Lecture 6 Flashcards
what are the 2 aspects of host defense?
- host resistance
- disease tolerance
how was tolerance discovered?
in plant kingdom
6 ways that disease tolerance can be acquired
- genetic
- receptor downregulation
- tissue repair
- circadian rhythm
- gut microbiota
- immune silencing
what is vigor?
healthy host –> no pathogen
what is tolerance?
host is protected despite the pathogen load –> increased host health for a given pathogen load
NORMALLY, does type 1 response drive host resistance or tolerance?
host resistance
NORMALLY, does type 2 response drive host resistance or tolerance?
tolerance
describe the relationship btwn type 1 and type 2 immunity
MUTUALLY ANTAGONISTIC –> both play a role in infection but oppose each other
what is the general role of type 1 immunity?
cytotoxic responses and host resistance
what is the general role of type 2 immuntiy?
- barrier defense
- tissue repair
- epithelial remodeling
describe the effect of the Hpb worm on mice
persistent and chronic but not replicating –> mice won’t get sick bc they tolerate it very well
location of Hpb in mouse infection
buries below crypts and villi and forms large granulomas
describe the lifecycle of Hpb (7 stages)
- swallow larvae
- break thru intestinal epithelium
- bury into mucosal layer and form granulomas
- matures in granulomas
- worm breaks out and creates another level of damage
- worm wraps around villi
- worms mate and release eggs
what type of immunity is typically involved in worm expulsion?
type 2
during what stage of the worm life cycle is TYPE 2 immunity involved?
during adult phase, at the end of infection
describe the role of type 2 immunity on worm expulsion
- damaged epithelial cells release alarmins which activate DCs and ILCs to make IL4/5/13 and activate macrophages and eosinophils which feed back on the epithelium
- IL4/5/13 reprogram the intestinal stem cell niche and change the differentiation pattern to create more goblet cells for weep and sweep response
how does type 2 involvement in worm expulsion differ from what we know about type 2 immunity?
normally, type 2 is involved in tolerance
but since it is triggering the weep and sweep response to reduce the pathogen load, it is responsible for HOST RESISTANCE here
are all mice equally susceptible to helminth infection? why?
no –> diff genetic backgrounds can make them more or less susceptible based on whether they are type 2 or type 1 biased
mice that are biased for type 2 are more susceptible or resistant to helminth infection?
RESISTANT
mice that are biased for type 1 are more susceptible or resistant to helminth infection?
SUSCEPTIBLE
what cytokine is produced by mice that are susceptible to helminth infection?
IFNy –> biased for type 1 response
what cytokine is produced by mice that are resistant to helminth infection?
IL13 –> biased for type 2 response
what is STAT6?
TF common in type 2 response for pro-inflammatory cytokines
do we expect a higher or lower worm burden in STAT6 KO mice?
STAT6 is involved in type 2 response which we know to be important in helminth infection
therefore STAT6 KO will have higher worm burden
what cytokines do we see in early Hpb response? what does this signify?
IFNy is upregulated early on in infection
indicates that type 1 and type 2 are both involved in helminth infection and are opposing each other
do we expect a higher or lower worm burden in IFNyr KO mice? why?
what does this indicate?
IFNyr KO mice have a lower worm burden because type 2 response can occur earlier and stronger to remove worms
indicates that IFNy compromises host resistance
why is the role of IFNy in helminth infection different from the normal role of IFNy?
IFNy normally is responsible for host resistance (type 1) but here it is COMPROMISING host resistance
how do we expect the levels of goblet cells to change in IFNyr KO mice? why?
MORE goblet cells making more mucous –> bc type 2 response is occurring earlier and stronger
looking at type 2-driven epithelial cells and goblet cells, how do their levels change in IFNyr KO?
more type 2-driven epithelial cells and goblet cells
what happened when WT and IFNyr KO mice are given very high dose of worms? what does signify?
WT mice were fine
IFNyr KO mice were dying midway in infection
indicates that IFNy plays a role in protecting the host
how did pathogen load change in IFNyr KO mice given a high dose of worms that survived? what does this signify?
IFNyr KO have no change in pathogen load
indicates that IFNy promotes disease tolerance
describe the granuloma in IFNyr KO mice
IFNyr KO mice had:
- bloody granulomas
- more granulomas
- bigger granulomas
(compared with WT)
describe the healing of granulomas in IFNyr KO mice
IFNyr KO mice had large scars in intestine
what is the role of IFNy in relation to tissue damage?
IFNy limits the tissue damage, therefore promoting tolerance
what does IFNy recruit at the granulomas? how do they know (2)?
IFNy recruits neutrophils to the granulomas
- saw increase in chemokines that recruit neutrophils
- in IFNyr KO mice, no neutrophils could be detected at granuloma
what happens to tissue damage if neutrophil activity is removed? how does this relate to IFNy?
lose neutrophil activity = more tissue damage
same results as IFNyr KO –> so IFNy must be recruiting the neutrophils
what happens to granulomas if neutrophil activity is removed?
lose neutrophil activity = large granulomas
is the epithelium responsible for the IFNy signaling?
no –> cre mouse for IFNy KO in IEC has no diff in signaling
what is the stroma?
cells underneath the epithelial lining which form the ECM
how do stromal cells interact with the immune system?
when there is physical damage in intestine, stromal cells migrate and help repair and recruit immune cells
based on the interaction of stroma with the immune cells, what is the hypothesis regarding IFNy and neutrophils activity?
is IFNy licensing stromal cells to induce neutrophil recruitment and allow tissue repair?
how does IFNy signaling affect the stromal architecture?
in IFNyr KO –> large disruption of actin filaments
therefore, IFNy is important for proper structure of stroma
what happens as a result of STROMAL IFNy signaling?
worm infection drives IFNy signaling to recruit neutrophils and licenses the stroma to change its structure and help reduce tissue damage
what happens to neutrophil-recruiting chemokines in IFNyr KO mice? what does this mean?
in IFNyr KO mice –> lose chemokine signaling that recruits neutrophils
therefore, IFNy is responsible for recruiting neutrophils
how can we confirm that IFNy signaling from STROMAL cells specifically is what recruits neutrophils?
use cre to make IFNy KO in stromal cells –> lose recruitment of neutrophils
if you gave IL4 to type 1 biased mice, what would happen to host resistance after HELMINTH infection?
IL4 is type 2 –> will drive the mouse towards type 2 response and promote host resistance
