Lecture 6 block 4 Flashcards


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lecture - innate and adaptive immunity and covid19

see main points of lecutre

  • background
  • effects on innate system
  • whos most at risk
  • children
  • data
2

background

  • understanding virus/host interaction = important
  • viruses suppress innate immune system/responses to get opportunity for replication + setting up of infection
  • emerging topic - interplay of innate immune response + cellular metabolism (immunometabolism) - relevant for viral respiratory infections
  • general idea: immune cells like macrophages/ DCs adapt the choice for the use of their metabolic systems to an immune activated situation that requires increased amounts of energy
    • ex: like will they use a lot of energy?
    • if immune system start working hard -> these cells will increase their metabolism by a lot
    • = immune activation require more energy
3

receptor for virus

possible theraputic targets for covid 19 - cytokine release syndrome

card image
  • head part = S1
  • stock part = S2
  • binding region to covid receptor by virus = ACE2 (recognize S1 part of virus)
  • binding of virus to ACE2 receptor
  • in order for virus to get in cell -> need TMPRSS2 (entry mechanism)
    • (serine protease)
  • NFKB stimulated by PRRs-> triggers inflammatory components (Like IL6)
    • = inflammatory cytokines = lot of inflammation
  • angiotensin 2 (AngII) inc in serum bc of reduction in ACE2-mediated degradation
    • bc ACE2 was used
  • increased AngII -> increased TNFa = more inflammation
  • tissues infected can be lung, kidney, small intestine, etc (anywhere the ACE2 receptor is)

= way of generating a lot of inflammatory cytokines from infection

symptoms - cough, dyspemia (shortness of breath)

4

Q: What is the cell (binding) receptor for the SARS-CoV-2 virus?
A) complement receptor, CR1

B) ACEII, angiotensin receptor

C) TNF alpha receptor

D) NF-kB receptor

ANSWER: B

5

Q: What may contribute to increased inflammation upon SARS-CoV-2 infection?

A) transcription factor NF-kB is stimulated by PRRs

B) Angiotensin 2 (AngII) increases in serum due to a reduction of ACE2-mediated degradation

C) increased AngII leads to increased TNFa

D) all correct

ANSWER: D

6

more info

  • initial site infection = resp tract
  • interacts w/ angiotensin converting enzyme 2 (ACE2) receptor
  • existing innate immune suppression prob underpin ensuing dysregulated inflammatory responses
  • severe cases characterized by:
    • inc inflammatory monocytes + neutrophils in blood + CD14 +CD16 + monocyte derived macrophages in airways + increased systemic levels of inflammatory cytokines + chemokines
  • if dont control early = high viral burden + disregulated/lethal inflammatory response
    • ex: acute respiratory distress syndrome
    • why seniors/those w/ co-morbidities = prone to covid (propensity to mount exaggerated inflammatory responses)
7

Spike protein

  • mechanism by which antibody protected - binds to molecules on outside of virus = prevents it being taken up
  • 1 reason prevented: if have Ag/Ab complex - bind complement + taken up by phagocyte or liver cells + get rid of it -> get rid of it by going to liver
  • (how that mechanism work against virus)
8

pathogenesis of cytokine storm

  • process of replication of covid - start w/ binding of viral S protein w/ ACEII receptors of host
  • = release viral genome + genome replication
  • infection in host lungs + interaction w/ blood vessels causes activation of host innate immunity -> release of cytokines -> eventually result in uncontrolled + exaggerated response = cytokine storm
9

how are children responding better to covid? or not getting?

bc they have a better innate immune system

  • children have reduced severe acute respiratory syndrome infection rates + lower risk of developing severe disease compared with adults
  • found single celled RNA sequencing in upper airway cells = significantly higher basal expression level of the genes coding for viral response of epithelial resp tract of healthy kids compared to adults
    • = better ability of their resp mucosa to respond to viral infection
    • supported by amount of innate immune cells in their upper airways (better innate immune system bc of the number of cells)
  • airway immune cells of kinds primed for virus sensing = stronger early antiviral response compared to adults
  • 4 groups: kids w w/o the infection and adults w/ w/o the infection
    • COV- kids had high amount each immune cell subset w/ dominance of neutrophils
    • adults - infection associated w/ immune cell influx (but the kids stayed stable)
    • **= if have good immune system to START w/, will get rid of virus, dont need to have generation of bad inflammation that will destroy body/make cytokine storm
      • children better bc their immune cells stay stable
    • children infected -> neutrophils had activated phenotype more than adults = childrens innate system more abundant in airways + respond better to infection
10

data from that paper:

neutrophils + immune total greater in uninfected children than in adults

  • left = covid -
  • right = infected

expression of ACEII (encoding entry receptor for covid) was SIMILAR btw adults/children (so that cant be reason for difference in their response)

11

RNA sequence analyses

4 groups - children / adutts covid -, and children/adults covid +

neutrophils in areas concentrated in children are missing in adults

same for macrophages

bottom line - children have increased of both BEFORE infection (know this alr)

12

see virus going in cell

  • go thru signaling processes
  • end w/ NFKb (transcription factor for inflammation)
    • make type 1 INF
  • measured compounds
  • in epithelial cells after infection -> big increase in markers of activation in children but NOT in adults
    • not only is their innate system better bc of the cells, but they also generate things that get rid of virus (have more active phenotype after infection)
13

Q: From publication by loske, saw that chuldren likely can response better to covid because:

A) CD8 T cells in children already immune to covid

B) B cells alr activated in children + they already have antibodies to covid

C) Children have highly increased amounts of innate immune cells in their upper airways + their epithelial cells show more activated phenotype upon infection

D) Expression levels of ACE2, encoding covid entry receptor are greater in children than adults

ANSER: C

14

pediatric covid patients show abundant viral mRNA + strong specific antiviral responses

  • significantly lower # children/adolescents have severe clinical presentations w/ need for hospitalization/ or lead to death
    • compared to other age groups
  • diff hypotheses to explain phenomenon:
    • reduced expression of viral receptor (ACEII) = DISPROVED
    • children/college students = main reservoirs of the virus
      • do very well against it but can still be infectious (not symptomatic but infectious)
15

antibody responses - benefits in treating w/ convalescent plasma

  • like mice studies - passive immunization can be way to prevent disease w/o inducing immune response
    • short period of time (bc half life of immunoglobulin IgG = 21 days)
      • mothers w/ IgG pass thru placenta + protect babies for at least 3 months
  • studies in treatment w/ convalescent plasma
    • antibodies that bind to S1 receptor binding domain block its interaction w/ ACEII, where those that bind to other regions of S1 and S2 can inhibit conformational change of the S protein + block membrane fusion
      • = passive immunization = good thing + protect ppl
16

Q: What is a good reason to vaccinate children to covid?

A) protect them from RNA viruses

B) protect them from diseases + others from contracting residual covid virus from them

C) so they will continue to wear masks all the time + display their unique artistry

D) to ensure that other covid variants will develop

ANSWER: B

17

targeting extracellular virions

  • neutralizing antibodies - target them
  • T cells - good way to get to virus thats entered cell
    • vaccines try to make T cells so recognize virus when gets in cell
  • antibodies very good bc get rid of virus coming in BEFORE get in cell
  • still need complete immune system bc need CD4 T cells to turn on B cells anyway
  • Need innate also to get everything going in beginning
18

neutralizing antibodies can be aquired artificially (passive) or naturally (vaccinated or surviving infection)

card image
  • passive immunization
  • its a good thing
  • neutralizing antibodies could block viral infection by bindng to the viral spike protein + prevent it from interacting w/ cellular receptor ACEII
  • the antibodies keep spike protein from activating ACEII receptor as above - keep it from doing what it wants to do
  • remember: Ag/Ab complex removed by complement C3 bind to FC of antibody (thats bound to antigen) -> go to liver
19

Q: What is an advantage of passive immunity?
A) gives lifelong immunity

B) quick, person can get antibodies quickly that could save them

C) requires the T and B cells to develop in the individual

D) is dependent on the inflammation not destroying the antibodies

ANSWER: B

20

Adipose tissue

expression of ACEII receptor present in adipose tissue -> can explain higher susceptibility/severity in obese covid patients

  • + more than just that

studies showed:

  • after cells infected -> immediate down regulation (elimination) of ACEII = reason for tissue damage
    • not good hypothesis (ACEII protective not detrimental) ???
21

other possible reasons for covid severity in obese ppl*** important

  • obesity has highly inflammation state -> cause secretion of monocyte chemoattractant, TNFa, IL1B, INFY, and IL6 normally
    • all = chronic/systemic inflammation
    • just as their normal state w/o infection
  • adipose tissue expresses receptors ACEII, DPP4, and CD147 for SARS
    • having adipose (excessive) tissue = you have more of the receptors for the virus to take advantage of/do more damage
  • adipose tissue of obese -> serve as COVID target organ as well as viral rservoir
    • could put out more and more virus bc of it
    • = feedback mechanism = more inflammation
    • = cytokine storm
22

Q: what is a possible reason for increased severe COVID disease in obese ppl?

A) obesity has highly inflammatory state causing secretion of MCP-1, TNFa, IL1B, INFY, IL6

B) Obese adipose tissue expresses increased receptors ACEII, DPP4, CD147 for SARS

C) adipose tissue of obese ppl could = covid target organ + viral reservoir

D) All of above

ANSWER: D

23

obesity associated w/ increased inflammation + poorer vaccine responses

  • elderly = lower vaccine response
  • 2 diff ppl in young group
    • lean body vs obese
  • lean ppl = better response to FLU vaccine
  • experiments in mice + ppl to investigate this
    • distinct cells are more autoimmune in obese ppl/fat mice = theyre more inflammatory
    • measured chemokines
    • B cells move towards chemokine receptor in adipose tissue
    • older mice had more inflammed B cells in adipose tissue
    • = hypothesis -> visceral adipose tissue contributes to inflammatory B cells (in aging + obesity)
24

reflections on changes + possible causes of human B cell immunity in aging, obesity, and COVID

participants - uninfected, lean, or obese

25

correlations btw serum proinflammatory + metabolic markers in the positive participants

  • CRP - indicate infection/inflammation
  • association w/ obese ppl / making good response to spike protein
26

spike specific IgG are negatively associated w/ SAA and CRP and positively associated w/ NEFA

  • shows ability to respond to spike protein
  • for BMI
  • IgG (immubnoglobulin) OD = less in obese ppl
  • + less in ppl who are inflammed
  • ***inflammation + obesity = negative contributors to antibody response
27

evaluation of spike specific IgG antibodies in serum of lean + obese COVID patients

card image

spike specific IgG antibodies in serum samples = higher in lean covid patients

lean ppl have higher antibody response than obese ppl

28

another thing:

  • ability make autoimmune antibodies can be generated in adipose tissues or by antigens in adipose tissues + released
  • present more in obese ppl
  • more autoimmune antibodies in obese ppl
  • bottom line - autoimmune immunoglobulin increased in obese ppl + obese covid patients
29

serum levels of CRP higher in obese vs lean covid patients

  • obese have more CRP (a marker for infection / inflammation) = they have more infection/inflammation than lean ppl
30

serum levels CRP are positively correlated w/ autoimmune IgG antibodies in lean + obese COVID patients

CRP HIGHER as adipose tissue increase

CRP HIGHER as auto antigen increase

= correlation btw CRP and autoimmune antibodies = possible causative agent in infections causing a lot of inflammation ***

31

summary of COVID data

  • spike specific IgG antibodies in serum samples HIGHER in lean covid patients
  • autoimmune IgG antibodies in serum samples HIGHER in obese patients
  • serum levels CRP HIGHER in obese vs lean
  • serum levels CRP positively correlated w/ autoimmune IgG antibodies in lean + obese covid patients

all = consistent hypothesis that obesity + inflammation go together

lean = better response to virus

increased inflammation = negative response

32

Q: most/highest antispike antibodies antibodies made by

A) obese covid patients

B) older covid patients

C) covid patients w/ highest levels CRP

D) lean covid patients

ANSWER: D

(obese ppl dont make good antibody response)

greater risk for severe effects

33

Q: highest levels autoimmune antibodies found in:
A) obese covid patients

B) younger covid patients

C) covid patients w/ lowest levels CRP

D) lean covid patients

ANSWER: A

obese = inflammatory = autoimmunity