RESUMEN
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/genética , Antígenos HLA/genética , Imitación Molecular/inmunología , Esclerodermia Sistémica/genética , Negro o Afroamericano/genética , Alelos , Secuencia de Aminoácidos/genética , Antígenos Virales/genética , Antígenos Virales/inmunología , Autoantígenos/inmunología , Biología Computacional , Conjuntos de Datos como Asunto , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA/inmunología , Humanos , Masculino , Mimiviridae/inmunología , Phycodnaviridae/inmunología , Estructura Secundaria de Proteína/genética , Medición de Riesgo , Esclerodermia Sistémica/epidemiología , Esclerodermia Sistémica/inmunología , Homología de Secuencia de Aminoácido , Población Blanca/genéticaAsunto(s)
Sistemas CRISPR-Cas/fisiología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/inmunología , Virus Gigantes/inmunología , Mimiviridae/inmunología , Acanthamoeba/virología , Inmunidad Adaptativa , Secuencia de Aminoácidos , Secuencia de Bases , Sistemas CRISPR-Cas/genética , Evolución Molecular , Virus Gigantes/genética , Virus Gigantes/fisiología , Interacciones Huésped-Patógeno , Sistema Inmunológico , Mimiviridae/genética , Mimiviridae/fisiología , Proteínas Virales/genética , Proteínas Virales/inmunología , Virófagos/genética , Virófagos/inmunología , Fenómenos Fisiológicos de los VirusAsunto(s)
Amoeba/virología , Eucariontes/virología , Virus Gigantes/genética , Metagenómica , Evolución Biológica , Virus Gigantes/clasificación , Virus Gigantes/inmunología , Virus Gigantes/aislamiento & purificación , Mimiviridae/clasificación , Mimiviridae/genética , Mimiviridae/inmunología , Mimiviridae/aislamiento & purificación , Fagocitosis , Filogenia , SimbiosisRESUMEN
Since their discovery, giant viruses have revealed several unique features that challenge the conventional definition of a virus, such as their large and complex genomes, their infection by virophages and their presence of transferable short element transpovirons. Here we investigate the sensitivity of mimivirus to virophage infection in a collection of 59 viral strains and demonstrate lineage specificity in the resistance of mimivirus to Zamilon, a unique virophage that can infect lineages B and C of mimivirus but not lineage A. We hypothesized that mimiviruses harbour a defence mechanism resembling the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system that is widely present in bacteria and archaea. We performed de novo sequencing of 45 new mimivirus strains and searched for sequences specific to Zamilon in a total of 60 mimivirus genomes. We found that lineage A strains are resistant to Zamilon and contain the insertion of a repeated Zamilon sequence within an operon, here named the 'mimivirus virophage resistance element' (MIMIVIRE). Further analyses of the surrounding sequences showed that this locus is reminiscent of a defence mechanism related to the CRISPR-Cas system. Silencing the repeated sequence and the MIMIVIRE genes restores mimivirus susceptibility to Zamilon. The MIMIVIRE proteins possess the typical functions (nuclease and helicase) involved in the degradation of foreign nucleic acids. The viral defence system, MIMIVIRE, represents a nucleic-acid-based immunity against virophage infection.
Asunto(s)
Mimiviridae/genética , Mimiviridae/inmunología , Virus/inmunología , Secuencia de Bases , Sistemas CRISPR-Cas/genética , Cromosomas/genética , ADN Helicasas/genética , ADN Helicasas/metabolismo , ADN Viral/genética , ADN Viral/metabolismo , Desoxirribonucleasas/genética , Desoxirribonucleasas/metabolismo , Genes Virales/genética , Genoma Viral/genética , Mimiviridae/clasificación , Mimiviridae/enzimología , Operón/genética , Proteínas Virales/genética , Proteínas Virales/metabolismo , Virus/genéticaRESUMEN
Acanthamoeba polyphaga mimivirus (APMV) is a giant, double-stranded virus of the Mimiviridae family that was discovered in 2003. Recent studies have shown that this virus is able to replicate in murine and human phagocytes and might be considered a putative human pathogen that causes pneumonia. However, there is little data regarding APMV and its host defense relationship. In the present study, we investigated how some components of the interferon (IFN) system are stimulated by APMV in human peripheral blood mononuclear cells (PBMCs) and how APMV replication is affected by IFN treatment. Our results demonstrated that APMV is able to replicate in human PBMCs, inducing type I Interferons (IFNs) but inhibiting interferon stimulated genes (ISG) induction by viroceptor and STAT-1 and STAT-2 dephosphorylation independent mechanisms. We also showed that APMV is resistant to the antiviral action of interferon-alpha2 (IFNA2) but is sensitive to the antiviral action of interferon-beta (IFNB1). Our results demonstrated the productive infection of professional phagocytes with APMV and showed that this virus is recognized by the immune system of vertebrates and inhibits it. It provides the first data regarding APMV and the IFN system interaction and raise new and relevant evolutional questions about the relationship between APMV and vertebrate hosts.
Asunto(s)
Interferón Tipo I/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Mimiviridae/inmunología , Mimiviridae/patogenicidad , Células Cultivadas , Humanos , Factores Reguladores del Interferón/metabolismo , Interferón Tipo I/farmacología , Mimiviridae/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy-subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens.
Asunto(s)
Artritis/virología , Colágeno/inmunología , Mimiviridae/inmunología , Proteínas Virales/inmunología , Animales , Anticuerpos Antivirales/inmunología , Artritis/inmunología , Bovinos , Colágeno/genética , Modelos Animales de Enfermedad , Humanos , Inmunización , Ratones , Ratones Endogámicos DBA , Mimiviridae/genética , Proteínas Virales/genéticaRESUMEN
INTRODUCTION: Antibodies against mimivirus, a recently discovered giant virus, have been found in patients presenting with pneumonia suggesting a potential role for this virus as a respiratory pathogen. Several bacterial and viral pathogens have been associated with the occurrence of acute exacerbations in COPD. However, a large part of these exacerbations have an unknown cause. In the present study we evaluated the presence of mimivirus in sputum samples of COPD patients. METHODS: From March 2009 until January 2010 all sputum samples collected during stable conditions and during exacerbations of COPD patients, referred for pulmonary rehabilitation, were included. All sputum samples were analysed by real-time PCR targeting mimivirus. Furthermore, serum samples were analysed for the presence of antibodies against mimivirus. RESULTS: A total of 220 sputum samples from 109 patients were eligible for inclusion. None of the sputum samples showed the presence of mimivirus DNA. Antibodies against mimivirus were detected in 3 serum samples from 3 patients, of which one showed an increase in antibody-titre. CONCLUSIONS: Although mimivirus was suggested as a potential respiratory pathogen, its presence could not be confirmed in the present study-population of patients with COPD.
Asunto(s)
Infecciones por Virus ADN/virología , Mimiviridae/aislamiento & purificación , Enfermedad Pulmonar Obstructiva Crónica/virología , Esputo/virología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Infecciones por Virus ADN/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mimiviridae/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
During January 2010, a husband and wife returned from Laos to France with probable parasitic disease. Increased antibodies against an Acanthamoeba polyphaga mimivirus virophage indicated seroconversion. While in Laos, they had eaten raw fish, a potential source of the virophage. This virophage, associated with giant viruses suspected to cause pneumonia, could be an emerging pathogen.
Asunto(s)
Anticuerpos Antivirales/inmunología , Mimiviridae/inmunología , Viaje , Adulto , Anticuerpos Antivirales/sangre , Femenino , Francia , Humanos , Laos , Masculino , Mimiviridae/genética , Proteínas Virales/genética , Proteínas Virales/inmunologíaRESUMEN
Viral diseases in the clinical setting have been extensively investigated. Viruses are now considered as potentially responsible for nosocomial infections, especially in intensive care unit (ICU) patients. Mimivirus is the largest virus known to date. Recent studies have suggested that Mimivirus could be responsible for both community-acquired and nosocomial pneumonia. These studies were mainly based on serologic diagnosis, which showed patients with community-acquired pneumonia have more antibodies to Mimivirus than healthy controls. Serologic evidence of Mimivirus pneumonia was also found in mechanically ventilated ICU patients. In a matched-cohort study in which ICU patients with serologic evidence of Mimivirus pneumonia were matched to ICU patients remaining seronegative for Mimivirus, positive serology was associated with an increased duration of both mechanical ventilation and ICU stay. Identification by PCR techniques remains difficult, probably because of the high level of polymorphism of nucleotide sequences of giant viruses. More studies are needed to confirm the clinical impact of Mimivirus in humans.
Asunto(s)
Mimiviridae/patogenicidad , Neumonía Viral/virología , Anticuerpos Antivirales/sangre , Infecciones Comunitarias Adquiridas/virología , Infección Hospitalaria/virología , Humanos , Unidades de Cuidados Intensivos , Mimiviridae/inmunología , Pruebas SerológicasRESUMEN
Francisella tularensis, a Gram-negative cocobacillus responsible for tularemia, especially severe pneumonia, is a facultative intracellular bacterium classified as a biological agent of category A. Acanthamoeba polyphaga mimivirus (APM) is a recently discovered giant virus suspected to be an agent of both community- and hospital-acquired pneumonia. During specificity testing of antibody to APM detection, it was observed that nearly all patients infected by F. tularensis had elevated antibody titers to APM. In the present study, we investigated this cross-reactivity by immunoproteomics. Apart from the detection of antibodies reactive to new immunoreactive proteins in patients infected by F. tularensis, we showed that the sera of those patients recognize specifically two proteins of APM: the capsid protein and another protein of unknown function. No common protein motif can be detected in silico based on genome analysis of the involved protein. Furthermore, this cross-reactivity was confirmed with the recombinant capsid protein expressed in Escherichia coli. This emphasizes the pitfalls of a serological diagnosis of pneumonia.