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<!doctype html>
<html lang="en">
<head>
<meta charset="utf-8">
<title>Immunity</title>
<meta name="author" content="Sarah Cobey">
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<body>
<div style="position: absolute; top:10px; left:10px; z-index:100;">
<a href="/sismid/immunity/">
<i class="fa fa-times-circle" style="color: #bbb; opacity: 0.1;"></i>
</a>
</div>
<div class="reveal">
<!-- Any section element inside of this container is displayed as a slide -->
<div class="slides">
<section data-background="#CC3333">
<h2 class="title">Immunity</h2>
</section>
<section>
<h3>Malaria and rain in India, 1987-2007</h3>
<img class="stretch" src="images/malaria_ts.png">
<div class="citation">
<a href="http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1000898">
Laneri et al. 2010
</a>
</div>
</section>
<section>
<h3>Influenza in St. Petersburg, 1968-2005</h3>
<img class="stretch" src="images/leningrad_flu.png">
</section>
<section>
<h3>Infections in Seattle, 1924-1933</h3>
<img class="stretch" src="images/seattle_ts.png">
<div class="citation">
<a href="http://www.tycho.pitt.edu/">
Project Tycho
</a>
</div>
</section>
<section>
<h3>At the base of infectious disease dynamics...</h3>
</section>
<section>
<h3>...we have consumers and resources</h3>
<img class="stretch" src="images/hare_lynx.jpg">
<div class="citation">
<a href="http://www.fftimes.com/node/209298">
Ben Slack (Fort Frances Times, 2008)
</a>
</div>
</section>
<section>
<h3>Seemingly complex dynamics are common</h3>
<img class="stretch" src="images/maclulich.png">
<div class="citation">
<a href="">
Maclulich 1937
</a>
</div>
</section>
<section>
<h3>With nonlinearity, correlations can mislead</h3>
<img class="stretch" src="images/hare_lynx_phase_portrait.png">
</section>
<section>
<h3>Partial solution: Mechanistic models</h3>
<br>
<p> $$H'=aH-bHL$$</p>
<p> $$L'=cHL-dL$$</p>
<br>
<p> $H$ hares, $L$ lynxes
<p> hare birth rate $a$, predation rate $b$,
<p> consumption rate $c$, death rate $d$ </p>
<p> (Other solutions: experiments, causal inference)</p>
</section>
<section data-background="#FFFF99">
<p>(working hypothesis)
<h3> Competition for susceptible hosts shapes the ecological and evolutionary dynamics of pathogens. </h3>
</section>
<section>
<h3>Implicit assumption of SIR model</h3>
<p> The susceptible fraction determines a pathogen's growth rate</p>
<br>
<p>$$I' > 0 \Rightarrow \frac{\beta S}{N} > \gamma$$
</section>
<section data-background="#99CCFF">
<h3>If the SIR model fits poorly, what next?</h3>
</section>
<section>
<h3>Other possibilities</h3>
<p> transient dynamics and noise
<p> host population structure
<p> ...
<p> more complex forms of immunity
<p> multiple "immunophenotypes"
</section>
<section data-background="#FFFF99">
<h3>How does the immune response "see" pathogens?</h3>
<p> (in ways that impacts fitness?) </p>
</section>
<section>
<h3>Immunity: Coordinated innate and adaptive responses</h3>
<img class="stretch" src="images/innate_adaptive.png">
<div class="citation">
<a href="http://www.garlandscience.com/product/isbn/9780815342434;jsessionid=jUIKR3YCu+EU9PPmbulBjg__">
Murphy 2011
</a>
</div>
</section>
<section>
<h3>Innate immunity</h3>
<p> Less specific
<p> Nearly memoryless
<p> <i>But diverse and dynamic</i></p>
</section>
<section>
<h3>The complement system</h3>
<p><i>Extremely fast destruction, tagging, and signalling</i>
<p>
<img src="images/mac.png" style="width: 20%; height: 20%;">
<p>Attacks via lectin, "alternative," and classical pathways
<p>Effective against viruses, bacteria, parasites
<p>Tags pathogens ("opsonization"), perforates (MACs)
<p>Attracts phagocytes
</section>
<section>
<h3>Macrophages</h3>
<p><i>Long-lived sentinels and killers</i>
<p>
<img src="images/macrophage.jpg" style="width: 30%; height: 30%;">
<p>Resting, primed, or hyperactive
<p>Display to T cells via MHC class II
<p>Secrete IL-1, TNF, complement proteins to kill and signal
</section>
<section>
<h3>Neutrophils</h3>
<p><i>"On call," do most of the dirty work</i>
<p>
<img src="images/neutrophil.png" style="width: 25%; height: 25%;">
<p>70% of WBCs, 100 billion produced daily, live 5 days
<p>Respond to IL-1, TNF, f-met peptides from macrophages
<p>Just kill and signal (e.g., IL-2)
</section>
<section>
<h3>Natural killer (NK) cells</h3>
<p><i>"On call" for some killing and signalling</i></p>
<img src="images/nk_cell.jpeg" style="width: 25%; height: 25%;">
<p>Target tumor cells, virus-infected cells, bacteria, parasites, fungi
<p>Activated by LPS, interferons produced by dying cells
<p>Kill cells bound by Abs (ADCC) or not expressing MHC class I
<p>Major supplier of cytokines like IFN-$\gamma$ and TNF
</section>
<section>
<h3>Toll-like receptors (TLRs)</h3>
<p>Pattern recognition receptors expressed on surfaces of lymphocytes
<p>10 identified in humans so far (TLR1-10)
<p>Recognize "pathogen-associated molecular patterns" (PAMPs)
<p>e.g., TLR3 recognizes dsRNA (viral infections), TLR4 lipopolysaccharide (LPS) on bacteria
</section>
<section>
<h3>Adaptive immunity</h3>
<img class="stretch" src="images/innate_adaptive.png">
<p> More specific
<p> Some memory
</section>
<section>
<h4>T cells recognize presented peptides</h4>
<img class="stretch" src="images/cellular.png">
<div class="citation">
<a href="http://www.garlandscience.com/product/isbn/9780815342434;jsessionid=jUIKR3YCu+EU9PPmbulBjg__">
Murphy 2011
</a>
</div>
</section>
<section>
<h3>MHC class I</h3>
<p>Bind peptides 8-11 amino acids long
<p>Expressed on almost every cell
<p>In humans, six genes encoded by HLA-A, HLA-B, HLA-C
<p>Recognized by CTLs (CD8+ T cells)
</section>
<section>
<h3>MHC class II</h3>
<p>Bind peptides 13-25 amino acids long
<p>Expressed only by immune cells
<p>In humans, encoded by HLA-D
<p>Recognized by helper T cells (CD4+ T cells)
</section>
<section>
<h3>Dendritic cells: Master intelligence</h3>
<p>
<img src="images/dc.jpg" style="width: 30%; height: 30%;">
<p>Use TLRs and other receptors to detect pathogens
<p>Sensitive to local cytokine profiles
<p>Once in lymph nodes, use diverse costimulatory molecules to activate T cells
</section>
<section>
<h3>T cells: Activated by antigen presentation</h3>
<p>Antigens presented by dendritic cells, macrophages, B cells
<p>Co-stimulation required (B7 binds to CD28)
<p>Dendritic cells provide "snapshot"
<p>Macrophages provide sustained support
<p>B cells can concentrate rare and familiar antigen
</section>
<section>
<img src="images/tcell_activation.png" style="width: 40%; height: 40%;">
<div class="citation">
<a href="https://en.wikipedia.org/wiki/T_cell">
Wikipedia
</a>
</div>
</section>
<section>
<h3>So... what are Th cells?</h3>
<p>Produced by rearrangement, educated in thymus
<p>If stimulated by DCs, proliferate (6-h doubling time)
<p>After several days, become "effector cells", which
<p>(1) remain in blood, helping B cells and CTLs, or
<p>(2) help innate and adaptive cells in infected tissue.
<p>Th cells secrete specific cytokine profiles!
</section>
<section>
<h3>General profiles of Th cells</h3>
<img src="images/il-2.png" style="width: 20%; height: 20%;">
<div class="citation">
<a href="https://en.wikipedia.org/wiki/Interleukin_2">
Wikipedia
</a>
</div>
<p>Th1: IL-2, IFN-$\gamma$, TNF (viruses and bacteria)
<p>Th2: IL-4, IL-5, IL-10 (parasite and mucosal infections)
<p>Th17: IL-17A, IL-17F, IL-21, IL-22 (mucosal infections)
<p>Signalling is local!
</section>
<section>
<h3>CTLs (CD8+ T cells): Kill infected cells</h3>
<img src="images/ctl.png" style="width: 20%; height: 20%;">
<div class="citation">
<a href="https://en.wikipedia.org/wiki/T_cell">
Wikipedia
</a>
</div>
<p>Activated in lymph node, requires Th
<p>Proliferates following activation, enters tissue
<p>Carefully kills infected cells via MHC I
<p>Requires IL-2 (often from Th) to keep proliferating
</section>
<section>
<h4>B cells recognize protein structure</h4>
<img class="stretch" src="images/humoral.png">
<div class="citation">
<a href="http://www.garlandscience.com/product/isbn/9780815342434;jsessionid=jUIKR3YCu+EU9PPmbulBjg__">
Murphy 2011
</a>
</div>
</section>
<section>
<h3>Two sources of B cell receptor diversity</h3>
<p>Rearrangement of variable gene segments
<p>Somatic hypermutation during affinity maturation
<p>Antibodies are secreted B cell receptors</p>
</section>
<section><h3>What does "antigenic variation" mean?</h3>
<p> Formally, variation in surface proteins (antibody targets)
<p> Broader concepts may be more useful
<div class="citation">
<a href="http://onlinelibrary.wiley.com/doi/10.1111/nyas.12493/abstract">
Cobey 2014
</a>, <a href="http://www.garlandscience.com/product/isbn/9780815342434;jsessionid=jUIKR3YCu+EU9PPmbulBjg__">
Murphy 2011
</a>
</div>
</section>
<section>
<h3>Adaptive immune memory</h3>
<p>Unclear how memory B and T cells selected
<p>Location of activation affects trafficking
<p>(some circulate, some resident)
</section>
<section>
<h3>Tolerance</h3>
<p>How does the immune system distinguish self from non-self?
<img class="stretch" src="images/spiderman.jpeg">
</section>
<section>
<h3>Tolerance by T cells</h3>
<p>Central tolerance: positive selection for non-self recognition
<p>Peripheral tolerance: lack of co-stimulation, activation-induced cell death, regulatory T cells
</section>
<section>
<h3>Tolerance by B cells</h3>
<p>"Receptor editing" occurs in bone marrow
<p>T cells prevent some binding to self
<p>Self-antigens rarely opsonized
</section>
<section data-background="#99CCFF">
<h3>How can natural and vaccine-induced immunity differ?</h3>
</section>
<section>
<h3>Heterogeneity in immune responses</h3>
<p>arises in innate and adaptive immunity
</section>
<section>
<h4>Polymorphism in TLRs affects susceptibility</h3>
<img class="stretch" src="images/tlr.jpg">
<div class="citation">
<a href="http://www.nature.com/nrg/journal/v13/n3/abs/nrg3114.html">
Chapman and Hill 2012
</a>
</div>
</section>
<section>
<h3>MHC shapes HIV dynamics</h3>
<img class="stretch" src="images/mhc_hiv.png">
<div class="citation">
<a href="http://www.nature.com/nm/journal/v22/n6/full/nm.4100.html">
Carlson et al. 2016
</a>
</div>
</section>
<section>
<img src="images/soay.jpg">
<div class="citation">
<a href="http://blogs.discovermagazine.com/d-brief/2013/08/21/single-gene-explains-sheeps-dilemma-long-horns-or-long-life/#.V5YdwZMrKHo">
Discover/Arpat Ozgul
</a>
</div>
</section>
<section>
<h3>Balancing selection</h3>
<p>Autoimmunity costly but increases winter survival
<img src="images/soay_survival.png">
<div class="citation">
<a href="http://science.sciencemag.org/content/330/6004/662.long">
Graham et al. 2010
</a>
</div>
</section>
<section>
<h3>Measuring antibody responses</h3>
<p>ELISAs
<p>neutralization assays</p>
<p>others (e.g., HAI/HI, SPR, protein microarrays)
<p>effector functions (ADCC, ADCP)</p>
</section>
<section>
<h3>ELISAs</h3>
<img src="images/elisa_types.png">
<div class="citation">
<a href="https://theory.labster.com/types-elisa/">
Labster Theory
</a>
</div>
</section>
<section>
<h3>Indirect ELISA</h3>
<img src="images/indirect_elisa.png">
<div class="citation">
<a href="https://ruo.mbl.co.jp/bio/e/support/method/elisa.html">
MBL
</a>
</div>
<p>Readout: Absorbance or optical density (OD)
</section>
<section>
<h3>Measuring T cell responses</h3>
<p>ELISPOT: assays individual T cells cytokine production</p>
<p>Antigen stimulation with flow cytometry
<p>Peptide:MHC tetramers to identify specificity
<p>Repertoire analysis
</p>
</section>
<section>
<h3>SARS-CoV-2 T cell responses in kids vs. adults</h3>
<img class="stretch" src="images/tcell_cohen.png">
<div class="citation">
<a href="https://www.nature.com/articles/s41467-021-24938-4">
Cohen et al. 2021
</a>
</div>
</section>
<section>
<h3>The new frontier</h3>
<p>Single-cell approaches
<p>Local measurements</p>
</section>
<section data-background="#FFFF99">
<h3>Not all immune responses matter</h3>
<p>"Correlates" v. "causes" of protection
<p>Partial clues: KOs, disorders, infection risk, evolution </p>
</section>
<section>
<h3>Escaping immunity</h3>
<p>Hide (human papillomavirus, HIV, EBV)
<p>Suppress (cytomegalovirus)
<p>Distract (hepatitis B virus)
<p>Disguise (HIV)
<p>Outrun (influenza A)
</section>
<section>
<h3>HPV: Hiding from the immune system</h3>
<img src="images/hpv_lifecycle.jpg">
<div class="citation">
<a href="http://mmbr.asm.org/content/73/2/348.long">
Lazarczyk et al. 2009
</a>
</div>
</section>
<section>
<h3>CMV: Immune suppression</h3>
<img src="images/cmvil10.jpg">
<div class="citation">
<a href="http://www.pnas.org/content/97/4/1695.long">
Kotenko et al. 2000
</a>
</div>
</section>
<section>
<h3>HBV: Distraction</h3>
<img src="images/hbvAg.gif">
<div class="citation">
<a href="https://onlinelibrary.wiley.com/doi/full/10.1111/j.1574-6968.1998.tb13171.x">
Yamaguchi et al. 2006
</a>
</div>
</section>
<section>
<h3>HIV: Disguise</h3>
<img src="images/hiv_glycans.jpg">
<div class="citation">
<a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(16)31020-8">
McCoy et al. 2016
</a>
</div>
</section>
<section>
<h3>Influenza: Outrun</h3>
<img src="images/h1n1_avidity.png">
<div class="citation">
<a href="http://science.sciencemag.org/content/326/5953/734.long">
Hensley et al. 2009
</a>
</div>
</section>
<section data-background="#99CCFF">
<h4> What are the most common pathogens in humans?</h4>
<h4> What does their abundance have to do with their immune interactions?</h4>
</section>
<section>
<h3>Human papillomaviruses</h3>
<p> Nearly 100% prevalence, but slow evolution</p>
<img class="stretch" src="images/pv_phylogeny.png">
<div class="citation">
<a href="http://emph.oxfordjournals.org/content/2015/1/32.full.pdf">
Bravo and Félez-Sánchez 2015
</a>
</div>
</section>
<section>
<h3>Enteroviruses: Common colds</h3>
<img class="stretch" src="images/enterovirus_ts.jpg">
<div class="citation">
<a href="http://www.virologyj.com/content/10/1/305">
Garcia et al. 2013
</a>
</div>
</section>
<section>
<h3>Rhinoviruses include >100 serotypes</h3>
<img class="stretch" src="images/rhinovirus_phylogeny.png">
<div class="citation">
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923423/">
Palmenberg et al. 2009
</a>
</div>
</section>
<section>
<h3>>90 serotypes of <i>Streptococcus pneumoniae</i></h3>
<img class="stretch" src="images/pneumo.png">
</section>
<section>
<h3>Flu facilitates pneumococcus</i></h3>
<img class="stretch" src="images/pneumo_flu.png">
<div class="citation">
<a href="http://www.nature.com/nrmicro/journal/v12/n4/abs/nrmicro3231.html">
McCullers 2014
</a>
</div>
</section>
<section data-background="#FFFF99">
<p> Competition for susceptible hosts generates complex dynamics
<p> Formal models beat intuition
<p> Pathogens interact with multiple immune populations
<p> Pathogens interact with very different hosts
<p> Pathogens show extensive diversity, not only antigenic
<p> Pathogens can compete with and facilitate one another
</div>
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