Malaria and rain in India, 1987-2007

Influenza in St. Petersburg, 1968-2005

Infections in Seattle, 1924-1933

At the base of infectious disease dynamics...

...we have consumers and resources

Seemingly complex dynamics are common

With nonlinearity, correlations can mislead

Partial solution: Mechanistic models



$H$ hares, $L$ lynxes

hare birth rate $a$, predation rate $b$,

consumption rate $c$, death rate $d$

(Other solutions: experiments, causal inference)

(working hypothesis)

Competition for susceptible hosts shapes the ecological and evolutionary dynamics of pathogens.

Implicit assumption of SIR model

The susceptible fraction determines a pathogen's growth rate

$$I' > 0 \Rightarrow \frac{\beta S}{N} > \gamma$$

If the SIR model fits poorly, what next?

Other possibilities

transient dynamics and noise

host population structure


more complex forms of immunity

multiple "immunophenotypes"

How does the immune response "see" pathogens?

(in ways that impacts fitness?)

Immunity: Coordinated innate and adaptive responses

Innate immunity

Less specific

Nearly memoryless

The complement system

Extremely fast destruction, tagging, and signalling

Attacks via lectin, "alternative," and classical pathways

Effective against viruses, bacteria, parasites

Tags pathogens ("opsonization"), perforates (MACs)

Attracts phagocytes


Long-lived sentinels and killers

Resting, primed, or hyperactive

Display to T cells via MHC class II

Secrete IL-1, TNF, complement proteins to kill and signal


"On call," do most of the dirty work

70% of WBCs, 100 billion produced daily, live 5 days

Respond to IL-1, TNF, f-met peptides from macrophages

Just kill and signal (e.g., IL-2)

Natural killer (NK) cells

"On call" for some killing and signalling

Target tumor cells, virus-infected cells, bacteria, parasites, fungi

Activated by LPS, interferons produced by dying cells

Kill cells bound by Abs (ADCC) or not expressing MHC class I

Major supplier of cytokines like IFN-$\gamma$ and TNF

Toll-like receptors (TLRs)

Pattern recognition receptors expressed on surfaces of lymphocytes

10 identified in humans so far (TLR1-10)

Recognize "pathogen-associated molecular patterns" (PAMPs)

e.g., TLR3 recognizes dsRNA (viral infections), TLR4 lipopolysaccharide (LPS) on bacteria

Adaptive immunity

More specific

Some memory

T cells recognize presented peptides

MHC class I

Bind peptides 8-11 amino acids long

Expressed on almost every cell

In humans, six genes encoded by HLA-A, HLA-B, HLA-C

Recognized by CTLs (CD8+ T cells)

MHC class II

Bind peptides 13-25 amino acids long

Expressed only by immune cells

In humans, encoded by HLA-D

Recognized by helper T cells (CD4+ T cells)

Dendritic cells: Master intelligence

Use TLRs and other receptors to detect pathogens

Sensitive to local cytokine profiles

Once in lymph nodes, use diverse costimulatory molecules to activate T cells

T cells: Activated by antigen presentation

Antigens presented by dendritic cells, macrophages, B cells

Co-stimulation required (B7 binds to CD28)

Dendritic cells provide "snapshot"

Macrophages provide sustained support

B cells can concentrate rare and familiar antigen

So... what are Th cells?

Produced by rearrangement, educated in thymus

If stimulated by DCs, proliferate (6-h doubling time)

After several days, become "effector cells", which

(1) remain in blood, helping B cells and CTLs, or

(2) help innate and adaptive cells in infected tissue.

Th cells secrete specific cytokine profiles!

General profiles of Th cells

Th1: IL-2, IFN-$\gamma$, TNF (viruses and bacteria)

Th2: IL-4, IL-5, IL-10 (parasite and mucosal infections)

Th17: IL-17A, IL-17F, IL-21, IL-22 (mucosal infections)

Signalling is local!

CTLs (CD8+ T cells): Kill infected cells

Activated in lymph node, requires Th

Proliferates following activation, enters tissue

Carefully kills infected cells via MHC I

Requires IL-2 (often from Th) to keep proliferating

B cells recognize protein structure

Two sources of B cell receptor diversity

Rearrangement of variable gene segments

Somatic hypermutation during affinity maturation

What does "antigenic variation" mean?

Formally, variation in surface proteins (antibody targets)

Broader concepts may be more useful

Adaptive immune memory

Unclear how memory B and T cells selected

Location of activation affects trafficking

(some circulate, some resident)


How does the immune system distinguish self from non-self?

Tolerance by T cells

Central tolerance: positive selection for non-self recognition

Peripheral tolerance: lack of co-stimulation, activation-induced cell death, regulatory T cells

Tolerance by B cells

"Receptor editing" occurs in bone marrow

T cells prevent some binding to self

Self-antigens rarely opsonized

How can natural and vaccine-induced immunity differ?

Heterogeneity in immune responses

arises in innate and adaptive immunity

Polymorphism in TLRs affects susceptibility

MHC shapes HIV dynamics

Balancing selection

Autoimmunity costly but increases winter survival

Not all immune responses matter

"Correlates" v. "causes" of protection

Partial clues: KOs, disorders, infection risk, evolution

Escaping immunity

Hide (human papillomavirus, HIV, EBV)

Suppress (cytomegalovirus)

Distract (hepatitis B virus)

Disguise (HIV)

Outrun (influenza A)

HPV: Hiding from the immune system

CMV: Immune suppression

HBV: Distraction

HIV: Disguise

Influenza: Outrun

What are the most common pathogens in humans?

What does their abundance have to do with their immune interactions?

Human papillomaviruses

Nearly 100% prevalence, but slow evolution

Enteroviruses: Common colds

Rhinoviruses include >100 serotypes

>90 serotypes of Streptococcus pneumoniae

Flu facilitates pneumococcus

Competition for susceptible hosts generates complex dynamics

Formal models beat intuition

Pathogens interact with multiple immune populations

Pathogens interact with very different hosts

Pathogens show extensive diversity, not only antigenic

Pathogens can compete with and facilitate one another