cells and kills them)
Interferons
Broad spectrum anti-viral agents
Three groups IFNα (14 types), IFNβ and IFNɣ
Produced in response to viral infection
Binds specific receptors of neighbouring cells
- neighbouring cell produces protein kinase R (PKR) which blocks virus entry
- limits spread of viral infections
- stops production of protein in cell (inhibits virus
production)
- stimulates endonuclease production which degrades viral mRNA
- stimulates NK cells and macrophages
Detecting an Infection
Pathogen associated molecular patterns (PAMP)
- non-antigen
- conserved microbial structures (repeat polysaccharides)
Pattern recognition receptors (PRR)
- on innate cells (dendritic cells)
- detect PAMPs
- e.g. toll-like receptors
Extracellular Infections - Adaptive
The infecting agent is detected and phagocytosed by APC (dendritic cells)
Cell moves to lymph node, maturing, presents
antigen to TH (CD4) via MHC-2
B cell activation
- direct contact with Ag - T independent (low affinity
IgM)
- with T cell help (high affinity IgG)
Antibody production and memory B cells
Humoral response
Intracellular Infections - Adaptive
Infection of host cell (viruses, some bacteria and parasites)
Host cell presents antigen to surface via MHC-1
Cytotoxic T cells (Tc) recognize antigen in association with MHC-1 and kill infected cell
- APC take up antigen and present to TH1 cells which stimulate Tc
Ways Microbes Evade the Immune System
Viruses became latent - no expression of viral Ag (Herpes viruses)
Produce antigenic variants - mutations, re-asortment (influenza virus)
Some viruses interfere with MHC production (HPV)
Bacteria with capsules - not digested in phagocyte (Strep. pneumoniae)
Bacteria that produce proteins that interfere with immune system
Some Bacteria hide (sequestered) in non phagocytic cells (Salmonella)
Some microbes reproduce faster than immune system can kill them
Parasites disguise surface antigens by producing host like molecules on their surface (Schistosomes)
Parasites can also release enzymes that digest Ig, INF-ɣ or proteins that induce production IL-10
Parasites can hide
Immune Response to HPV
HPV infections produce low titre of neutralising antibodies
- antibodies that prevent virus from attaching to host cells
- these antibodies are directed to L1 protein of the capsid (major protein)
- response is mostly genotype specific but some cross protect
Cell mediated response (cytotoxic T cell)
- may be key to resolving infection
- low level (mostly E7 specific, some E6)
- CTL more abundant at sight of infection
How does HPV Avoid the Immune System
HPV does not cause any major cellular damage
- no innate response, no inflammation
- HPV only infects basal epithelial cells
- HPV only produces non-secretary proteins at low levels
- No viraemia
- infected cells not lysed
- limited production of antigen for systemic presentation
- avoids cytotoxic T cells (CD8) (E5 product inhibits transportation of MHC class 1 to cell surface and E7 interrupts production of MHC class 1 - target for NK cells)
Flaviviruses
Most arbo-viruses (insect borne infections)
- yellow fever, Dengue, West Nile
- mosquito delivered infection
Some Flaviviruses (Dengue, West Nile) cause host cell to over express MHC class 1
- targets for Cytotoxic T cells
But viraemia is quick (direct to blood) and CMI takes time
Influenza
RNA virus
- single stranded RNA
- RNA mutates much more that DNA (no proof reading)
- Genome in 8 segments
Surface
- haemagglutinin (H) spikes for attachment
- neuraminidase (N) for release
- immune response (neutralising Ab) directed to H and N
Influenza - Antigenic Drift and Shift
Antigenic Drift
- minor changes due to host immune selection of mutants with slightly altered H & N (every 2-3 yrs)
- types A and B.
Antigenic Shift
- major change in H & N due to recombination between human and animal types
- segmented genome increases chances of reassortment (interchange of gene segments of two viruses in one cell)
- humans/birds/pigs
- type A.
HIV
It is a retrovirus
ssRNA, rapid mutation, no proof reading for RT, error prone
Every possible single-point mutation occurs between 10^4 and 10^5
times per day in infected person
Most important gp120 (used for attachment)
HIV Immunity
Evidence to date suggests HIV-specific T-cell responses provide protective immunity
HIV exposed individuals who do not become persistently infected:
- develop HIV-specific cytotoxic T-cells and T-helper cells
- develop HIV Abs
- abs do not neutralize?
- immune system does not clear infection
Some epitopes must be conserved in gp120 to bind to CD4
- mutation in Envelope are sparse in escape virus and did not map to epitopes?
The ‘Glycan Shield’ of HIV
gp120 is highly glycosylated
Long stretches of sugar molecules coat surface
Mutations occurred in N-linked glycosylation sites
These changed the position of stretches of sugar (shielding the epitope)
- preventing antibody attachment
- but allowing receptor binding
CD4 cells becomes infected
Damage due to HIV
Immune system does the damage through:
- Inflammation
- has deleterious effects on cells/tissue if not limited
- reactive oxygen species and destructive enzymes - Cytokine Storm
- overproduction of cytokines in response to an infection
- up to 150 different mediators
- primary cytokines TNF, IL-6 and IL-1
- also IFNɣ and IL-12
Superantigens
Certain bacterial toxins and viral proteins stimulate all T cells that express Vβ T cell receptor (TCR) and α chain of MHC class II Bind to both TCR and MHC class II but not binding clefts Activates a large number of T cells (5-30%) leading to release of large amounts of cytokines
Dengue Haemorrhagic Fever
4 serotypes of Dengue (1 4)
Primary infection by one type may lead to Dengue fever or be asymptomatic
Second infection with a different type lead to Dengue Haemorrhagic Fever or Dengue Shock Syndrome
- severe and often fatal without treatment
Dengue Haemorrhagic Fever - Immune Enhancement
A.k.a Antibody dependant enhancement ADE
Antibodies from the first infection bind but do not neutralise second infection (low affinity)
Monocytes have Fc
receptors and pick up virus via antibodies and disseminate through body - enhancing infection
Staphylococcus aureus
Important pathogen in humans
Production of toxins
- toxic shock syndrome (TSS), food intoxication
- one toxin in TSS is toxic shock syndrome toxin -1 (TSST-1)
- this is a superantigen which leads to a cytokine storm
Coagulase positive
- produce coagulase to form clots and aggregates of cocci to protect from immune system
Slime
- inhibits neutrophil chemotaxis and phagocytosis
Protein A
- produced by Staph aureus
- binds Fc portion of IgG
- can not cross link
- can not activate complement
- phagocytes can’t use Fc receptor
Tuberculosis
Mycobacterium tuberculosis is an obligate intracellular bacterial pathogen
Infection taken up by mononuclear phagocytes, present to T cells => Th1 response (INF-ɣ, TNF, IL-2)
- leading to cytotoxic T cells (CMI)
Th1 activates macrophages
- large amounts of INF-ɣ produced
- granuloma formation
INF-ɣ Assay for TB
Diagnosis of latent TB
T cells respond quickly to TB antigens with production of INF-ɣ
Blood collected - early secretory antigen
target 6 added - leave overnight - measure INF-ɣ
level
More reliable than skin test
Immune System and TB
Macrophages phagocytose TB by complement receptors (opsonisation by C’)
Bacteria can survive in macrophages
- inhibiting macrophage activation
- capsule (toxic)
- inhibits phagosome formation
- invades cytoplasm avoids phagosome
- most remain dormant
Damage to tissue via immune response
- recruitment of immune cells by cytokines
- formation of tubercles (macrophages, T cells, bacteria)
- liquefaction of tubercule causes spread of bacteria leading to more immune response
Immunity and Parasites
These are extracellular infection
Ag presented by APC via MHC-2
Response in Th2 subset of CD4 cells
Stimulation of B cells => IgE production
Characterised by IgE production, eosinophilia and increase in mast cells
Eosinophils and mast cells have IgE Fc receptors
IgE binds to the surface of helminth via variable region
Two or more IgE bind and form bridge between helminth and eosinophil / mast cell force release of granules
Ways Parasites Evade the Immune System
Antigenic disguise
- synthesize host like Ag on surface
- absorb host molecules on surface
Produce chemicals that inhibit immune response
- induce production of IL10 to suppress T and B cell response
Some adult helminths induce immune response to immature worms preventing re-infection (reduce competition)
Hide from the immune system
- intracellular habitat (Malaria, Toxoplasma, Leishmania)
- surround by cyst wall (Trichinella larva)
- helminths in GI tract only
Rheumatic Fever
β-haemolytic Streptococci throat infection
Antibodies made against bacterial cell wall (M protein)
Cross react with myocardial proteins
Inflammation of heart (carditis)
Human Coronaviruses
4 common human coronaviruses
– common colds (Rhinoviruses most common)
- HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1
3 coronaviruses with high pathogenicity
- SARS-CoV (SARS-CoV-1, Severe Acute Respiratory Syndrome)
- MERS-CoV (Middle Eastern Respiratory Syndrome)
- SARS-CoV-2
SARS-CoV-2 sheds while person is asymptomatic (or presymptomatic) - rapid spread through community
- SARS-CoV-1 shedding occurs only when person is symptomatic
SARS-CoV-2 Immune Response
Most patients recover
Detectable Abs in blood, 10-15 days
More severe disease the more neutralising Abs
People with less severe disease probably due to innate response clearing virus
How long will Abs protect
- common cold CoV - abs are short term
- SARS-CoV-1 and MERS-CoV - abs last years
Abs to receptor binding domain (RBD) of spike protein for neutralisation
COVID-19
Virus invades (dose is important)
Low dose (no disease or mild disease)
IL-1b and IL-6 secreted by epithelial cells
Inflammation
- macrophages and monocytes recruited
- more inflammation, IL-6 and TNF
- dysfunctional response leads to more neutrophils and eosinophils
- less T cell response - lower engagement of adaptive immune
response
- older people have higher myeloid cells and less lymphoid cells
- drives an inflammatory response - cytokine storm => severe disease
