Lecture 11 Preventing infection Flashcards
A pathogen has to
- Colonise host tissues
- Avoid host defence
mechanisms - Grow within host tissues
- Cause damage to the
host
Colonisation vs infection
Colonisation refers to microorganisms that are carried normally by the host, cause no harm and produce no overt symptoms
Infection is the invasion of a host organism’s bodily tissues by disease causing organisms. This can result in
disease. Ranging from mild, involving redness and inflammation through to more serious disease, such as bloodstream infections
What prevents infection?
Immune system – numerous cell types
Innate immunity:
NON SPECIFIC, general, IMMEDIATE response, NO IMMUNOLOGICAL MEMORY
(humoral: enzymes, cytokines) (cellular: phagocytes, NKCs, pattern receptors)(inflammation, complement system)
Adaptive immunity:
SPECIFIC to ANTIGEN, exposure-response LAG, IMMUNOLOGICAL MEMORY
(humoral: antibodies, cytokines)(cellular: B cells, T cells)(antigen processing and presentation)
Most are circulatory except:
- Alveolar macrophages (fixed macrophages and dendritic cells have protrusions to bring pathogens in)
- M cells (microfold cells in the gut, don’t have as many villi as surrounding gut cells - key mediators in pulling in pathogens through the epithelial layer (through phagocytosis, endocytosis, transcytosis) and feed to macrophages in the tissues or bloodstream)
Phagocytes- Professional Killers
The professional phagocytes are: monocytes macrophages neutrophils tissue dendritic cells mast cells
Bacteria taken up by endocytosis and destroyed within a phagolysosome
- bacteria are engulfed
- taken up into a phagosome
- ph lowers in the phagosome
- in professional phagocytes, phagosome fuses with the lysosome
- release of cell products and presentation on phagocyte surface
Phagocytes - opsonisation
Uptake can be enhanced by opsonisation
Phagocytes are the interplay between the innate and adaptive immune system:
- antibodies recognise structures on the surface of a bacteria
- macrophages have an FC receptor
- part of an antibody is called the FC chain
- if a macrophage has an FC receptor it will pick up a bacteria and coat it with antibody
- coating of a bacteria is called opsonisation
- c3b is a protein involved in the complement cascade (extra reading?) C3b has a thioester bond which makes it really reactive so it will react with amine and hydoxyl groups on the surface of the bacteria and bind to the bacteria covalently
- macrophages have a c3b receptor, stronger interaction and macrophages more likely to take up the pathogen
- if the pathogen has been subjected to antibodies (FC) and C3B uptake is a lot stronger
Phagocytes - reactive oxygen species
Professional phagocytes destroy pathogens in part through reactive oxygen species (ROS) in the lumen of the phagolysosome, but they can also be secreted by macrophages
ROS’s stem from the production of superoxide anion
(O2•− ) by NADPH oxidase. The O2•− is rapidly
transformed to numerous other reactive oxygen species
(ROS),mainly H2O2, hydroxyl radicals (OH•), and HOCl.
Known as the ‘respiratory burst’.
Professional phagocytes destroy pathogens in part through reactive oxygen species (ROS) in the lumen of the phagolysosome
Phagocytes - phagolysosome
Antibacterial effect involves acidification of the
phagosome followed by fusion with the lysosome
Macrophages acidify the phagosomal lumen by recruiting V-ATPase (H+ pump)
Phagocytes - antimicrobial peptides
Some are inserted into the membrane of the phagosome or the phagolysosome
Delivered to the phagosome by granular organelle in neutrophils and by fusion with the lysosome in macrophages
NRAMP - natural resistance associated macrophage protein (strips divalent magnesium from bacteria so they can’t grow)
Lactoferrin - host protein that strips iron: makes iron unavailable to bacteria
Antimicrobial peptides: defensins and cathelocidins: bind to the membrane causing cellular destruction
Lysosome breaks down the sugar chains in peptidoglycan
Phospholipases digest the lipid bilayer
Proteases
Phagocytes
Phagocytes - cytokines
To aid the phagocyte in microbial killing, cytokines are released causing further activation of the phagocyte and recruitment of additional monocytes
Such an effect can be mediated through the initial recognition of bacterial molecules by specific receptors present on the host cell
PAMPS (pathogen associated molecular patterns) are recognised by TLRs
DAMPS recognise host cell damage
Phagocytes - PAMPS and TLRS
Lipopolysaccharides, DNA, cell surface proteins etc are all PAMPs which are recognised by TLRs
NODS recognise peptidoglycan
Cytokines: generic term
chemokines - chemotactic and chemokinetic for leukocytes: stimulate cell migration and attract phagocytic cells and lymphocytes. Central role in inflammatory response.
hematopoetins - stimulate and regulate growth and differentiation processes involved in blood cell formation (hematopoeisis)
interleukins - produced by lymphocytes and monocytes, regulates the growth and differentiation of other cells, particularly lymphocytes and hematopoeic stem cells
TNFs - cytotoxic to tumour cells, promote inflammation, fever and shock (and some apoptosis)
see medical micro notes!
Phagocytes as antigen presenting cells (link to adaptive immune response!)
Following destruction of an ingested microbe, what happens?
Phagocytes, especially macrophages can act as antigen presenting cells (APC’s): a link to the adaptive immune response
Phagocytes as APC’s – recognition by CD8+ T cells
CD8+ T cells, cytolytic T lymphocytes
Recognise antigen presented by MHC I molecules
MHC I molecules, comprised of two polypeptides
Present antigens originating from the cytosol
APC Phagocytes killing pathways (II)
Two major killing mechanisms, perforin and the CD95
pathway
- Perforin delivered from cytoplasmic granules that fuse with the membrane of the APC forming pores to allow granzymes to enter the infected cell
- CD95 pathway, FasL expression increases on CTL
and binds to Fas on the APC leading to apoptosis.
Both pathways lead to apoptosis which rather than cell
lysis, triggers the dead cells to be taken up by nearby
macrophages
CD4 T cells
•Phagocytes are APC’s – recognition by CD4+ T cells
CD4+ T cells, T-helper cells (Th) cells. Th0, Th1, Th2
Different Th cells produce different cytokines
Need a co-receptor in addition to MHC/peptide/TCR complex (costimulation). TH1 cells aid cytotoxic t cells, TH2 cells help the b cells. The b cells go onto produce memory cells (adaptive response).
Recognise antigen presented by MHC I molecules - beta2 microglobulin is a key part of the presentation of antigen to CD8 t cells. The proteosome chops up foreign cell products from the CYTOSOL, send them to the ER to be sent to MHCI (NOT FROM THE PHAGOSOME)
MHC II molecules, comprised of two polypeptides
CD4 recognise MHC II
Present antigens originating from the phagosome, peptides slightly longer than those presented by MHC I
CD8 T cells are the t killer cells (cytotoxic), when encounters an antigen, it is activated , some turn into cytotoxic T lymphocytes, others into memory cells. CTLs secrete perforin and granzymes
Trimolecular complex: t cell receptor, MHC presentation and an antigen
CD1 presents the lipid debris - triggers natural killer t cells (different t cell again!)
LOOK AT MICRO NOTES ON CD95 and PERFORIN KILLING PATHWAYS
Summary
Invading pathogens engulfed by professional phagocytes
– Subjected to a number of antimicrobial effects
– Phagocytes, simultaneously activated through recognition of PAMP’s
Phagocytes can present degraded products to the specific immune response
These products(antigens/epitopes) recognised by T cells
B cells that produce antibodies are a memory response
T helper cells effect the adaptive immune response, and memory t cells are formed
CD4 T cells recognise antigen which originated from the phagosome, presented in the context of MHCII, along with different co receptors which trigger different T helper cells, which act to effect cytotoxic T lymphoctes of be cells.
