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Adenovirus infections [keywords]
- Genetic Vaccination against Experimental Infection with Myotropic Parasite Strains of Trypanosoma cruzi. [Journal Article]
- Mediators Inflamm 2014.:605023.
In earlier studies, we reported that a heterologous prime-boost regimen using recombinant plasmid DNA followed by replication-defective adenovirus vector, both containing Trypanosoma cruzi genes encoding trans-sialidase (TS) and amastigote surface protein (ASP) 2, provided protective immunity against experimental infection with a reticulotropic strain of this human protozoan parasite. Herein, we tested the outcome of genetic vaccination of F1 (CB10XBALB/c) mice challenged with myotropic parasite strains (Brazil and Colombian). Initially, we determined that the coadministration during priming of a DNA plasmid containing the murine IL-12 gene improved the immune response and was essential for protective immunity elicited by the heterologous prime-boost regimen in susceptible male mice against acute lethal infections with these parasites. The prophylactic or therapeutic vaccination of resistant female mice led to a drastic reduction in the number of inflammatory infiltrates in cardiac and skeletal muscles during the chronic phase of infection with either strain. Analysis of the electrocardiographic parameters showed that prophylactic vaccination reduced the frequencies of sinus arrhythmia and atrioventricular block. Our results confirmed that prophylactic vaccination using the TS and ASP-2 genes benefits the host against acute and chronic pathologies caused by T. cruzi and should be further evaluated for the development of a veterinary or human vaccine against Chagas disease.
- Immunohistochemistry analysis of pulmonary infiltrates in necropsy samples of children with non-pandemic lethal respiratory infections (RSV; ADV; PIV1; PIV2; PIV3; FLU A; FLU B). [JOURNAL ARTICLE]
- J Clin Virol 2014 Jul 3.
Acute viral respiratory infections represent a globally important cause of morbidity and mortality in childhood. An individual's cellular response appears to play a critical role in recovery from infections, given that individuals with impaired cellular immunity, congenital or acquired, have more severe diseases and secrete the virus for longer periods.The aim of this study was to immunohistochemically evaluate the expression of the cell surface antigens CD4, CD8, CD25, CD14 and CD74, in pneumonic infiltrates in the alveolar septa using paraffin-embedded lung samples from autopsies of immunocompetent children who died of lethal, non-pandemic, severe acute respiratory infections.From 794 cases of pediatric autopsies of patients with severe respiratory disease (between 1960 and 2004), 193 cases were selected for this study. To identify subpopulations of inflammatory cells in the alveolar septa, cell surface antigen expression was assessed by immunohistochemistry using the following primary antibodies: anti-CD4, anti-CD8, anti-CD14, anti-CD25 and anti-CD74.The TCD8+ lymphocyte count was higher in the virus-positive group (p=0.04) and was also much higher among cases that were positive for more than three viral types (p=0.016). There were fewer CD14+ cells in cases of AdV (adenovirus) infection (p=0.002), and there was a predominance of CD74+ cells in the histopathological pattern defined as interstitial pneumonitis (p=0.037).The results of this study demonstrate that TCD8+ lymphocytes present in the alveolar septa participate to a greater extent in the response toward viral pneumonia, while CD14+ cell numbers are often reduced in cases of AdV.
- A registry of HLA-typed donors for production of virus-specific CD4 and CD8 T lymphocytes for adoptive reconstitution of immune-compromised patients. [JOURNAL ARTICLE]
- Transfusion 2014 Jul 20.
Virus-specific CD4 and CD8 T lymphocytes from HLA-matched donors are effective for treatment and prophylaxis of viral infections in immune-compromised recipients of hematopoietic stem cell transplant recipients. Adoptive immune reconstitution is based on selection of specific T cells or on generation of specific T-cell lines from the graft donor. Unfortunately, the graft donor is not always immune to the relevant pathogen or the graft donor may not be available (registry-derived or cord blood donors).Since the possibility of using T cells from a third-party subject is now established, we screened potential donors for T-cell responses against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, the viruses most frequently targeted by adoptive immune reconstitution. Specific T-cell responses against viral antigens were analyzed in 111 donors using a miniaturized interferon-γ release assay.Responders to CMV were 64%, to EBV 40%, and to adenovirus 51%. Simultaneous responders to the three viruses were 49%. CMV-specific CD4 and CD8 T-cell lines could be generated from 11 of 12 donors defined as positive responders according to the T-cell assay.These data demonstrate that a large fraction of volunteers can be recruited in a donor registry for selection or expansion of virus specific T cells and that our T-cell assay predicts the donors' ability to give rise to established T-cell lines endowed with proliferative potential and effector function for adoptive immune reconstitution.
- Real-time PCR Identification of Agents Causing Diarrhea in Rwandan Children Less than Five Years of Age. [JOURNAL ARTICLE]
- Pediatr Infect Dis J 2014 Jul 16.
Knowledge about causes of acute diarrhea among children in developing countries is insufficient. Molecular methods might improve diagnostics of infectious gastroenteritis, but due to the high sensitivity, findings may be difficult to interpret.Feces samples from Rwandan children 0.5-5.0 years of age, with diarrhea for less than 96 hours (patients, n=544) or without diarrhea for 14 days (controls, n=162), were analyzed by real-time PCR targeting 17 pathogens.At least one agent was detected in 94% of patients and in 79% of controls, with higher rates in sick children for rotavirus (42% vs. 2%, p<0.0001) and enterotoxigenic Escherichia coli (ETEC) -estA (21% vs. 9%, P=0.0006). Detection rates did not differ significantly for adenovirus (39% vs. 36%), ETEC-eltB (29% vs. 30%), Campylobacter (14% vs. 17%) or Shigella (13% vs. 10%), but for Shigella the Ct (threshold cycle) values were lower (pathogen loads were higher) in sick children than in controls. By multivariate analysis, including gender and age, detection of rotavirus (p<0.0001), ETEC-estA (P=0.001), Shigella (P=0.004) and norovirus genogroup II (P=0.009) was associated with symptomatic infection, and a Ct value below a cut-off (in the range 28-29) improved identification of ETEC-estA, Shigella and norovirus genogroup II.Real-time PCR can detect essentially all diarrheagenic agents, and provides Ct values that improve identification of clinically relevant infections.
- Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and-mouth disease virus replication. [JOURNAL ARTICLE]
- J Virol 2014 Jul 16.
Several studies have demonstrated that administration of type I, II, or III interferons (IFNs) delivered using a replication-defective human adenovirus 5 (Ad5) vector can effectively control foot-and-mouth disease (FMD) in cattle and swine during experimental infections. However, relatively high doses are required to achieve protection. In this study, we identified the functional properties of a porcine fusion protein, poIRF7/3(5D), as a biotherapeutic and enhancer of IFN activity against FMD virus (FMDV). We showed that poIRF7/3(5D) is a potent inducer of type I IFNs including IFNα, β, and ω but not type III IFN (IL28B), without inducing cytotoxicity. Expression of poIRF7/3(5D) significantly and steadily reduced FMDV viral titers by up to 6 log10 in swine and bovine cell lines. Treatment with an IFN receptor inhibitor (B18R) combined with an anti-IFNα antibody neutralized the antiviral activity in the supernatants of Ad5-poIRF7/3(5D) transduced cells. However, several transcripts with known antiviral function, and including type I IFNs, were still highly up-regulated (ranging from 8 to over 500 fold increase) by poIRF7/3(5D) in the presence of B18R. Furthermore, mice treated with Ad5-poIRF7/3(5D) showed antiviral activity in sera that was associated with high induction of IFNα and resulted in complete protection against FMDV challenge at 6, 24 or 48 hours post-treatment. This study, highlights for the first time, the antiviral potential of Ad5-poIRF7/3(5D) in vitro and in vivo against FMDV. Importance: FMD remains one of the most devastating diseases that affect livestock worldwide. Effective vaccine formulations are available but are serotype specific and require approximately 7 days for protective immunity. We have shown that vector-delivered IFN is an option to protect animals against many FMDV serotypes as soon as 24 h and for about 4 days post administration. Here we demonstrate that delivery of a constitutively active transcription factor that induces the production of endogenous IFNs and potentially other antiviral genes is a viable strategy to protect against FMD.
- Type 1 interferon-induced IL-7 maintains CD8(+) T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis. [JOURNAL ARTICLE]
- Cell Mol Immunol 2014 Jul 14.
Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-α receptor knockout (IFNAR(-/-)) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Rα) or PD-L1 were i.p. injected. We found that CD8(+) T cells in IFNAR(-/-) mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-γ production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR(-/-) and control mice. Injection of PD-L1-specific mAb in IFNAR(-/-) mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR(-/-) mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8(+) T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8(+) T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8(+) T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.Cellular & Molecular Immunology advance online publication, 14 July 2014; doi:10.1038/cmi.2014.49.
- Simultaneous typing of nine avian respiratory pathogens using a novel GeXP analyzer-based multiplex PCR assay. [JOURNAL ARTICLE]
- J Virol Methods 2014 Jul 12.
A new, rapid, and high-throughput GenomeLab Gene Expression Profiler (GeXP) analyzer-based multiplex PCR method was developed for simultaneous detection and differentiation of nine avian respiratory pathogens. The respiratory pathogens included in this study were avian influenza subtypes H5, H7, and H9, infectious bronchitis virus (IBV), Newcastle disease virus (NDV), infectious laryngotracheitis virus (ILTV), Mycoplasma gallisepticum (MG), Mycoplasma synoviae (MS) and Haemophilus paragallinarum (HPG). Ten pairs of primers were designed using conserved and specific sequence genes of AIV subtypes and respiratory pathogens from GenBank. Single and mixed pathogen cDNA/DNA templates were used to evaluate the specificity of the GeXP-multiplex assay. The corresponding specific DNA products were amplified for each pathogen. The specific DNA product amplification peaks of nine respiratory pathogens were observed on the GeXP analyzer. Non-respiratory avian pathogens, including chicken infectious anemia virus, fowl adenovirus, avian reovirus and infectious bursal disease virus, did not produce DNA products. The detection limit for the GeXP-multiplex assay was determined to be 100 copies/μl using various pre-mixed plasmids/ssRNAs containing known target genes of the respiratory pathogens. Further, GeXP-multiplex PCR assay was 100% specific when 24 clinical samples with respiratory infections were tested in comparison with conventional PCR method. The GeXP-multiplex PCR assay provides a novel tool for simultaneous detection and differentiation of nine avian respiratory pathogens.
- Etiology and clinical outcomes of acute respiratory virus infection in hospitalized adults. [Journal Article]
- Infect Chemother 2014 Jun; 46(2):67-76.
Etiologies and clinical profiles of acute respiratory viral infections need to be clarified to improve preventive and therapeutic strategies.A retrospective observational study at a single, university-affiliated center was performed to evaluate the respiratory viral infection etiologies in children compared to that in adults and to document the clinical features of common viral infections for adults from July 2009 to April 2012.The common viruses detected from children (2,800 total patients) were human rhinovirus (hRV) (31.8%), adenovirus (AdV) (19.2%), respiratory syncytial virus (RSV) A (17.4%), RSV B (11.7%), and human metapneumovirus (hMPV) (9.8%). In comparison, influenza virus A (IFA) had the highest isolation rate (28.5%), followed by hRV (15.5%), influenza virus B (IFB) (15.0%), and hMPV (14.0%), in adults (763 total patients). Multiple viruses were detected in single specimens from 22.4% of children and 2.0% of adults. IFA/IFB, RSV A/B, and hMPV exhibited strong seasonal detection and similar circulating patterns in children and adults. Adult patients showed different clinical manifestations according to causative viruses; nasal congestion and rhinorrhea were more common in hRV and human coronavirus (hCoV) infection. Patients with RSV B, hRV, or AdV tended to be younger, and those infected with RSV A and hMPV were likely to be older. Those with RSV A infection tended to stay longer in hospital, enter the intensive care unit more frequently, and have a fatal outcome more often. The bacterial co-detection rate was 26.5%, and those cases were more likely to have lower respiratory tract involvement (P = 0.001), longer hospital stay (P = 0.001), and higher mortality (P = 0.001).The etiologic virus of an acute respiratory infection can be cautiously inferred based on a patient's age and clinical features and concurrent epidemic data. Large-scale prospective surveillance studies are required to provide more accurate information about respiratory viral infection etiology, which could favorably influence clinical outcomes.
- Correlations among persistent viral infection, heart function and Chinese medicine syndromes in dilated cardiomyopathy patients. [JOURNAL ARTICLE]
- Chin J Integr Med 2014 Jul 14.
To investigate the correlations among persistent viral infection, heart function and Chinese medicine (CM) difined-syndromes in patients with dilated cardiomyopathy (DCM).Fifty patients with DCM in the First Affiliated Hospital of Zhejiang Chinese Medical University from October 2009 to December 2011 were selected as the research subjects, and 30 healthy people were simultaneously selected as the normal control group to detect persistent viral infections after admission. The CM syndrome type and grade of heart function were then evaluated. The expression level of Coxsackie adenovirus receptor (CAR) was detected using the flow cytometry (FCM) technique, coxsackie virus RNA (CVB-RNA) using reverse transcription polymerase chain reaction (RTPCR), and the plasma brain natriuretic peptide (BNP) level with a Triage meter plus diagnosis instrument. Finally, the parameters such as left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by ultrasonic cardiogram. Person correlation analysis was used for measured data, Spearman correlation analysis for rating data, and the Chi-square test for numerical data.CVB-RNA was positive in 22 patients (44%) with DCM, while only 6 cases (20%) were CVB-RNA-positive in the normal control group, with a significant difference between the two groups (P<0.01). The expression level of CAR was significantly elevated in the DCM group compared with the normal control group (P<0.01). In CVB-RNA-positive patients (22 cases), the expression level of CAR was significantly higher than in CVB-RNA-negative patients (28 cases; <0.01). In the DCM patients, there was a positive correlation between the CAR expression and the BNP level (r=0.34, <0.05), while no significant difference was found between the CAR expression and the LVEF and LVEDd (r=-0.32, 0.30, P>0.05). There was no clear correlation between virus infection and the CM syndrome types in DCM patients (r=-0.22, P>0.05). According to the sequence of syndrome types: phlegm → qi deficiency → blood stasis → hydroretention with asthenic yang (from low to high), a positive correlation was existed between the BNP levels and CM syndrome types (r=0.139, P<0.05).The expression of CAR on the surface of white cells could be used to detect persistent viral infection. The expression level of CAR and heart function in DCM patients were highly correlated. The expression level of BNP may serve as an objective index for differentiating CM syndromes for patients with DCM.
- Gastrointestinal pathogens detected by multiplex nucleic acid amplification testing in stools of pediatric patients and patients returning from the tropics. [JOURNAL ARTICLE]
- Infection 2014 Jul 12.
Gastrointestinal infections are caused by a broad spectrum of pathogens. Conventional diagnostic procedures are resource and time consuming due to single pathogen testing, often in different laboratories.We analyzed 312 consecutive stool samples from pediatric patients (n = 127) with gastroenteritis or from adult travelers returning from the tropics with suspected parasite infestation (n = 185) using commercial multiplex nucleic acid amplification testing (NAT) (xTAG gastrointestinal pathogen panel, Luminex) covering 15 diarrhea-causing pathogens. The results of the positive samples and a representative number of negative samples were compared to standard methods, including NAT, direct antigen detection (DAD), bacterial culture and microscopy.Of the 185 samples from adult travelers, 21 (11 %) were multiplexNAT-positive, with enterotoxigenic Escherichia coli (4 %) being the predominant pathogen. Microscopic examination revealed Blastocystis hominis in 23 % not covered by the panel. MultiplexNAT scored positive in 66 pediatric samples (52 %), with rotavirus (27 %) being the most prevalent. All adenovirus-, rotavirus-, Clostridium difficile- and Cryptosporidium-positive samples were confirmed in external laboratories, but only 40 % of norovirus- and 29 % of Giardia-positive samples. Analysis of frozen specimens by bacterial culture showed the highest discrepancies with the multiplexNAT.Our study demonstrates broad detection of relevant gastroenteritis pathogens by multiplexNAT with a short turnaround time. This is important for diagnosis, infection control and empiric management of gastroenteritis patients, but may be selectively complemented by bacterial culture and resistance testing.