Micrb 265 lec 12
What does the gut microbiome instruct?
Both the innate and adaptive immune response
Why is bacterial diversity important in the gut?
It helps establish a tolerogenic immune response
What does tolerogenic mean in this context?
It promotes tolerance to beneficial microbes and limits unnecessary inflammation
What cells help the immune system discriminate between friend and foe in the gut?
Tolerogenic dendritic cells and T regulatory cells
What is the key contrast between mutualists and pathogens in the gut?
Mutualists promote anti-inflammatory responses while pathogens promote pro-inflammatory responses
What cytokine was emphasized as part of the anti-inflammatory response promoted by mutualists?
IL-10
What do mutualists encourage dendritic cells to do?
Give weak signals that promote anti-inflammatory T cell responses
What type of T cells are promoted by mutualists?
T regulatory cells
What kind of environment do pathogens promote?
A pro-inflammatory environment
What Bacteroides fragilis product was specifically emphasized?
Polysaccharide A
What is polysaccharide A?
A capsular polysaccharide from Bacteroides fragilis
How does polysaccharide A promote a healthy colon?
It is taken up by dendritic cells, which drive T cells to become Treg cells and promote anti-inflammatory cytokines
What diseases were linked to microbial dysregulation?
Inflammatory bowel disease, asthma, and allergies
What is the gut-brain axis?
Communication between the gut microbiome and the brain
What are two major routes of gut-brain communication mentioned in lecture?
The vagus nerve and circulation
What kinds of conditions were associated with gut microbiota changes affecting the CNS?
Autism, schizophrenia, and mood disorders
What effect did repeated stress have on the gut microbiome in the lecture example?
It changed the Bacteroides population
Why do changes in Bacteroides matter?
They affect cytokine release by immune and epithelial cells in the gut
What happened in germ-free mice colonized with Lactobacillus rhamnosus?
They completed stressful tasks more easily and had lower anxiety
What possible brain-related change was seen in the Lactobacillus-colonized mice?
Altered neurotransmitter receptors
What important caution did the professor emphasize about gut-brain axis research?
It is an active research area and mechanisms are not fully understood
What amino acid was emphasized in microbiome-brain signaling?
Tryptophan
What does Clostridium sporogenes make from tryptophan?
IPA
What does IPA stand for?
Indolepropionic acid
What are the key effects of IPA?
It supports gut homeostasis, reduces pro-inflammatory signaling, increases tight junction proteins, and acts as a neuroprotectant
What do lactobacilli make from tryptophan?
I3A
What is the important immune effect of I3A?
It increases IL-22 production
What can tryptophanase-expressing bacteria make from tryptophan?
Indole
Why is indole metabolism important systemically?
It can be linked to harmful effects such as vascular disease and chronic kidney disease
What is infection?
The growth of microorganisms on a host
What is disease in pathogenesis?
The tissue damage resulting from infection
What is the first step in bacterial pathogenesis?
Adherence
Is invasion always required for disease?
No
After adherence, what usually comes next in pathogenesis?
Invasion through the epithelium
What happens during multiplication in pathogenesis?
Bacteria grow and produce virulence factors and toxins
What mediates bacterial attachment?
Receptor-ligand interactions
What bacterial structures can mediate attachment?
Capsules, fimbriae, pili, and flagella
What pathogen was used as an example of highly specific mucosal attachment?
Neisseria gonorrhoeae
Where does Neisseria gonorrhoeae adhere?
Genitourinary tract, eye, rectum, and throat
Why does Neisseria gonorrhoeae show tissue specificity?
Its Opa protein binds host proteins found only in those tissues
What host receptor on sperm is bound by gonococcal LOS?
ASGPR
What are the two main invasion mechanisms?
Zipper and trigger
What happens in the zipper mechanism?
Adhesin binding causes host cytoskeleton changes that engulf the bacterium
What pathogen was used as the zipper mechanism example?
Listeria
What happens in the trigger mechanism?
A type III secretion system injects effectors that cause membrane ruffling and cytoskeletal rearrangement
What pathogen was used as the trigger mechanism example?
Salmonella
What can happen after bacteria are internalized?
They can stay inside or exit out the other side
What enzyme was used as an example of a tissue-destroying virulence factor?
Hyaluronidase
How does hyaluronidase help bacteria invade?
It degrades hyaluronic acid between cells, helping bacteria move into deeper tissues
What are exotoxins?
Secreted bacterial proteins that interfere with host cell processes and cause tissue damage
What are the three main exotoxin types?
AB toxins, cytolytic toxins, and superantigen toxins
What is an enterotoxin?
An exotoxin whose site of action is the small intestine
How do AB toxins work in general?
The B subunit binds and helps the A subunit enter the cell, and the A subunit has enzymatic activity
What does the B subunit of an AB toxin do?
Binds the host cell and helps transport the A subunit across the membrane
What does the A subunit of an AB toxin do?
Has enzymatic activity inside the host cell
What was the key effect of the shiga-like toxin example?
It cleaves ribosomal RNA, inhibits protein synthesis, and causes vascular damage leading to hemorrhage
What kind of toxin is botulinum toxin?
An AB toxin
What does botulinum toxin block?
Release of acetylcholine-containing vesicles
What paralysis does botulinum toxin cause?
Flaccid paralysis
Why does blocking acetylcholine release cause flaccid paralysis?
The muscle cannot receive the signal to contract
What is special about botulinum toxin potency?
It is the most potent biological toxin known
What are cytolytic toxins?
Toxins that lyse cells, usually by disrupting membranes
Why are cytolytic toxins also called hemolysins?
They were first discovered because they lyse red blood cells
How do cytolytic toxins damage cells?
They form pores in membranes, disrupting osmotic balance and causing lysis
What bacteria were emphasized as major producers of superantigen toxins?
Staphylococcus aureus and Streptococcus pyogenes
How do superantigens differ from normal antigen responses?
They non-specifically activate huge numbers of T cells
How many T cells are normally activated by a specific antigen?
Up to about 0.001%
How many T cells can superantigens activate?
Up to about 20%
What is the consequence of superantigen activity?
Massive cytokine release and widespread inflammation
What can superantigen toxins lead to clinically?
Hypotension, intestinal disruption, organ failure, and death
What syndrome is associated with superantigen toxins?
Toxic shock syndrome
What are the major epithelial defenses emphasized in mammalian immunity?
Physical barrier, high salt, low pH, mucus, lysozyme, and normal microbiota
How does mucus help defend against bacteria?
It traps microbes and can be shed to remove them
What does lysozyme do?
Cleaves peptidoglycan in bacterial cell walls
What are CAMPs?
Cationic antimicrobial peptides
How do CAMPs work?
They poke holes in bacterial membranes
What is the main protective role of IgA on mucosal surfaces?
It binds pathogens and prevents their adhesion to the epithelial layer
What else can IgA do besides block binding?
Cross-link pathogens so they can be cleared
What are phagocytes?
Immune cells that engulf and degrade microbes
What do phagocytes recognize on pathogens?
PAMPs
What does PAMP stand for?
Pathogen-associated molecular pattern
What does PRR stand for?
Pattern recognition receptor
What is TLR4?
A pattern recognition receptor that recognizes LPS
What happens when TLR4 recognizes LPS?
It dimerizes and triggers inflammatory gene expression
Why is LPS recognition helpful to the host?
It triggers inflammation against Gram-negative pathogens
How can bacterial capsules help pathogens evade immunity?
They shield surface molecules from PRRs
How can pathogens evade TLR4 recognition of LPS?
By remodeling LPS, such as changing acyl chains or charges
What effect can missing acyl chains on LPS have?
Poorer recognition by TLR4-MD2
What effect can added phosphoethanolamine on LPS have?
It changes charge and interferes with TLR4 recognition
What was the key activity takeaway about ETEC compared with EIEC?
ETEC makes exotoxins but EIEC does not
What was the key activity takeaway about Staphylococcus aureus immune evasion?
It can use molecules that help hide from pathogen recognition
What was the key activity takeaway about Mycobacterium tuberculosis compared with E. coli?
It can live inside macrophages
What was the Week 12 probiotic example involving Bacillus and Staphylococcus aureus?
Bacillus makes fengycin, which blocks AIP binding and prevents quorum sensing
What is AIP in Staphylococcus aureus?
Auto-inducing peptide used for quorum sensing
Why is blocking AIP signaling helpful?
It prevents activation of virulence genes
What is the simplest memory chain for S. aureus quorum sensing inhibition?
Bacillus makes fengycin, fengycin blocks AIP receptor signaling, quorum sensing fails, virulence drops