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Exploration Du Virome Humain : De La Symbiose À La Pathologie

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Exploration Du Virome Humain : De La Symbiose À La Pathologie Exploration du virome humain : de la symbiose à la pathologie Christelle Desnues, CR CNRS IHU Méditerranée Infection, Marseille Séminaire Collège de France, le 17/01/2018 Picture from ScienceNews, 2013 What are viruses? Simple definitions for real complexity… Virus means “poison, venom” in Latin Viruses are small (with exceptions), infectious, obligate intracellular parasites depending on host cells to replicate. Because they lack the resources for independent existence, they exist on the borderline of the definition of life. The virion (virus particle) consists of a nucleic acid genome surrounded by coat proteins (capsid) that may be enveloped in a host-derived lipid bilayer. Viral genomes consist of either RNA or DNA. They may be single-, double, or partially double stranded. The genomes may be circular, linear, or Introduction to the human virome segmented. Why working on viruses? §Viruses are everywhere… üMost abundant biological entity in aquatic and terrestrial environments (10 31) üInfect organisms from the 3 domain of life (Eukaryotes, Bacteria, Archaea) Virus-like Abundances in 1 ml of seawater particles Virus/phages 106-108 Heterotrophic bacteria 1,000,000 Photosynthetic bacteria 100,000 Bacteria Protozoa 4,000 or archea Algae 3,000 Zooplankton <<1 § Viruses impact the ecosystem functions Introduction to the human virome Through their lytic and lysogenic cycles, viruses play a fundamental role on microbial growth rates, nutrient cycling, genetic exchanges (and thus diversity, adaptation and evolution) Suttle, Nature (2005) Desnues et al., Nature (2008) Viruses and humans ü It is estimated that there are 100 times more viruses in our body than human cells Haynes & Rohwer (2010) 13 Human cells ≈ 10 Viral particles ≈ 1015 Bacterial cells ≈1014 ü The number of free virions varies from 109 particles/g for body barriers (gut, oropharynx, skin) to 107 and 105 particles/ml for urine and blood, respectively Haynes & Rohwer (2010) Mokili, Curr. Op. Virol. (2012) Introduction to the human virome ü Collectively, this viral flora is known as the human virome The human virome is defined as the repertoire of all viruses that are found on the surface and inside our body This includes viruses that cause acute, latent or chronic, symptomatic or asymptomatic infections The human virome ü Dysbiosis by predating on Viruses causing beneficial strain transcient acute infections ü Maintain homeostasis by Influenza and Ebola virions killing pathogens Lytic Virus causing Bacteriophages persistent, and archaeal latent viral viruses infection Temperate 8% of the human genome ü Change the microbial host Each adult is chronically phenotype infected by 8-10 viruses Human Virgin et al., Cell (2009) endogenous Introduction to the human virome ü Increased pathogenicity, Virgin, Cell (2014) retroviruses antibiotic resistance, and perhaps new metabolic capacity The human silent virome The human body is a composite of highly heterogeneous ecosystems and viral communities differ in terms of abundance and composition within anatomical sites Nervous system Circulatory system Herpesviridae Adenoviridae Anelloviridae Bornaviridae Baculoviridae Inoviridae Herpesviridae Microviridae Integumentary system Marseilleviridae Parvoviridae Herpesviridae Anelloviridae Myoviridae Hepeviridae Myoviridae Circoviridae Polyomaviridae Flaviviridae Papillomaviridae Inoviridae Papillomaviridae Bunyaviridae Podoviridae Microviridae Poxviridae Paramyxoviridae Polyomaviridae Parvoviridae Siphoviridae Retroviridae Siphoviridae Respiratory system Adenoviridae Anelloviridae Digestive system Iridoviridae Parvoviridae Herpesviridae Anelloviridae Herpesviridae Coronaviridae Marseilleviridae Circoviridae Mimiviridae Picornaviridae Myoviridae Microviridae Myoviridae Orthomyxoviridae Papillomaviridae Picobirnaviridae Papillomaviridae Paramyxoviridae Podoviridae Reoviridae Phycodnaviridae Polyomaviridae Caliciviridae Podoviridae Poxviridae Astroviridae Poxviridae Siphoviridae Virgaviridae Siphoviridae Picornaviridae Genito/urinary system Introduction to the human virome Adenoviridae Herpesviridae Viral Groups Papillomaviridae - double stranded DNA viruses Polyomaviridae - single stranded DNA viruses Anelloviridae - double stranded RNA viruses - (+)single stranded RNA viruses - (-) stranded RNA viruses - Retroviruses Popgeorgiev et al., Intervirology (2013) How to study viruses? Researches and progresses in virology are technollogically-driven 40’s: Electron microscopy 50’s : cell culture Visualization of viral particles. 80’s: Molecular biology Isolation and production of virions. Study of Rapid detection of Elucidation of novel viruses (or ultrastructure and the mechanisms of infection variants). cellular/tissular Quantification of localizations Experimental viral loads. models « Gold standard » in clinical diagnostic Introduction to the human virome How to study viruses? Classical technics for virus discovery/ identification • Lack of standard protocol • Some viruses are unable to propagate in cell culture conditions Cellular • Viral derivation through repetitive cell infection • Lack of standard protocol • High antigenic diversity Serological • Low cross reactivity • Absence of conserved genes among all viruses • New emerging or highly divergent viral genomes are not detected Molecular • Detection limitations depending on the sample Introduction to the human virome Classical technics for The metagenomic era virus identification Introduction to the human virome Viral metagenomics consist in the sequencing of all viral nucleic acids from a sample (culture independent) and in their analysis using bioinformatics How to study viruses? Researches and progresses in virology are technollogically-driven 40’s: Electron microscopy 50’s : cell culture Visualization of viral particles. 80’s: Molecular biology Elucidation of Isolation and ultrastructure and production of Mid-2000: NGS virions. Study of Rapid detection of cellular/tissular novel viruses (or localizations the mechanisms Meta-analyses: of infection variants). Quantification of study of viruses at Experimental viral loads. the community models scale « Gold standard » (composition, in clinical structure, function diagnostic diversity). Introduction to the human virome Viral discovery NGS=Next-Generation Sequencing Schematic steps for determination of human virome and its impact on health Introduction to the human virome Delwart, PLoS Pathogens (2013) The virome, a neglected part of the microbiome… 10000 8000 microbiome 6000 virome 4000 2000 1000 800 NGS 600 400 number of publications 200 The virome 0 1995 2000 2005 2010 2015 years The human virome: the hidden face of the iceberg What we currently know What is left to be discovered Human virome The human virome An essential part of our own ecology remains terra incognita Virus-host interactions go beyond simple parasitism Positive, neutral or negative interactions depend on the anatomical site, the immune/genetic status of the host and the presence of other viruses/microbes Inside the human virome: the good, the bad and the neutral… The example of the blood compartment Characterization of the blood virome is critical: - For the safety of blood-derived transfusion products (currently screened for HIV-1 and 2, human T-lymphotropic virus-1 and 2, hepatitis C virus, hepatitis B virus, West Nile virus, and Zika virus) The blood virome - For the survey and identification of emerging pathogens Asymptomatic blood donors Shotgun libraries – sanger sequencing 3 libraries (total of 50 blood samples) 22 sequences: The blood virome - Novel anelloviruses - HHV3 (Varicella zoster virus) - Other eukaryotic viruses - bacteriophages Viral DNA sequences in the genome sequences from total blood of 8,240 individuals About 5% did not 1 petabyte correspond to Sequences of 94 different 19 were from human DNA (1 million DNA viruses known human (0.01% of gigabytes) of were viruses The blood virome these were sequence data identified similar to viral sequences) 19 human viruses Greater prevalence of circulating viruses in men than in women (different innate and adaptative immune responses?) Higher prevalence and higher loads in the younger groups Herpesviruses (0.1-20% of individuals) Cytomegalovirus, Epstein-Barr virus, Herpes Simplex virus, and human herpesviruses 6, 7 and 8 Other human viruses (< 1%): papillomaviruses, parvoviruses, polyomavirus, The blood virome: persistent viruses adenovirus, human immunodeficiency virus and human T-lymphotropic virus Several persistent viral infection Persistent viral infection is a process in dynamic and metastable equilibrium The blood virome: persistent viruses The benefice of persistent viral infections The physiological role of most of these viruses in humans has yet to be defined Promote human health Indirectly and/or Directly By eliminating other By viral interference pathogens through cross- immunity v Latent infection with murine gammaherpesvirus 68 (a model for EBV) or murine CMV (a model for human CMV) confers protection against Listeria monocytogenes and Yersinia pestis in mice The blood virome: persistent viruses Barton et al., Nature (2007) v Individuals with HIV, co-infected with Human Pegivirus (HPgV, also called GBV-C virus or hepatitis G virus) delay progression to AIDS Xiang et al., NEJM (2001) anelloviruses Anelloviruses (9%) of the samples Small ssDNA viruses from the Anelloviridae family Three main viral groups: - Torque Teno Virus (TTV, 1997) The blood virome: - Torque Teno Mini Virus (TTMV, 2000) - Torque Teno Midi Virus (TTMDV, 2007) Anelloviruses
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