IL VIROMA
FABRIZIO MAGGI Dipartimento di Ricerca Translazionale, Università di Pisa
UOC Virologia Universitaria, AOUP
All the nucleic acids (ssDNA, dsDNA, ssRNA, dsRNA) belonging to the virus-like particles associated with a particular habitat, defined over a range of scales from the entire body to a specific organ or tissue
D e f i n i t i o n
Wylie et al. Transl Res 2012; Virgin, Cell 2014; Zou et al. Microbiome 2016; Freer et al. Curr Med Chem 2018
~60% ~30% ~10%
Handley, Genome Med 2016; Houldcroft et al. Nat Rev 2017
• inadeguate bioinformatic tools for
virome analysis
• lack of robust virome database
• of the US$ 920 million invested in microbiome research from 2012 to 2014, only 3% of research was dedicated to studies of virome
L i m itat io n s o f hum a n v i ro m e st u d y i n g
C o m p o s i t i o n
18
18
12
16
5
3
n. viral families
109 particles / gram (gut, oropharynx, skin) 105 - 107 particles / ml (blood, urine)
Popgeorgiev et al. Intervirology 2013; Rascovan et al. Annu Rev Microbiol 2016
S t r u c t u r e
Wylie et al. Transl Res 2012; Virgin, Cell 2014; Zou et al. Microbiome 2016; Freer et al. Curr Med Chem 2018
Core
Variable host
genetic
host physiology (immune system)
host pathobiology (disease status)
host lifestyle (diet)
host environment
host drug therapy
De Vlaminck et al. Cell 2013
V i r o m e s t r u c t u r e i s a f f e c t e d b y i m m u n e m o d u l a t i o n a n d a n t i v i r a l t h e r a p y
T h e h e a l t h y v i r o m e
Moustafa et al. PLOS Pathogens 2017; Rampelli et al. Environ Microbiol 2017; Pilar et al. PNAS 2016
Bacteriophages in ~ 50% of individuals:
• Caudovirales • Microviridae
Eukaryotic viruses • Anelloviridae • Herpesviridae • Papillomaviridae • Adenoviridae
BLOOD 8,240 individuals
GUT
Prevalence
Eberl, Mucosal Immunol 2010; Rosario and Breitbart, Curr Op Virol 2011; Mokili et al. Curr Op Virol 2012
T h e c o m p l e t e v i r o m e
The most sequence reads by metagenomic analyses has features of viral genetic material but no taxonomic
classification
" Me ga" v i ro me
" Lo w - leve l" v i ro m e
60%
20%
20%
The "dark" virome
"The "grey " virome"
The "known" virome
T h e " ex pa nding " v i r us e s
Vu et al. J Clin Virol 2016; Lau et al. Transfusion 2017; DeCaprio et al. Nat Rev 2013
The expanding tissue tropism The expanding viral families T h e A s t r o v i r u s s t o r y
Classic HAstV (1975)*
feces
liquor
blood nasopharyngeal
swab
urine MLB1 (2008)
MLB1 (2008) MLB2 (2011) VA1 (2009)
MLB1 (2008) MLB2 (2011) VA1 (2009)
MLB1 (2008) MLB2 (2011) VA1 (2009)
* Year of first identification
T h e P o l i o m av i r i dae s t o r y
V i r o m e a n d i m m u n e s y s t e m
Virgin et al. Cell 2009
“N ORM A L” i m m u ne system
Virome Immune system
“ I m m u n o l o g i c i m p r i n t ”
R e s p o n s e t o n e w i n fe c t i o n s , va c c i n e s ,
o r n o v e l v i ra l va r i a n t s
I n f l a m m a t o r y a n d n o t i n f l a m m a t o r y d i s e a s e s
d y n a m i s m
Virome: equilibrium between health and disease
Rascovan et al. Annu Rev Microbiol 2016
Crohn’s disease
Type I diabetes
Asthma
V i r o m e – m i c r o b i o t a i n t e r a c t i o n
Pfeiffer and Virgin, Science 2016; Karst, Nat Rev Microbiol 2016
Vi r a l d i s e as e o r
n o d i s e ase
Indirect
Mechanisms of interaction
Direct
Bacteria and/or bacterial components or products interacting with virus:
LPS (poliovirus, MMTV, HIV)
Peptidoglycan (poliovirus)
HBGA glycans (norovirus)
Defensins (adenovirus)
Butyric acid (HIV, EBV, KSHV)
Inducing a tolerogeneic microenvironment (MMTV)
Suppressing Ab production (rotavirus, norovirus)
Suppressing IFN signaling (norovirus)
Microbiota skews the antiviral immune response by:
The “do uble fa c e ” o f t he m ic ro b i o ta
Monedero et al.,Trends Biotech 2018; Iturriza-Gomara and Cunliffe, JID 2017
A n t i - v i r a l e f f e c t
P r o - v i r a l e f f e c t
FMT
responders
P ha ge s a nd fe ca l m ic ro b ia l t ra n s p la ntat io n
Zuo et al. Gut 2017
The restoration of virome community is as important as that of bacterial microbiome in FMT Donor selection based on virome characteristics should be considered in FMT practice
Pts. with Clostridium difficile infection (CDI)
(FMT)
CDI recipients with Caudovirales: • higher richness in donor • higher colonisation level of donor-derived taxa
A n e l l o v i r u s T T V a n d p o s t - t ra n s p l a nt c o m p l i c a t i o n s
2
3
4
5
6
7
8
0 10 20 30 40 50 60 70 80 90 120
150
180
360
TTV
DN
A
(Log
10 c
opie
s /
ml)
Days post - transplant
CMV pos (n. 69)
CMV neg (n. 136) p < 0.001
De Vlaminck et al. Cell 2013; Maggi et al. Sci Rep 2018
Me
an
TT
V D
NA
*
(Log
cop
ies/
ml
95%
CI)
A n e l l o v i r u s T T V v i r e m i a p r e d i c t s C M V r e a c t i va t i o n
+ - 3
4
5 n. 69
n. 136
n. 205; p = 0.001
* measured between 0 and 10 days post-transplant
Me
an
TT
V D
NA
*
(Log
cop
ies/
ml
95%
CI)
Total
Maggi et al. Sci Rep 2018
C M V d e t e c t i o n a c r o s s 4 m o n t h s p o s t - t x
n. 39
n. 27
n. 66; p = 0.033
n. 109
n. 30
n. 139; p = 0.038 3
4
5 Kidney Liver
+ - + -
T TV index in l i ve r / k idney t ra ns p la nt re c ip ie nt s
> 3.45 log10 copies/ml higher probability of CMV
reactivations
TAKE-HOME MESSAGE :
TTV viremia above 3.45 log DNA copies/ml within the first 10 days post-transplant correlates with higher propensity to CMV reactivation
following liver/kidney transplantation
≤ 3.45 log10 copies/ml lower probability of CMV
reactivations
Maggi et al. Sci Rep 2018
C o n c l u s i o n s
Our understanding of the human virome is still fragmented and standardized methods are required for providing a more accurate study of the virome
Assessing the human virome as a whole will be of interest in medical diagnosis and give highly valuable information to monitor the patient management
By now, novel associations and routinely unemployed kinetics of viruses within the virome have important clinical implications for the relationships between transplantation, graft rejection and viral reactivation