Download Immune system activation - UCSF Immunology Program

Viruses
Obligate intracellular organisms
Bypass barriers - insects vectors, animal bites,
trauma, ulcerations
Exploit mucosal M cells
Co-evolution with receptors drives narrow host
specificity
Viremia needed to seed organs required for
transmission - kidneys (urine), skin, salivary glands
(secretions), respiratory (sputum) and digestive tracts
(feces)
Immune cells make
good targets…
Viruses
Flavors: ssRNA, dsRNA, DNA
Encoded within virally encoded capsid proteins
Enveloped or not
Classes: Lytic (cytopathic) (polio, flu) versus
nonlytic (hepatitis B, LCMV)
Latency: special property of some lytic viruses
Micro-evolution: RNA viruses near mutational
thresholds/many defective particles; DNA viruses
can use transient gene amplification
Innate response to viruses - nucleic acid recognition
cGAS
STING
Pichlmair and Reis e Sousa, Immunity 27:370, 2007
Cytosolic dsRNA detectors - RNA helicases/RIG-I/MAVS (Mda5)
Li S et al, MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. eLIFE 2013;2:e00785
Cytosolic DNA detectors – the cGAS/STING pathway
Diner EJ, RE Vance. Taking the STING out of cytosolic DNA sensing. Trends Immunol 2013
The cGAS/STING pathway is essential for the cytosolic DNA interferon response
Li X-D et al. 2013. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science
341:1390-4.
Key players: interferons
Issacs and Lindemann, Proc R Soc London B Biol Sci 147:258-67, 1957
Type 1 interferons: interferon-/interferon- (14)
Type 2 interferon: interferon-
Hybrid interferons: interferon- (3) {IL-28A, IL-28B, IL-29}
Auto-enforcing loop: IRF-3 > IFN > Stat1/2 + IRF-9 > IRF7 > IFN’s
Nature 472:481, 2011
IFNs induce multiple genes with anti-viral activities
Why all the interferons and what do they do?
The ‘bleb’ hypothesis
M
DC
Apoptosis - cell turnover, tissue
development, etc.
Tolerance
Immune system activation
Type 1 IFNs overcome inability to respond to apoptotic ‘blebs’
MpD
C
B
Clearance - ligands,
opsonins, receptors
Nucleic acid sensors -TLRs 7,8,9/helicases
Apoptosis thresholds
Type 1 IFNs
DC and B cell activation
X
Tolerance
Cell activation
inhibitors
X
Immune system activation
Interferonopathies – exogenous and genetic
1. Exogenous – type 1 IFN treatment (MS, HCV, etc.)
5-30% of patients receiving type 1 IFNs get auto-antibodies (ANA, etc)
and ~5% get autoimmune disease (anti-thyroid Ab’s, vitiligo, diabetes).
2. Disease ‘signatures’ of elevated type 1 IFNs
Systemic lupus erythematosis
Pre-activation state of latent tuberculosis
3. Genetic interferonopathies (high serum type 1 IFN, autoantibodies,
cranial calcifications, mycobacterial susceptibility)
Aicardi-Goutieres (Trex1 mutation – DNA exonuclease)
Spondyloenchondrodysplasia
ISG15 deficiency (negative regulator of IFN signaling)
SAVI (STING-associated vasculopathy with onset in infancy) - a gain-offunction STING mutation
Viruses attack common cellular defense pathways
Medina RA, A Garcia-Sastre, Influenza A viruses: new research developments. Nature Rev Microbiol 9:590, 2011.
Relevant Life Cycle Issues
1. An intestinal infection of wild waterfowl.
2. Crosses to mammals through close contact.
3. Multiple ‘crosses’ enhance capacity to establish
mutants and reassortment variants
adapted to mammalian hosts.
4. HA species specificity:
sialic acid -2,3 galactose linkage (avian intestine; human LRT)
sialic acid -2,6 galactose linkage (human trachea)
both (pig trachea)
5. NA compatibility:
human viruses gain -2,6 activity
stalk length (longer NA enhances activity in humans)
6.HA, NA Adaptations
HA glycosylation; HA1/HA2 fusion domain (expanded basic amino
acid repeat in highly pathogenic chicken H5/H7/H9 flu -HPAIenhances spectrum of proteases that can activate HA fusion
event; may explain pathogenicity of co-infection with bacteria)
Medina RA, A Garcia-Sastre, Influenza A viruses: new research developments. Nature Rev Microbiol 9:590, 2011.
Mutation and reassortment drive influenza A epidemics and pandemics
Influenza Pandemics
Year
Common Name
Subtype
Origin
Deaths
1889
-
H2N2
?Europe
6 million
1898
-
H3N2
?Europe
0.5 million
1918
Spanish Flu
H1N1*
?Eurasia
40 million
1957
Asian Flu
H2N2*
China
4 million
H3N2*
China
2 million
1968^
Hong Kong Flu
1977^
Russian Flu
H1N1+
China/Russia
1 million
2009^
Swine Flu
H1N1*
N. America
>18,000
* Contained elements from avian viruses
+
Laboratory-derived from frozen stock (persons pre-’50s immune)
^Antigenic variants continue to co-circulate
Asian Live-Animal Markets The Great Zoonotic Mixer
Live chickens and
ducks in same cages
A new pandemic influenza virus, H1N1/09
USA estimates: 22 million infected, 3900 deaths
Relevant Immunology
Innate immunity:
Type 1 IFNs, TNF-, MxA, IFIT
and IFITM proteins
HA antibodies:
Neutralize infectivity, protective
NA antibodies:
Restrict viral spread
Cytotoxic CD8 T cells:
M2, PB2, HA, NP specificity common
M2 specificity almost universal
The Most Common Human TCR in the World
CD8 TCR / chains
V17/V10.2
Influenza A Matrix Protein
amino acids 58-66
HLA-A2 (A*0201)
Stewart-Jones et al. Nature Immunol 7:657, 2003
Why do they die?…
Human Immunodeficiency Virus
Worldwide:
35 million infected
29 million dead
14,000 new infections/day
2/3 infected persons in Africa
U.S.:
~1 million infected including 400,000 dead
(appeared 1983)
Worldwide Estimates of Numbers of HIV-Infected Persons
Origins of HIV
(9 genes)
Chahroudi A, et al. Science 335:1188, 2012.
HIV Origins - Primate Lentiviruses
HIV-1
SIVcpz - West equatorial Africa
= M group (chimps)
Cameroon
= N group (chimps)
Gabon
= O group (gorillas)
HIV-2
SIVsm (sooty mangabey)
Infection/Disease in areas of active bushmeat trade.
HIV Origins
SIVcpz - Asymptomatic infection of chimpanzees
(up to 1% in areas of west Central Africa)
HIV-1: M group consists of 11 clades
Last common ancestor entered human population
around 1890 (+ 30 yrs)
Spread and recombination among founder HIV clades
HIV is a primate lentivirus
Lentiviruses can infect nondividing cells
Replication driven from long terminal repeats
Structural genes - gag, pol, env
Regulatory genes - tat, rev
Accessory genes - vif, vpr, vpu, nef
HIV life-cycle
APOBEC
TRIM5,
TREX1,
SAMHD1
Tetherin
Innate HIV Resistance by APOBEC3G
Arias JF et al., Frontiers Microbiol 3 (275):1-12, 2012.
HIV vif sequesters
APOBEC enzymes from
the budding virions
Martin-Serrano J, SJD Neil.
Host factors involved in
retroviral budding and release.
Nature Rev Microbiol 9:519,
2011.
HIV Pathogenesis
1. Entry at sites of M cells or trauma (STDs)
M
2. Transit to LN via C-type lectins* on dendritic cells
*DC-SIGN, MR, Langerin
DC-SIGN
3. Peak CD4+ T cell infection days 4-7
4. Viremia peaks day 14
5. All lymphoid tissues infected by day 23
HIV infection occurs
predominantly at mucosa
Dendritic cells mediate transit of
virus to regional lymph nodes via
CLRs
Massive loss of mucosaassociated lymphocytes of the
small intestine precedes systemic
CD4 T cell loss
Proposed epithelial damage mediates sustained
activation of mucosal T cells after HIV infection
Brenchley, Price & Douek, Nat Immunol 7:235, 2006
HIV Receptors
CD4
1o Infection: M-tropic, CCR5
R5
Progressive CD4 T cell
destruction
X4
Turnover 1010
virions/day
CXCR4
T-tropic
Syncytium-forming
Natural History of Untreated HIV Infection
Natural HIV Resistance
1. CCR5D32 - slow progression if infected
20% W. European Caucasians heterozygous
1% homozygous
Successful bone marrow tx
2. HLA class I homozygosity - rapid progression
3. Rare HLA class I alleles - slow progression
(suggests virus near mutational threshold)
Natural HIV Resistance
Scherer A, et al. PNAS 101:12266-70, 2004.
Science 334:89-94, 2011
Why no HIV vaccine?
1.
Escape variants/altered peptide ligands - virus operates near mutational
threshold
2.
Neutralizing antibodies low-affinity, arise late (conformationally hidden,
glycan shielding, mutational escape, evolutionary escape from ‘natural
antibodies’, polyclonal B cell activation may impede)
3.
Loss of CD4 help required for CD8, antibody responses
4.
Immune exhaustion with PD-1 expression on CD4 and CD8 anti-HIV T
cells
5.
Prolonged time required to develop broadly neutralizing protective
antibodies (bnAbs)
Kwong PD, JR Mascola. 2012. Human antibodies that neutralize HIV-1: Identification, structures, and B cell ontogenies.
Immunity 37:412-25.