Immunosenescence et CMV Vaccins et vieillissement

DPML: Mise à jour diagnostique
Autour du vieillissement :
Laboratoire et bilan biologique
Immunosénescence
et CMV,
Vaccins et
vieillissement
Pascal Meylan, Institut de
Microbiologie et Service des
Maladies Infectieuses
agenda
• Le système immunitaire et son vieillissement
• Vieillissement et infections
• Cytomegalovirus, biologie et impact sur le
système immunitaire
• CMV et mortalité
• CMV, immunosénescence, et vaccins
• CMV et maladies cardiovasculaires
• conclusions
Le système immunitaire et son
vieillissement
2) Output thymique
1) TLR
5) inflamm-aging
3) Répertoire appauvri
4) Spent
lymphocytes
D’après Lang et al, NPG, 2012;12:171, Panda et al, J Immunol, 2010; 184:2518, Mitchell et al, Clin Exp
Immunol , 2010;161:497,
Vieillissement et infections: les
exemples bien connus
• Liés à une baisse documentée de
l’immunité
– Réactivation tuberculeuse
– Zona (réactivation de VZV)
– Listériose
• Liés à une baisse de l’immunité et/ou
d’autres lignes de défense
– Pneumonie
– Infection urinaire
Vieillissement et infections: une
relation quantitative
ID
All cause
Curns AT et al, Arch Int Med, 2005;
KT, symptomatic infection, treated, with
asymptomatic recurrences (protracted)
CMV DNA, PBL
CMV DNA, Plasma
infectious units
D+/R700
10 7
6
10 6
* ***
500
400
10 5
asx
300
*
200
10 4
10 3
asx
10 2
sx
100
10 1
10 0
0
0
30
60
90
120
150
days post transplant
180
6
IU/10 PBL
600
copiesp/10 PBL or ml
10 8
predictors of protracted infection:
stepwise multivariate logistic
regression
entering age, D and R serostatus (excluding D-/R-) and start PBL infectivity
predictor
OR (95% CI)
p
age (decade)
2.28 (0.91-5.69)
0.076
donor + serostatus
dropped for p>0.1
0.28
recipient + serostatus
0.031 (0.003-0.329)
0.007
peak PBL infectivity
7.79 (1.75-34.57)
0.004
(Log)
Muheim et al, Transplantation, 2002, 74:226
CMV: a crash course
• Prototype β-herpesvirus
• Latency in mononuclear cells (lung), reactivates
stochastically, kept under control by cellular immune
responses
• Causes mild or no disease in normal host, CMV syndrome or
end organ disease in compromised host (foetus,
immunocompromised)
• SOT patients:
– Risk factors: serostatus pattern, organ type and intensity of
immunosuppression, acute rejection and its treatment, septic
episodes
– Directs effects (CMV disease)
– Indirects effects (immune dysregulation: favors acute and
chronic rejection, graft loss, increase the risk of other
opportunistic infection
CMV latency and reactivation
• Lytic infection (many cell types including
endothelial cells) or latency (monocytes)
• Latency, related to chromatinization of the IE
promoter (the CMV genetic « match ») and cellular
transcription factors concentrations
• Latency can be established almost exclusively in
monocytic myeloid progenitors, including dendritic
cells
• In cells of the mononuclear lineage, cell
differentiation lights on the match, with the
subsequent expression of the lytic CMV genetic
program
MB Reeves, Virus Res, 2011;157:134, Reeves and Sinclair, J Virol, 2013;87:10660
Cytomégalovirus: le palmares clinique
• Cause # 1 d’infections congénitales (0.1-1%
des naissances)
– Cause # 1 de surdité acquise dans l’enfance
• Cause # 1 historique de morbidité et de
mortalité chez les transplantés d’organes
– Rôle encore important dans la survie des greffes
• Agent étiologique important dans:
– Syndrome mononucléosique
– Syndrome de Guillain-Barré
• Role encore à clarifier dans la survie aux
soins intensifs
Impact of Antiviral Preventive Strategies on the Incidence and Outcomes of
Cytomegalovirus Disease in Solid Organ Transplant Recipients
American Journal of Transplantation, O Manuel et al
Volume 13, Issue 9, pages 2402-2410, 5 AUG 2013 DOI: 10.1111/ajt.12388
http://onlinelibrary.wiley.com/doi/10.1111/ajt.12388/full#ajt12388-fig-0003
multistep model of CMV
reactivation and recurrence
MJ Reddehase et al, Journal of Clinical Virology 25 (2002) S23/S36
CMV and T cell responses
• CMV-infected individuals respond to a
bunch of CMV antigens and in total devote
up to several dozen % of their T cells to
CMV (CD4+ and CD8+)!
• Such levels of T cell response only known
for chronic infections such as HIV
Sylwester AW et al, J Exp Med, 2005;673
CMV and T cell responses
Sylwester AW et al, J Exp Med, 2005;673
CMV infection and mortality
• Seropositivity = infection
• Random sample of the EPIC-Norfolk population
based cohort (nord de Londres)
• Baseline CMV IgG level (Diasorin)
• All cause mortality increased with CMV
seropositivity (HR 1.16, 95%CI 1.07-1.26),
progressively across antibody level tertiles
• Effect persisted after adjusting to socio-economic
level and other possible confounders
• Effect seen in smaller and more defined
populations
Gkrania-Klotsas et al, Clin Infectious Diseases, 2013, 56:1421, on line Feb 26, 2013
CMV infection and mortality
•Cause-specific analyses suggested that
increased mortality from
– cardiovascular disease (HR, 1.06 [95% CI, .91–1.24])
– cancer (HR, 1.13 [95% CI, .98–1.31])
– and other causes (HR, 1.23 [95% CI, 1.04–1.47)
all appeared to contribute to the overall
associations
Gkrania-Klotsas et al, Clin Infectious Diseases, 2013, 56:1421, on line Feb 26, 2013
CMV and immune exhaustion or
senescence
• Aging characterized by
immunosenescence
(immune risk profile)
– CD4/CD8 ratio <1
– Reduced absolute
numbers of B cells
– Accumulation of CD8 T
cells expressing CD57
and lacking CD28 (late
stage of differentiation)
– Poor T cell proliferation
after polyclonal
stimulation
– CMV seropositivity
Karrer et al, Exp Gerontol, 2009;44:689 , Wikby et al, Mech Aging Dev, 2006;127:695
Consequences of immune
senescence
• A high immune risk profile is associated with
increased mortality in the very elderly (<85 year
old)
• Reduced naive T cell numbers and diversity may
compromise responses to neo-antigens and
favor infections
• « A relationship between CMV IgG level and
CMV reactivation or long term outcomes has not
yet been evidenced »
Karrer et al, Exp Gerontol, 2009;44:689, Gkrania-Klotsas et al, Clin Infecti Dis, 2013, 56:1421, on line Feb 26, 2013
Age et CMV: impact sur les réponses à
des antigènes (vaccins!)
• Vaccinations chez les personnes âgées
– Influenza
– Pneumocoque
– Tp
– Zoster
• Tous des réponses anamnestiques
• Tous induisent des réponses atténuées
avec l’âge
Age et CMV: impact sur les
réponses à la vaccination influenza
• End-points cliniques:
– maladie d’allure grippale
ou grippe
– Hospitalisation, décès
etc.
• End-points
sérologiques
– Confondus par les
expositions préalables
– Pas validés chez la
personne âgée
• Probabilité d’être
vacciné lié à l’état de
santé
Lang et al, Clin Interv Aging, 2912;7:55, Legrand et al, Vaccine, 2006;24:6605
Age et CMV: impact sur les
réponses à la vaccination influenza
Role of spent CD8 or CD4 T
cells? (trivalent 2010-11)
Role of immunological
memory? (2009 H1N1)
Derhovanessian et al, Vaccine, 2013;31:685; Wald et al, J Med Virol, 2013;85:1557
CMV, vascular lesions and aging
• Role of CMV well established in transplant
vasculopathy (animal models, risk factor and
therapeutic test in heart transplants)
• In kidney transplant,
CMV infection is a
risk
factor for atherosclerotic events in addition to chronic
rejection (coronary,
cerebral and peripheral
a
atheromatosis)
Courivaud et al, J Infect Dis 2013;207:1569, Potena et al, Transplantation, 2006;82:398
What about the general
population?
• Many studies have related CMV seropositivity with all
cause/cardiovascular disease mortality in various (elderly)
populations, frequently in interaction with inflammatory
markers (IL-6, CRP)
• The NHANES III campaign, enrolling a population based US
sample, 1988-94, >25 y-old
• “Our study sample is limited to subjects that were 25 years of
age and older (range 25–90 years of age) at time of
examination (N = 15242 (48.7%)), were tested for CMV
serostatus and CRP level (N = 14164 (92.9%)) and eligible for
mortality follow-up on December 31st, 2006 (N = 14153
(99.9%). Forty-eight subjects (0.3%) were excluded from the
analyses of CVD-related mortality because their cause of
death could not be ascertained
Simanek et al, PLOS One, 2011;6:e16103
What about the general
population?
Unadjusted Kaplan-Meier survival curves for cardiovascular disease (CVD)-related mortality by combined
cytomegalovirus (CMV) serostatus and C-reactive Protein (CRP) level for 13963 subjects, >25 years of age
Simanek et al, PLOS One, 2011;6:e16103
What about the general
population?
CMV Seropositive and High CRP Level
Unadjusted Kaplan-Meier survival curves for cardiovascular disease (CVD)-related mortality by combined
cytomegalovirus (CMV) serostatus and C-reactive Protein (CRP) level for 13963 subjects, >25 years of age
Simanek et al, PLOS One, 2011;6:e16103
Potential mechanisms?
• Direct endothelial infection (localized?)
• Induction of inflammatory cytokines
• Induction of autoimmune responses (cross
reactivity between CMV UL122 , US 28
and HSP60)
• TLR-mediated inflammatory responses
Stassen et al, J Clin Virol, 2006;35:349, Jeffery et al, J Virol, 2013;87:6530
Conclusions
• CMV is a virus which latency is indeed always
« simmering » (mijoter, köcheln): chronic rather
than latent?
• This has a major impact on the immune system,
probably a major cause for immunosenescence
(and a very peculiar recombinant vaccine
platform!)
• It interacts with other CV risk factors to accelerate
atheromatosis
• CMV correlates with decreased survival!
• Overall, the effect of CMV on survival raises
issues on CMV preventive approaches
PD Griffiths, Lancet Infect Dis, 2012;12:790
Eradicating CMV?
• 60-80% of world population infected
• Burden of disease
• gB vaccine (for childbearing age women) 50% protective, other in
development
• Potential impact on CMV prevalence of vaccinating toddlers and 12
year old children on congenital infections?
Congenital infections born to seropositive
women by reactivation
Congenital infections born to seropositive
women by reinfection
Congenital infections born to
women with primary infection
Pass et al, New Eng J Med, 2009;360:1191, Griffiths PD, Lancet Infect Dis, 2012;12:790