Chapter 17: Innate Host Defenses Flashcards
two parts of the immune system of mammals
innate or nonspecific immunity
adative or specific immunity
innate immunity is a pre-existing (pre-infection) system of cells, tissues and organs and molecules
Physical Barriers - SKin
3 layers to the skin: epidermis, dermis and hypodermis
epidermis is dead cells, dermis and hypodermis are living cells
hypodermis is the connective tissue and fats
dermis is live cells (approx 15 layers) that pass up, and dessicate upwards at the same time as filling up keritin. (add lipids for waterproofing)
=> kerritin is very hard for fungi and bacteria to digest
immune system in bacteria
restriction enzymes and crisper
Physical barriers
skin
mucous membranes
endothelia
bacteria cannot penetrate through intact skin
only exception is S. aureus causes scalded skin syndrom => produciton of enzyme that can cut the connective fibres that holds the layers of skin together, give them access to breach this physical barrier.
fungi can cause superficial skin infections in tropical climates
Epidermis
consists of dead cells filled with the protien keratin and lipids
resistant to mechanical attack - bacteria and viruses cannot penetrate it
mostly dry, salt, and acidic - inhibits bacteria, especially gram-negatives
dessicated epidermis is not very nutritious
fatty acids secreted onto skin are toxic (from lipases)
=>
secretion of lysozyme (breaks down peptidoglycan)
desquamaiton
skin cells slouphing off
help to get rid of bacteria on the surface of your skin
dry skin vs wet skin
there is 100-1000fold more bacteria that live on wet skin than on dry skin per square centimeter
sweating
increases salt conc. on skin to dessicate the microbes
especially helps to inhibit gram negative bacteria
What kind of bacteria moslty live on skin
mostly gram negatives, and a few gram positives
salty sweat to inhibit the growth of gram negative bacteria
Dermis
contains hair follicles, sweat and oil glands and blood/ lymphatic vessels (carry immune cells to skin)
=> the dermis contains parts of the adaptive immune system as well
the hypodermis contains fat and connective tissue
Mucosal membranes
usually a single layer of epitheliad cells covered with a thick (or thin) layer of mucus which trap debris and microorganisms
lines the respiratory tract, difestive tract and urinary tract
mucus is mobile, flushes away trapped microorganisms, in respiratory tract ciliated epitheliad cells propel the mucus (cilia plus peristalsis from the muscular movements) => especially important in the respiratory tract. With out this cilia you can become much more susceptible to streptococcus pneumoniae
Endothelia
epitheial cells line the urogential tract, blood vessesl, and lymphatic system vessels
tight junctions between cellst to prevent bacteral and fungi from passsing through (prevent bacteria from entering capillaries)
also forms the blood-brain barrier to protect CNS
Mechanical defenses
shedding (exfoliation) of skin cells
expulsion of mucus from lungs and movement of mucus in gastrointestinal tract
flushin of urine (low pH)
Tears (also contain lysozyme)
hairs in nose, design of upper respiratory tract (nose hairs, and 90 degree bend of throat to nasal cavity to incoming air hits the back of the throat)
Chemical defenses
olic acid
Lactoperoxidase system
acidic skin
defense in depth
=> not just one single defense
=> reduces the likelyhoood that any one microorganism can get through
lactoperoxidase system
lactoperoxidase oxidises oxidises iodide, bromide, and thiocyanate using hydrogen peroxide to produce hypoiodide, hypobromite, and hypothiocyanite (IO-, BrO-, OSCN-) which in turn oxidize proteins in pathogens
hydrogen peroxide is produced by glucose oxidase
found in saliva, mucus, and milk
Oleic acid
produced by skin microorganisms from sebum lipids
=> low pH and toxicity of long chain fatty acids
sebum is cleaved into a glycerol and long chain fastty acids like oleic acids, (long chain fatty acids are fairly toxic to microorganisms)
lysozyme
an enzyme whihc hydrolyzes the glycosidic bond between NAG and NAM in peptidolygan
effective agaisnt most gram positive bacteria
=> some bacteria modify their peptidoglycan to become resistant to lysozyme (prevents the enzyme form binding to it)
=> other enzymes are also present to attack peptidoglycan like proteases and such
found in tears, saliva, mucus, on skin
=> why milk is naturally semi-antibiotic, unfortunately, pasturization denatures this enzyme activity
Lactoferrin
a protien which binds to and sequesters iron
lack of iron inhibits the growth of most microorganisms
(important because iron is needed in relativly high abundance in cells)
=> why bacteria perform haemolysins and synthesis sidirophores to trap iron
found in tears, saliva and muscus
Lactic acid
fermentation of glycogen in urinary tract to lactic acid
glycogen is secreted into the urinary tract
lactic acid bacteria ferment this
lactic acid or really protonated organic acid is toxic// antibacterial
Surfactants
produced in the alveoli by type II cells (at the bottom of the respiratory tracts, bottom of alvioli?)
breaks surface tension
consist of lipoproteins and phospholipids
phopholipids act as detergents, include dipalmityoulphophatidycholic, phosphatidylcholine, phosphatidylglycerol and cholesterol
lipoproteins SP-A and SP-D are collectins, they bind to the surface of bacterial cells and activate the complement system
=> collectins make bacteria sticky? and help macrophages eat them
Transportation of antibiotics into Gram negative cells
use a siderophore that a Gram negative produces, covalently ligate it to an antibiotic. The bacteria will take up the siderophore, and trojan hore antibiotic is brought into the Gram-negative cells
not needed with Gram positives because their is not an outer membrane you have to worry about
antimicrobial peptides
AMPs
a number of different short protiens or poptides that are produced by all mammals and many other organsims
=> short protiens, 30 aa or 60aa
generally contain positively charged aa and hydrophobic aa and so AMPs are amphiphilic
usually act on the membraneand cause pores to form
(not all do this tho)
broad spectrum (the positive charges are important here. Positive charged AMPs attack negativley charge bacterial cell walls. Whereas they are repelled by our neutral to slightly positive cell membranes, usually)
some have other roles to inhibit microorgansims from the inside = proteins/ cell wall synthesis, DNA daamage
=> or can collapse proton gradients and such
some have dual functions
secreted by skin, epitheliad cells, marcrophage and neutrophils
Two classes of AMPs
defensins and cathelicidins
Cathelicidin
in humans, LL-37, a peptide of 37aa and 2 adjecent leucines
L-37 disrupts membranes and is effective against bacteri, fungi and viruses
Defensins
are bount 30aa, cationic peptides with many cysteines, also disrupt membranes and is effective against bacteria , fungi and viruses (viruses with lipid membranes)
less active agaisnt mammalian cell membranes
Acute phase proteins
generally antibacterial
secreted by liver cells and circulate in the blood, increase in response to inflammaiton and infection (in the blood)
C-reactive protiens (CRP)
ferritin and transferrin
= iron binding proteins
mannose-binding lectin (MBL)
lectins are proteins that bind carbohydrates
AMPs as theraputics
trying to use them as antibiotics
hard for a microorganism to become generally resistant to AMPs
problem = you own body will degrade foreign AMPs
Complement system
a number of protiens found in the blood which become activated by certain triggers and have antibacterial activity
most important are the C1 to C9 protiens
cleavage of a C protein into Ca, Cb leads to activation and the cascade
3systems of complement activation = classical, alternate, and lectin binding
Result i the formaiton of the membrane attack complex (MAC) which creates pores in membranes
Other functions of complement system
opsonization, inflammation, and chemotaxis
Opsonization is the process of attaching a compound/ protein to the surface of a bacterium which allow macrophage to detect and phagocytize them more quickly
Cytokines
small soluable protein or peptide messengers
produced by immune system cells but also other cells types and usually activate other immune system cells
BInd to receptors on cell surfaces
=> interleukins secreeted by WBCs and act moslty on other leukocytes
(IL-1, IL-2, IL-6…)
Chemokines attract cells to the sites of infecitons (inflammaiton)
=> CXC-x, CC-x, RANTES, MIP, MCP-1
Interferons
primarily anti-viral defense
TYPEW 1 interferons (a and b) are produced by cells infeced with a virus and act on neighbouring cells
stop these cells from making RNA and DNA and protien which are the components of viruses
Type II IFN gamma is an immune system cell activaotr and an inflammatory agent
Two cell lineages
myeloid and lymphoids
both derived form pluripotent hematopoietic stem cells
Lymphoid stem cells produce NK cells, and T and B lymphocytes
Myeloid stem cells
myeloid stem cells produce megakaryocytes which produce platelets and also erythrocytes, mast cells and myeloblasts
myeloblasts give rise to basophils, neutrophils, eosinophils, and monocytes which give rise to macrophage and DCs
Neutrophils (polymorphonuclear neutropils, PMN)
pphagocytose bacteria in blood stream and in tisuse
granules contain antibacterial compounds, can be released our of the cells
create extracellular DNA meshes or traps which contain lactoferrina nd myeloperoxidase
eosinophils
mostly for defense against protozoa and multi-cellular parasites
basophils
release substances (histamine) which promote inflammation
mast cells
also release substances whcih promote inflammation
migrate into the tissues
Natural killer cells
drecognize and kill abnormal cells including those infected with viruses and macteria
induce abnormal cells to udnergo apoptosis using perforin and granzymes
do not need activation
Monocytes
macrophages and Dendritic cells
macrophage leave bloodstram and enter tissue (unlike neutrophils) where they differentiate into tissue-specific (tissue resident) macrophage, often have different names
Neutrophils also have multi-lobed nuclei
macrophages also help to get rid of cellular debris, M2 type is anti-inflammatory
(M1 is pro inflammatory)
phagocytic and produce cytokines
DC capture antigens and present them to leukocytes
Extravasation or Diapedesis
passage of leukocytes from the bloodstream into tissues
cytokines and complement protien C5a attract the leukocytes and cause capillary endothelial cells to produce molecules which the leukocytes attach to
when leukocytes reach an endothelial cell-cell junction they bind, flatten out and squeese through the junction into the tissue
=> Transendothelial migration
Pathogen recognition
pathogen associated molecular pattens (PAMPs)
overall types or categories of macromolecules, not specific
found on the surface of bacteria and fungi
- peptidoglycan
- flagellin
- lps
- nucleic acids, = dsRNA
Recognized by pattern recognition receptors (PRR) which are protiens on or inside phagocytic cells (and othe cell types)
PRR activation
PRRs are activated by PAMPs (or DAMPs)
PRRS are protiens on or inside phagocytic cells and other cell types
upon binding of PAMP to PRR, the phagocyte is activated
also allows phagocytes to recognize damaged cells and remove them
Pathogen degredation
phagocytosis is the engulfment of a particle (pathogen) by a macrophage or neutrophil
forms a membrane enclosed phagosome
lysomes are membrane enclosed vesicles containing antibacterial enzymes and compounds
lysosomes fuse with phagosomes to form phagolysomes and the pH drops activating the antibacteral enzymes
=> lysozyme, phospholipase and proteases
respiratory burst
Respiratory burst
increases in oxygen uptake to produce ROS such as H2O2, O2* and *OH
Inflammation and fever
due to increased permeability of the blood vessels
=> histamine released by mast cells
=> fluid enters tissue(ie swelling = edema)
Cells migrate into tissue
=> macrophages and neutrophils
=> They can release proinflammatory compounds
Also redness (erythema), heat, pain and altered function
Chronic inflammaiton
inflammation usually only lasts a few days, if longer it is chronic
due to the presence of pathogens or abnormal regulation of inflammation
may lead to formation of granulomas which wall off pathogens
=giant multinuclear macrophage cells
=> other cells including fibroblasts
=> Formation of collagen fibres and caalcium deposition
Chronic inflammaiton and alterations to tissue
formation of collagen fibres
remodelling of tissue
(chronic inflammation activates leukocytes which secreate proteases, thus preventing tissue repair and remodelling)
also prevents M1 => M2 conversion, M2 cells promote angiogenesis
Fever
increase in body temperature due to exogenous pyrogens (LPS) and or endogenous pyrogens (IL-1 and TNF)
may help in slowing virus replication
may help in immune cell functiona nd replicaiton
