Block 4 lecture 5 Flashcards


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1

Bacteria evolved ways to outwit host immune system

  • proteases = 1 weapon of bacteria
    • cleave + neutralize key signaling molecules
    • streptococci bacteria (group A + B)
      • have cell-envelope proteases (CEPs) = subtillisin-like serine proteases
    • C5a peptidase (protease) cleave chemokine (CXCL8) + C5a itself
      • 1 way bacteria go around host response, by getting rid of C5a anaphylatoxin that generate inflammation + call phagocytes
    • concluded: peptidase can be used for vaccine - try to block that step in bacteria (target proteases) = resolution of strepococcal infections
      • idea for cobmbatting well established bacterial mechanisms for survival
2

generartion of anaphylatoxins C3a + C5a + subsequent degradations by CEPs (cell envelope proteases made by group A/B streptococci)

know alternative use C3 convertase- C3bBb

know classical/lectin use C3 convertase - C4b2a

whole system we already know

basically know here C3a + C5a can be CLEAVED by protease = neutralize them

  • = bacteria evade innate immune system
3

staph aureus

  • important in MRSA
  • their proteases cleave specific components of host immune system
  • peptides interfere w/ deposition of complement on bacterial surface
  • its protease cleave C3 = opsonization is compromised
    • C3b degraded by H and I
      • because its NOT on the surface of bacteria, so host body gets rid of it to protect own cells
  • secrete proteases that inhibit neutrophil serine proteases
  • MAINLY - staph make many diff proteases that cleave many parts of immune system including C3b -> inactivate innate immune system
4

Q: Extracellular bacteria, streptococcus pyrogenes, can evade the innate immune system by:

A) attaching to neutrophils

B) Making a protease/peptidase to cleabe complement C5a

C) releasing toxic molecules for NK cells

D) Generating glomerulonephritis

ANSWER: B

5

Q: Staphylococcus aureus can evade the innate immune system when:
A) A staph protease cleaves CD1084 and improves neutrophil function

B) A staph carbohydrate attaches to the TLR to activate B cells

C) A staph protease cleave complement, C3, and C3b is degraded by factors H and I

D) It activates CXC chemokines and neutrophil activation and chemotaxis

ANSWER: C

6

Mouse models of enteric bacterial pathogens

Enteropathogenic E. coli (EPEC) in humans responsible for diarrhea, morbidity, mortality

Citrobacter rodentium - murine pathogen that normally induces self-limiting enteritis

  • acts like EPEC in humans = its very studied in this mouse model
  • gram negative

Both = attaching + effacing enteropathogens

  • purple = bacteria on intestinal pedestals
  • confined to intestinal lumen + dont invade deeper to tissues (stay on top)
    • = attach + loss of border microvilli = effacing lesions

blue = host nuclei

red = actin on host cell

green = lipopolysaccharide receptor TLR4 on bacterial surface

citrobacter elicit Th1 cytokine response + lesions similar to infla. bowel disease

7

cont.

  • colonization of small intestine w/ the microbe (commensal): segmented filamentous bacterium (SFB)
    • induced CD4 T cells that make IL17 + IL 22 in lamina propria
    • correlated w/ increased gene expression for inflammation+ antimicrobial defenses = enhanced resistance to pathogen citrobacter rodentium
  • = manipulation of this pathway can be possible opportunity to enhance immunity/treatment /of autoimmune disease or infections
8

composition of microbiota = important in susceptibility to citro (shows innate barrier function as colonization resistance + an inducer of aspects of both innate + adaptive immunity)

  • left:
    • Jackson - mice infected w/ citrobacter
    • Taconic - housed w/ mice w/ lots of bacteria
    • saw that mice infected no longer had lot of bacteria
      • aquired microbiota thru digesting eachothers fecal matter = protected from bacterial colonization
      • found taconic mice gave jackson mice resistance
        • could tell bc the taconic mice had higher levels of certain bacteria
    • point: could find which bacteria were responsible for generating protection in jackson mice
9

Acute mucosal infection w/ citrobacter

either WT mice or Knock out

  • B cell deficient (eliminated (-/-) IgM
    • = MuMT/ = do NOT survive (all)
  • WT survive - protected by immune system
  • Mice w/o CD8 - still fine
  • BUT eliminate CD4 = all die
  • eliminate BOTH B/T cells (RAG2-/-) = mice die
  • bottom line = need both CD4 cells + B cells to survive citrobacter
    • *** remember B cells need CD4 T cells (they dont need CD8) to make antibody
10

Q: Major lymphocytes needed for survival of an acute mucosal infection w/ citrobacter rodentium are:

A) Only CD8 T cells

B) B and all T cells (CD8 and CD4)

C) CD4 T and B cells

D) Only B cells

ANSWER: C

11

can TRANSFER immunity

  • serum transfer to CD4 -/- mice (have no CD4 T cells)
  • if transfer saline to CD4 -/- -> still die
  • transfer serum thats NOT immune (preimmune = before mice were immunized) -> doesnt have antibodies = mice die
  • transfer acute serum (mouse actively infected) OR convalescent serum (immunized + survived + antibody in serum)

= to survive need antibody in serum transferred that is specific to the pathogen (acute or convalescent)

= passive immunization (mice dont make active immune response)

12

Q: Protection/survival from citrobacter could also be shown by giving the infected mice:
A) Saline

B) Pre-immune serum

C) Serum from another unimmunized mouse

D) acute/convalescent serum from an infected mouse

ANSWER: D

13

citrobacter in lumen become coated w/ IgG

  • see in flow diagram - bacteria stained w/ green marker
    • marker detect bacteria
  • see cells in gut neutrophils = positive (stain w/ c rodentium) + cells not neutrophils dont stain = neutrophils are active + ingest IgG coated citrobacter
14

Q: Antibody to Citrobacter can be shown to be important in fighting infection by binding to:
A) T cells

B) B cells

C) citrobacter + neutrophils

D) DC (dendritic cells)

ANSWER: C

15

AMPS - antimicrobial peptides/proteins

  • key in helping to get rid of bacteria
  • come primarily from Paneth cells
    • bind + disrupt bacterial membranes
    • = major producer of AMPs
  • overall + charge
  • C-type lectins = AMPS
    • connection to lectin pathway
16

Q: Antimicrobial peptides/proteins (AMPs) in the intestine

A) Come primarily from paneth cells

B) Work by disrupting bacterial membranes

C) Have hydrophobic interactions w/ bacterial membranes

D) All correct

ANSWER: D

17

Cytokines and AMPs

  • early cytokine gene expression important in protection
  • IL22 functions: proinflammatory, protect epithelial cells from damage, induce AMP reg3gamma
    • IL22 -/- = mice DIE w/ citrobacter
    • = IL22 important for early and later
    • come from innate lymphoid cell ILC
18

REG

= family of C-type lectins (an AMP)

  • made by paneth cells
  • REG3 in mice/humans in intestine
  • work against gram + AND - bacteria
  • recognize targets by binding to peptidoglycan + antibacterial properties disrupt cell wall
19

REG3gamma mediates protection vs citrobacter DOWNSTREAM of IL22

  • *** remember IL22 needed for survival for infected

IL22 indespensible for induction of REG proteins

  • paneth cells make REG3gamma via TLRs by PAMPS. REG3 specifically target gram neg/pos bacteria - binds to their surface peptidoglycan layer
  • IL22 produced by ILC and CD4 cells
20

Q: IL22 produced by ___ which induce REG3y

A) CD4 T or ILC (innate lymphoid cells)
B) B cells

C) Eosinophils

D) Plasma-forming cells

ANSWER: A

21

professional innate immune cells

  • myeloid lineage
    • granulocytes (like neutrophils)
    • macrophages
    • dendritic cells
  • lymphoid lineage cells
    • = fam of cells predominant at mucosal surfaces are critical in early defense
      • stimulate production of AMPs
    • NK cells (also ILC type)
      • = first ILC ("classic")
    • Innate lymphoid cells (ILC)
    • LTi (lymphoid tissue inducers
      • major early producers of IL17/22
22

Innate lymphoid cells (ILC)

fam cells predominant at mucosal surfaces + critical in early defense by stimulating production of antimicrobial proteins (AMPs)

IL22,17,4,5,13,INFy, etc

-new categories of lymphocytes

-prominent in intestinal mucosa

-dont express recombined antigen receptors - instead sense environmental cues

-deliver inflammatory functions before adaptive cells

-similar to innate version of CD8, CD4, Th1, etc

23

where IL22 come from?

  • IL23 come from how its induced
  • NK cells make INF gamma
  • ILC make IL22
  • CD4 make IL22
  • Dendritic cells make IL23
    • use MYD88 to signal IL23
      • subsequently induce IL22
  • many innate sources of IL22
    • ILC = LTi, NKp46, neutrophils
    • CD4 (adaptive)

IL23-> IL22

*DC make IL23, which lead to other cells + ILC which make IL22

  • ***therefore IL23 indirectly make/cause IL22 production

remember* - IL22 induce REG3y

24

summary

card image

BOTTOM LINE: 3 steps

  • DC make IL23
    • -> causes IL22 to be made
  • ILC make IL22
    • induces REG3y to be made
  • Paneth cells make REG3y which kill bacteria
25

summary - flow chart of interacting cascades

know:

  • TLR activation of dendritic cells -> make IL23
  • -> IL23 receptor on ILC -> make IL22
  • -> IL22 receptor on paneth cells -> make REG3y
  • = bacterial killing

= how intestine get rid of a lot of bacteria

26

how does neutrophil get to this place???

already covered this:

  • neutrophil get to bacteria (this case = intestine) by chemokine CXCL8
  • go towards the CXCL8 gradient made by pathogen activated macrophages
27

Q: Neutrophil direction to the tissue sites of infection is mediated by:

A) Rolling adhesion of neutrophils to bacteria in the gut interior

B) Chemokine CXCL8 made by pathogen activated macrophages at infection site

C) neutrophil squeezing btw IL2T cells + B cells in bone marrow

D) TB binding to the neutrophil + directing it to sites of infection

ANSWER: B

28

remember pentraxins

  • conserved from invertebrates
  • link btw innate immunity and other parts in immune system
  • pentraxin = prototypic humoral parttern recognition molecule (PRR)
  • tissue repair + regulation of cancer related inflammation along with its defense vs infection
  • CRP = pentraxin, made by hepatocytes as acute phase protein in response to IL6
29

Q: which complement component (in addition to C3b) is needed to activate macrophages to phagocytose via CR1?

A) C1

B)C4b

C) C5a

D) C9

ANSWER: C

30

Q: A possible progression of an acute-phase response is:

A) Bacteria-C (complement) - Ab(antibody) - Tcells _MBL

B) Bacteria - macrophage - IL6 - hepatocytes - CRP (c reactive protein)

C) bacteria - neutrophils - T cells - Ab

D) Bacteria - T cells - B cells - Ab

ANSWER: B

31

review - acute phase response

  • Act very quick (in 1 day)
  • CRP and MBL
  • acute phase response increase supply of recognition molecules of innate immunity
  • bacteria induce macrophages to make IL6 -> act on hepatocyte to induce synthesis of acute phase proteins
  • CRP triggers classical complement pathway w/o Ab
  • MBL binds C4 -> release Ca + activate complement

***IL6 = inflammatory cytokine