MIrocm 442 Ch 5-7 Flashcards
Includes external defenses and internal defenses
innate immunity (1st line of defense)
-primary response takes time
-targeted to specific microbes
-clonally rearranged receptors
-immunologic memory
adaptive immunity (takes days initially)
-physical and chemical barriers
-mucous membranes
external defenses
-complement
-phagocytic cells
-pattern recognition receptors
-inflammatory response
internal defenses
-antibodies via plasma cells
-cell-mediated response (t-cells)
humoral response
thick layer of dead cells in the epidermidis
skin
contain lysozyme, which digests peptidoglycan
tears
antibacterial enzymes
saliva
mucus and cilia trap and remove organisms
respiratory
-mucus=viscous, contains antimicrobial properties
-inner mucus=essentially sterile
-cell surface mucins prevent pathogen binding
GI tract mucosa
thick due to secretions
mucus
most bacteria in GI tract is in
outer layer
secrete gel-forming mucins
goblet cells
secrete antimicrobial defensins and other proteins
paneth cells
transport antigens from gut lumen to cells of immune system
M-cells
the 3 pathways of complement activation
classical, lectin, and alternative
links innate and adaptive arms of the immune system -> antigen-antibody complexes
classical
mannose-binding lectin, lectin=protein that binds to sugar, recognizes bacterial sugars
lectin
pathogen surfaces -> biophysical characteristics of pathogen surface allows inactivation of complement
alternative
outcomes of complement activation
- inflammation and chemotaxis
- osponization (removal of pathogens)
- pathogen lysis (membrane attack complex)
genetic deficiencies in terminal complement components predispose to…
Nisseria infections
osponization targets
particles for uptake or phagocytosis but osponization-independent mechanisms can also trigger uptake
neutrophils have both
complement and antibody receptor to perform phagocytosis
ROS helps
the phagolysosome by binding to it and helping degrade bacteria
NADPH oxidase (which produces ROS) deficiency causes
chronic granulomatous disease
PRR are present
-on the cell surface
-in intracellular compartments
-in the cytoplasm
PRR bind to
PAMPs
Lipoproteins on GP bacteria
TLR1 and TLR2
LPS and GN
TLR4
flagellin and GN
TLR5
DNA on both GP and GN
TLR9
TLR signaling cascade leads to
- cellular activation
- cytokine production
Bacteria avoid TLR by
-modulating structures to prevent recognition
-interfering with signaling pathways
Inflammoses are in the
cytoplasm
-multi-protein innate immune sensing complexes
-have sensor proteins that detect conserved PAMPs and danger signals
Inflammoses
pro-inflammatory programmed cell death
pyroptosis
activate the protease caspase-1 and related proteases to activate cytokines and initiate pyroptosis
Inflammoses
cytokines cause
- vasodilation
- increase vascular permeability
inflammatory cells migrate into
tissue
B cell receptors/antibodies have
4 components
-light chain + heavy chain = variable region
-constant region = part of heavy chain
3 functions of antibodies
- neutralization
- osponization
- complement activation
T-cell receptor DNA is
rearranged and creates a dimer
cytosolic pathogen peptides bind to
MHC class I and presented to CD8 T-cells
extraceullular pathogen peptides bind to
MHC class II and presented to CD4 T-cells
CD4 helper t-cells
activate B cells & macrophages, produce cytokines
CD8 cytotoxic t-cells
kill infected cells and produce cytokines
agent characteristics
-virulence, dose, toxicity
-ability to survive in different environments
-antibiotic susceptibility
agent interventions
control/eliminate the infection at its source
Host characteristics
-behavior (age, sex, sexual practices, hygiene)
host susceptibility
-genetics
-immunological status
-anatomic structure
-disease or medications
host interventions
-treat infection
-immunize
-behavior modification
environment characteristics
-place, geology, climate
-biologic factors -> insects transmit the agent
-socioeconomic factors -> crowding, sanitation, access to healthcare
environment interventions
-sanitation, water
-preventive services
-spray to reduce mosquitoes
-bed nets
resevoir
environment in which the infectious agent normally lives, grows and multiplies
environmental reservoirs
-plants
-soil
-water
skin to skin, kissing, sex, contact with soil/vegetation, droplet spread (sneezing/coughing)
direct transmission
airborne (measles can live in air for hours), vehicle borne, vector borne
indirect transmission
food, water, fomites
vehicle-borne transmission
mosquitoes, fleas, ticks
vector-borne transmission
reproduction number (how many people can 1 person infect)
R-naught (R0)
- infectious period
- mode of transmission
- contact rate (location, public health measures, not specific to a disease)
factors for R-naught calculation
observed>expected at a particular time and place
outbreak
used to generate a DNA fingerprint for a bacterial isolate, bacteria from same strain will be indistinguishable -> gold standard
PFGE
individual gene or whole genome
sequencing
to establish link need not only DNA relatedness but
epidemiological connection
natural or innate properties
intrinsic resistance
-mutation
-horizontal gene transfer
-often under selection pressure
acquired resistance
-efflux pumps
-permeability barriers
-target bypass
intrinsic resistance examples
-efflux pumps
-inactivate the antibiotic
-modify the antibiotic target
acquired resistance examples
-transformation
-conjugation
-transduction
types of horizontal gene transfer
taking up free dna from environment
transformation
transfer from one bacterium to another (plasmids/mobile elements)
conjugation
bacteriophage infection -> phage picks up dna during infection and inserts it into another cell
transduction
biofilms make it hard for antibiotics to
reach the target bacteria
-metabolic byproducts
-reduced oxygen
-differences in pH
-some antibiotics sensitive to these changes
altered microenvironment in communities
-subpop. go metabolically dormant
-antibiotics=less effective
-revert back to normal later
bacterial persister cells
-exoplysaccharides, proteins, dna
-hard for antiobiotics to penetrate
sticky and slimy matrix of communities
beta-lactams
cell wall inhibitors
glycopeptides
cell wall inhibitors
fluoroquinolones
dna targeting
macrolides, lincosamides
ribosomal inhibitors
tetracyclines
ribosomal inhibitors
aminoglycosides
ribosomal inhibitors
2 main enzymatic steps in cell wall synthesis
- crosslinked via stem peptides
- polymerized into glycan strands
-nitromidazoles
-rifampin
-sulfonamides
-polymyxins
other processes of antibiotic classes
transpeptidase
PBP that crosslinks
glycosyltransferase
PBP that polymerizes
different bacteria can have…
both or one of the PBPs
what inhibits the transpeptidase activity of the PBPs
beta-lactams -> form a complex and PBPs can no longer crosslink -> cell wall integrity compromised
-penicillins
-cephalosporins (start with ceph)
-carbapenems (end in penem)
-monobactems
-beta-lactam/beta-lactamse inhibitors
-cefiderocol
classes/subclasses of beta-lactams
cefiderocol + carbapenems
broad-spectrum
1-5 generations
cephalosporins
- producing beta-lactamases to hydrolyze/inactivate the antibiotic
beta-lactams resistance mechanisms
-amoxicillin/clavulanate
-ampicillin/sulbactam
-piperacillin/tazobactam
combination drugs with beta-lactamases
beta-lactamases common in
GN -> chromosomal or plasmid-encoded beta-lactamases e.g. e.coli and klebsiella
- mutating PBPs to lower the affinity for the antibiotic e.g. MRSA
beta-lactams resistance mechanisms
-acquired mecA gene from mobile genetic element integrates into chromosome
-mecA encodes an alternative PBP2 protein called PBP2s
-reduced affinity for methicillin and other similar beta-lactams
MRSA
- efflux pumps move the antibiotic out of the cell (see ya!)
beta-lactams resistance mechanisms
- prohibiting entry by decreasing membrane permeability
beta-lactams resistance mechanisms
vancomycin -> bind peptidoglycan D-ala D-ala dipeptide to block Tpase crosslinking
glycopeptide
-used as a broad spectrum drug against GP
-too large to pass outer membrane (intrinsic resistance)
vancomycin
-horizontal gene transfer that encodes for D-ala D-lactate ligase
-vancomycin doesn’t recognize anymore
VRE (vancomycin-resistant enterococcus)
end floaxin
fluoroquinolones
relax/unwind over-twisting positively supercoiled DNA by cleaving and reuniting the strands
type II topoisomerases, dna gyrase and topoisomerases IV in fluoroquinolones
-target site mutations in gyrase/topoisomerase
-efflux pumps and permeability barriers
fluoroquinolones
peptide chain transfer blocked
oxazolidinoes -> ribosomal inhibitor
block trnas from A site on 30S subunit
tetracyclines -> ribosomal inhibitor
induce codon misreading at site A
aminoglycosides -> ribosomal inhibitor
peptide exit tunnel/translocation blocked
macrolides + lincosamides -> ribosomal inhibitor
resistance:
-aminoglycoside-modifying enzymes
-mutations in ribosomal rRNA
-mod of ribosome by methyltransferases (its a hat!)
-decrease membrane permeability
ribosomal inhibitor
helpful for stopping toxin production e.g. staphylocoocal toxic shock syndrome + necrotizing soft tissue
ribosomal inhibitor
-prodrug enters cell + anaerobic environment promotes reduction to nitroso intermediate products
-these products cause DNA to break
mitroimizadoles/metroindazole
-intra-abdominal infections
-bacterial vaginosis
-brain abscess
mitroimizadoles/metroindazole
-inhibits rna polymerase
-combo therapy
-penetrates osteoblasts
-DIFFUSES WELL INTO BIOFILMS
rifampin
-folate (B9 synthesis)
-important pathway for dna synthesis
-trimethoprim/sulfamethoxazole (SXT) blocks 2 steps in this pathway
sulfonamides
intrinsic resistance example:
enterococcus can take up folate from the environment as an alt. source= target bypass
sulfonamides
-disrupt OM of GN
-hydrophillic cationic ring + hydrophobic tail = inserts into membranes
-toxic to kidneys + brain
polymyxins
not sure what patient is infected with
empiric coverage
-effectively targets all PBPs
-amp. targets 4 & 5
-ceftriaxone targets 2 & #
dual beta-lactam therapy (enterococcus)
aminoglycoside + cell wall inhibitor
dual therapy (enterococcus)
