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2.
J Clin Immunol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430354

RESUMO

The original version of this article unfortunately did not display the appropriate captions in the figure. The correct version is displayed below.

4.
J Infect Dis ; 2018 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-30107546

RESUMO

Objective: Immune activation is associated with morbidity/mortality in HIV-infection despite antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods: Nineteen markers of immune activation/inflammation were measured over 96 weeks in HIV-infected Ugandan children in CHAPAS-3 (ISRCTN69078957) and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques including next-generation sequencing. Results: Of 249 children included, 120 were HIV-infected ART-naïve and 22 ART-experienced (median (IQR) age 2.8(1.7-4.0) and 6.5(5.9-9.2) years; median baseline CD4% 20(14-24) and 35(31-39)). 107 were HIV-uninfected controls. Median (IQR) CD4% increase was 17(12-22) at week-96 in ART-naïve children, and viral load was<100 copies/mL in 76%/91% ART-naïve/experienced. Immune activation decreased with ART. Children could be divided by immune activation markers into clusters: cluster-1 (majority HIV-uninfected); cluster-2 (mixed HIV-uninfected/ART-naïve/ART-experienced); and cluster-3 (majority ART-naïve). Immune activation was low in cluster-1, decreased in cluster-3, and persisted in cluster-2. Blood microbial DNA levels were negative/very low across groups, with no difference between clusters except Enterobacteriaceae (higher in cluster-1,p<0.0001). Conclusion: Immune activation decreased with ART, with marker-clustering indicating different activation patterns by HIV/ART status. Levels of bacterial DNA in blood were low regardless of HIV/ART/immune activation status. Microbial translocation did not drive immune activation in this setting.

5.
J Infect Dis ; 218(10): 1592-1601, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-29986093

RESUMO

Background: Varicella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples. Methods: Enrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS. Results: Viral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades. Conclusions: Low viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.

6.
J Infect Dis ; 218(8): 1261-1271, 2018 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-29917114

RESUMO

Background: Adenoviruses are significant pathogens for the immunocompromised, arising from primary infection or reinfection. Serotyping is insufficient to support nosocomial transmission investigations. We investigate whether whole-genome sequencing (WGS) provides clinically relevant information on transmission among patients in a pediatric tertiary hospital. Methods: We developed a target-enriched adenovirus WGS technique for clinical samples and retrospectively sequenced 107 adenovirus-positive residual diagnostic samples, including viremias (>5 × 104 copies/mL), from 37 patients collected January 2011-March 2016. Whole-genome sequencing was used to determine genotype and for phylogenetic analysis. Results: Adenovirus sequences were recovered from 105 of 107 samples. Full genome sequences were recovered from all 20 nonspecies C samples and from 36 of 85 species C viruses, with partial genome sequences recovered from the rest. Whole-genome phylogenetic analysis suggested linkage of 3 genotype A31 cases and uncovered an unsuspected epidemiological link to an A31 infection first detected on the same ward 4 years earlier. In 9 samples from 1 patient who died, we identified a mixed genotype adenovirus infection. Conclusions: Adenovirus WGS from clinical samples is possible and useful for genotyping and molecular epidemiology. Whole-genome sequencing identified likely nosocomial transmission with greater resolution than conventional genotyping and distinguished between adenovirus disease due to single or multiple genotypes.

7.
Clin Infect Dis ; 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29800111

RESUMO

Background: Norovirus is a leading cause of worldwide and nosocomial gastroenteritis. This study aimed to assess the utility of molecular epidemiology using full genome sequences, compared to routine Infection Prevention and Control (IPC) investigations. Norovirus genomes were generated from new episodes of norovirus at a pediatric tertiary referral hospital over 19 months (n=182). Phylogeny identified clusters of related sequences which were verified using epidemiological and clinical data. Results: Twenty four clusters of related norovirus sequences ("sequence clusters") were observed, including eight previously identified by IPC investigations ("IPC outbreaks"). Seventeen sequence clusters (involving 77/182 patients) were corroborated by epidemiological data ("epidemiologically supported clusters"), suggesting transmission between patients. Linked infections were identified among 44 patients who were missed by IPC investigations. 33% of norovirus sequences were linked suggesting nosocomial transmission. 24% of patients had nosocomial infections from an unknown source. 43% were norovirus positive on admission. Conclusions: We show that there are frequent introductions of multiple norovirus strains with extensive onward nosocomial transmission of norovirus in a paediatric hospital with a high proportion of immunosuppressed patients nursed in isolation. Phylogenetic analysis using full genome sequences is more sensitive than classical IPC investigations for identifying linked cases and should be considered when investigating norovirus nosocomial -transmission. Sampling of staff, visitors and the environment may be required for complete understanding of the sources of infection and transmission routes in patients with nosocomial infections that are not linked to other patients and among patients with phylogenetically linked cases but no evidence of direct contact.

8.
J Infect ; 76(3): 225-240, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29305150

RESUMO

BACKGROUND: Current estimates suggest that even in the most resourced settings, the aetiology of encephalitis is identified in less than half of clinical cases. It is acknowledged that filling this gap needs a combination of rigorous sampling and improved diagnostic technologies. Next generation sequencing (NGS) methods are powerful tools with the potential for comprehensive and unbiased detection of pathogens in clinical samples. We reviewed the use of this new technology for the diagnosis of suspected infectious encephalitis, and discuss the feasibility for introduction of NGS methods as a frontline diagnostic test. METHODS: A systematic literature review was performed, using MESH and text word searches for variants of "sequencing" and "encephalitis" in Medline and EMbase, and searching bibliographies and citations using the Web of Science database. Two authors independently reviewed, extracted and summarised data. FINDINGS: The review identified 25 articles reporting 44 case reports of patients with suspected encephalitis for whom NGS was used as a diagnostic tool. We present the data and highlight themes arising from these cases. There are no randomly controlled trials to assess the utility of NGS as a diagnostic tool. INTERPRETATION: There is increasing evidence of a role for NGS in the work-up of undiagnosed encephalitis. Lower costs and increasing accessibility of these technologies will facilitate larger studies of these patients. We recommend NGS should be considered as a front-line diagnostic test in chronic and recurring presentations and, given current sample-to-result turn-around times, as second-line in acute cases of encephalitis.

9.
Clin Infect Dis ; 65(12): 2122-2125, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29020238
10.
J Clin Virol ; 96: 44-48, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28950185

RESUMO

BACKGROUND: Norovirus causes chronic infections in immunocompromised patients with considerable associated morbidity. It is not known whether chronic infections involve super- or re-infections or relapses. OBJECTIVES: To retrospectively investigate whether longitudinal sampling in chronically infected patients demonstrates persistent infection with the same virus, or super- or re-infection. STUDY DESIGN: Norovirus full genomes were generated from 86 longitudinal samples from 25 paediatric patients. Consensus sequences were used for phylogenetic analysis and genotyping. RESULTS: Super-infections occurred in 17% of chronically infected patients who were continuously PCR positive; including two with mixed norovirus infections. The median duration of infection was 107days longer in those with super-infections; however this was not statistically significant. A third of patients with interrupted norovirus shedding continued to be infected with the same virus despite up to 2 months of PCR negative stools, classified as a relapse. The majority (67%) of patients with interrupted shedding were re-infected with a different genotype. CONCLUSIONS: Chronically infected patients who are continuously PCR positive are most likely to remain infected with the same virus; however super-infections do occur leading to mixed infection. Patients with interrupted shedding are likely to represent re-infection with a different genotype, however relapsing infections also occur. Our findings have implications for infection control as immunosuppressed patients remain susceptible to new norovirus infections despite current or recent infection and may continue to be infectious after norovirus is undetectable in stool. The relevance to children without co-morbidities remains to be determined.


Assuntos
Infecções por Caliciviridae/epidemiologia , Infecções por Caliciviridae/virologia , Norovirus/classificação , Norovirus/isolamento & purificação , Recidiva , Superinfecção/epidemiologia , Superinfecção/virologia , Adolescente , Criança , Pré-Escolar , Doença Crônica , Feminino , Técnicas de Genotipagem , Humanos , Lactente , Estudos Longitudinais , Masculino , Norovirus/genética , Estudos Retrospectivos , Análise de Sequência de DNA
11.
PLoS One ; 12(6): e0179572, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28662035

RESUMO

Noroviruses are a leading cause of human gastroenteritis worldwide. The norovirus genotype GII.4 is the most prevalent genotype in the human population and has caused six pandemics since 1995. A novel norovirus lineage containing the GII.P16 polymerase and pandemic GII.4 Sydney 2012 capsid was recently detected in Asia and Germany. We demonstrate that this lineage is also circulating within the UK and USA and has been circulating since October 2014 or earlier. While the lineage does not contain unique substitutions in the capsid, it does contain polymerase substitutions close to positions known to influence polymerase function and virus transmission. These polymerase substitutions are shared with a GII.P16-GII.2 virus that dominated outbreaks in Germany in Winter 2016. We suggest that the substitutions in the polymerase may have resulted in a more transmissible virus and the combination of this polymerase and the pandemic GII.4 capsid may result in a highly transmissible virus. Further surveillance efforts will be required to determine whether the GII.P16-GII.4 Sydney 2012 lineage increases in frequency over the coming months.


Assuntos
Infecções por Caliciviridae/epidemiologia , Gastroenterite/virologia , Norovirus/patogenicidade , Humanos , Norovirus/classificação , Filogenia , Reação em Cadeia da Polimerase
12.
Rev Med Virol ; 2017 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-28271593

RESUMO

Norovirus is acknowledged to be a leading cause of acute gastroenteritis worldwide, and its importance as a cause of chronic infection in immune deficient hosts is increasingly recognised. Current evidence suggests that a coordinated response of innate immune mechanisms, CD8+ cytotoxicity and a humoral response, with CD4+ orchestration, is necessary for norovirus clearance. We explain how primary immune deficiency impairs these host defences and predisposes to chronic infection, associated with protracted diarrhoea, weight loss, and requirement for parenteral nutrition. The mucosal villous atrophy frequently seen in norovirus infection appears to be immune mediated, suggesting that some functional immune response is required in order for chronic norovirus infection to become symptomatic in primary immune deficiency. We provide a comprehensive summary of published cases of norovirus infection in patients with primary immune deficiency. Spontaneous viral clearance has been described; however, the majority of reported cases have had prolonged and severe illness. Treatment strategies are discussed in detail. Approaches that have been tried in patients with primary immune deficiency include exclusion diets, enteral and intravenous immunoglobulins, breast milk, immunosuppressants, ribavirin, and nitazoxanide. To date, only ribavirin has been used with apparent success to achieve clearance of chronic norovirus in primary immune deficiency, and randomised controlled trials are needed to evaluate a number of promising therapies that are discussed.

13.
Acta Neuropathol ; 133(1): 139-147, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27770235

RESUMO

Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuVJL5 isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections.


Assuntos
Encéfalo/virologia , Encefalite Viral/virologia , Vacina contra Caxumba/efeitos adversos , Vírus da Caxumba/isolamento & purificação , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doença Crônica , Encefalite Viral/complicações , Encefalite Viral/diagnóstico por imagem , Encefalite Viral/terapia , Evolução Fatal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Vírus da Caxumba/genética , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico por imagem , Imunodeficiência Combinada Severa/terapia
14.
J Clin Virol ; 84: 1-6, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27615516

RESUMO

BACKGROUND: Diarrhoea in children is a common disease; understanding the incidence of causative viruses can aid infection control and vaccine development. OBJECTIVES: Describe the incidence and characteristics of gastroenteric viruses including norovirus genotypes in a paediatric hospital cohort. STUDY DESIGN: Norovirus, adenovirus, sapovirus, astrovirus, rotavirus qPCR and norovirus genotyping results for all stool specimens (n=4786; 1393 patients) at a UK paediatric tertiary referral hospital June 2014-July 2015. RESULTS AND DISCUSSION: 24% (329/1393) of patients were positive for a GI virus; the majority were positive for norovirus (44%, 144/329) or adenovirus (44%, 146/329). The overall incidence of rotavirus (2%) is reduced compared to pre-vaccination studies; however the incidence of other GI viruses has not increased. Norovirus infections had a significantly higher virus burden compared to other GI viruses (P ≤0.03); sapovirus infections had the lowest viral burden. The number of norovirus cases per month did not follow the typical winter seasonal trend of nationally reported outbreaks. The number of cases per month correlates with the number of hospital admissions (R=0.703, P=0.011); the number of admissions accounts for 50% of the variability in number of cases per month. The breadth of genotypes seen (48% non-GII.4), suggests a community source for many norovirus infections and has implications for vaccine development. All GI viruses caused chronic infections, with the majority (50-100%) in immunocompromised patients. Incidence or duration of infection in chronic norovirus infections did not differ between genotypes, suggesting host-mediated susceptibility.


Assuntos
Infecções por Caliciviridae/epidemiologia , Fezes/virologia , Gastroenterite/epidemiologia , Gastroenterite/virologia , Hospitais Pediátricos , Norovirus/genética , Vírus/isolamento & purificação , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/virologia , Adenovírus Humanos/genética , Infecções por Caliciviridae/virologia , Pré-Escolar , Doença Crônica/epidemiologia , Diarreia/epidemiologia , Diarreia/virologia , Surtos de Doenças , Feminino , Genótipo , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Masculino , Norovirus/isolamento & purificação , Filogenia , Rotavirus/genética , Rotavirus/isolamento & purificação , Sapovirus/genética , Sapovirus/isolamento & purificação , Reino Unido/epidemiologia , Viroses/virologia , Vírus/classificação , Vírus/genética
16.
J Clin Microbiol ; 54(10): 2530-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27487952

RESUMO

Norovirus full-genome sequencing is challenging due to sequence heterogeneity among genomes. Previous methods have relied on PCR amplification, which is problematic due to primer design, and transcriptome sequencing (RNA-Seq), which nonspecifically sequences all RNA, including host and bacterial RNA, in stool specimens. Target enrichment uses a panel of custom-designed 120-mer RNA baits that are complementary to all publicly available norovirus sequences, with multiple baits targeting each position of the genome, which overcomes the challenge of primer design. Norovirus genomes are enriched from stool RNA extracts to minimize the sequencing of nontarget RNA. SureSelect target enrichment and Illumina sequencing were used to sequence full genomes from 507 norovirus-positive stool samples with reverse transcription-real-time PCR cycle threshold (CT) values of 10 to 43. Sequencing on an Illumina MiSeq system in batches of 48 generated, on average, 81% on-target reads per sample and 100% genome coverage with >12,000-fold read depth. Samples included genotypes GI.1, GI.2, GI.3, GI.6, GI.7, GII.1, GII.2, GII.3, GII.4, GII.5, GII.6, GII.7, GII.13, GII.14, and GII.17. When outliers were accounted for, we generated >80% genome coverage for all positive samples, regardless of CT values. A total of 164 samples were tested in parallel with conventional PCR genotyping of the capsid shell domain; 164/164 samples were successfully sequenced, compared to 158/164 samples that were amplified by PCR. Four of the samples that failed capsid PCR analysis had low titers, which suggests that target enrichment is more sensitive than gel-based PCR. Two samples failed PCR due to primer mismatches; target enrichment uses multiple baits targeting each position, thus accommodating sequence heterogeneity among norovirus genomes.


Assuntos
Fezes/virologia , Genoma Viral , Norovirus/isolamento & purificação , Hibridização de Ácido Nucleico/métodos , RNA Viral/genética , Análise de Sequência de DNA/métodos , Manejo de Espécimes/métodos , Infecções por Caliciviridae/virologia , Humanos , Masculino , Norovirus/genética
17.
Clin Infect Dis ; 62(9): 1136-1138, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26908782

RESUMO

Norovirus incidence was compared between severe combined immunodeficiency children with (n = 10) and without (n = 8) B cells. 60% of B+ and 63% of B- patients developed norovirus infections therefore norovirus replication in B lymphocytes is not essential for infection.


Assuntos
Linfócitos B/virologia , Infecções por Caliciviridae/patologia , Norovirus/imunologia , Imunodeficiência Combinada Severa/virologia , Adolescente , Linfócitos B/patologia , Infecções por Caliciviridae/imunologia , Criança , Pré-Escolar , Humanos , Lactente , Estudos Retrospectivos
18.
Virus Evol ; 2(1): vew017, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30288299

RESUMO

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle.

19.
Arch Dis Child ; 101(2): 177-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26613943

RESUMO

BACKGROUND: The advent of PCR testing for the presence of viral genomes has led to the identification of parvovirus B19 (PVB19) as a causative agent of myocarditis. METHODS: The clinical presentation, course and outcome of children with PVB19 myocarditis was ascertained through a retrospective review. The PVB19 viral genome was detected by PCR from whole blood or endomyocardial biopsy specimens in patients presenting with new onset heart failure. RESULTS: Seventeen patients presented at a median age of 1.3 years (range: 0.4-15.4 years) in cardiac failure with a mean fractional shortening of 15±3%. Eleven patients required mechanical ventilation and intravenous inotropes and seven required extra-corporeal mechanical oxygenation. Four of the five deaths occurred in patients who had a short prodromal illness of less than 48 hours. All patients with ST segment elevation died (n=4). All non-fulminant cases survived. Event-free survival occurred in 11/17 (65%) patients. Five (29%) patients died and one patient underwent heart transplantation. Complete recovery of cardiac function occurred within a median of 12 months (range: 1-48) in five patients. There was incomplete recovery in five patients and one patient had persistent dilated cardiomyopathy. CONCLUSIONS: PVB19 can cause a devastating myocarditis in children. Children with fulminant myocarditis, ST segment changes or a short prodrome have the worst outcome. Transplantation may be considered, but is rarely required in the acute period if mechanical circulatory support is utilised. If the initial presentation is survived, recovery of the myocardium can occur even in those who had fulminant myocarditis.


Assuntos
Miocardite/virologia , Infecções por Parvoviridae/diagnóstico , Parvovirus B19 Humano/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Miocardite/diagnóstico , Miocardite/fisiopatologia , Miocardite/terapia , Infecções por Parvoviridae/fisiopatologia , Infecções por Parvoviridae/terapia , Reação em Cadeia da Polimerase/métodos , Prognóstico , Recuperação de Função Fisiológica , Estudos Retrospectivos , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
20.
Sci Transl Med ; 7(307): 307ra154, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26424569

RESUMO

Type I interferon (IFN-α/ß) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/ß in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/ß receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/ß. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/ß responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/ß in human antiviral immunity.


Assuntos
Antivirais/metabolismo , Imunidade , Receptor de Interferon alfa e beta/deficiência , Evolução Fatal , Genes Recessivos , Teste de Complementação Genética , Humanos , Lactente , Interferons/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais
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