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
