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


  • 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

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)


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



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



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)

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)

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

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

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)


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)


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)

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



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)

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

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



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

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

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



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) ???

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

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



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)

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

participants - uninfected, lean, or obese


correlations btw serum proinflammatory + metabolic markers in the positive participants

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

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

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

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

lean ppl have higher antibody response than obese ppl


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

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

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 ***


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


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


(obese ppl dont make good antibody response)

greater risk for severe effects


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


obese = inflammatory = autoimmunity