Adenovirus infections [keywords]
- Adenovirus siMDM2 and NDRG2 Gene Therapy Inhibits Cell Proliferation and Induces Apoptosis of Squamous Cell Carcinoma. [JOURNAL ARTICLE]
- Cell Biochem Biophys 2015 Nov; 73(2):513-518.
Squamous cell carcinoma (SCC) is one of the most common skin cancers. In the present study, we explored the effects of depletion of murine double minute gene 2 (MDM2) together with overexpression of N-myc downstream-regulated gene 2 (NDRG2) on cutaneous SCC. In order to achieve high efficiency of gene knockdown and overexpression in SCC-13 cells, recombinant adenovirus carrying siMDM2 and NDRG2 expression construct was produced. We found Ad-siMDM2, Ad-NDRG2, and Ad-siMDM2-NDRG2 infections inhibit the growth of SCC-13 cells in vitro, and Ad-siMDM2-NDRG2 infection has the highest inhibitory effect. Subcutaneous injections of Ad-siMDM2, Ad-NDRG2, and Ad-siMDM2-NDRG2 into SCC-13 xenograft nude mice resulted in the reduction of tumor volume. Moreover, we found that apoptosis protein caspase 3 was up-regulated in the Ad-siMDM2-, Ad-NDRG2-, and Ad-siMDM2-NDRG2-treated groups. Our data indicate that the adenovirus-mediated MDM2 silencing and NDRG2 overexpression can synergistically inhibit local cancer cell proliferation, induce apoptosis, and further prevent metastases of SCC. Our study provides a promising method that can be further developed as a new therapeutic approach against SCC.
- Outbreak of acute febrile respiratory illness caused by human adenovirus B P14H11F14 in a military training camp in Shandong China. [JOURNAL ARTICLE]
- Arch Virol 2016 Jun 28.
This study reports an outbreak of acute febrile respiratory illness caused by human adenovirus B [P14H11F14] in a military training center in China between May and June 2014. In total, 164 military personnel were affected, and two patients were admitted into the intensive care unit of the military regional central hospital. A HAdV-B [P14H11F14] virus was confirmed as the etiological pathogen of this acute outbreak of febrile respiratory illness based on clinical manifestations, epidemiological characteristics, specific molecular detection results, phylogenetic analysis, and serological assays. The virus was isolated by the rhabdomyosarcoma cell culture method, and the complete sequences of the E1A, penton base, hexon, and fiber genes were determined and deposited in the GenBank database. Phylogenetic and sequence homology analyses indicated that the isolated strain is most closely related to some HAdV-55 strains from mainland China. However, this strain appeared to be less virulent than former HAdV-55 strains. According to the chest X-ray results of 31 affected patients, there was no radiological evidence of pneumonia. The most frequent symptoms in these patients were sore throat (95.12 %, 156/164) and tonsillitis (93.29 %, 153/164). During the course of the outbreak, incorrect response measures and some potential risk factors, such as fire training and marching training, may have exacerbated the spread of the infection. This outbreak illustrates the urgent need to improve the epidemiological and etiological surveillance of HAdV infections and to improve the ability of doctors and health officials in basic units of the Chinese army to respond effectively to febrile respiratory illness.
- Impact of co-infections with enteric pathogens on children suffering from acute diarrhea in southwest China. [Journal Article]
- Infect Dis Poverty 2016; 5(1):64.
Acute diarrhea is a global health problem, resulting in high morbidity and mortality in children. It has been suggested that enteric pathogen co-infections play an important role in gastroenteritis, but most research efforts have only focused on a small range of species belonging to a few pathogen groups. This study aimed to assess the impact of co-infections with a broad range of enteric pathogens on children aged below five years who suffer from acute diarrhea in southwest China.A total of 1020 subjects (850 diarrhea cases and 170 healthy controls) were selected from four sentinel hospitals in Kunming, Yunnan province, southwest China, from June 2014 to July 2015. Stool specimens were collected to detect five virus (rotavirus group A, RVA; norovirus, NoV; Sapovirus, SaV; astrovirus, As; and adenovirus, Ad), seven bacterial (diarrheagenic Escherichia coli, DEC; non-typhoidal Salmonella, NTS; Shigella spp.; Vibrio cholera; Vibrio parahaemolyticus; Aeromonas spp.; and Plesiomonas spp.), and three protozoan (Cryptosporidium spp., Giardia lamblia, and Blastocystis hominis, B. hominis) species using standard microbiologic and molecular methods. Data were analyzed using the partial least square regression technique and chi-square test.At least one enteric pathogen was detected in 46.7 % (n = 397) of acute gastroenteritis cases and 13.5 % (n = 23) of healthy controls (χ(2) = 64.4, P < 0.05). Single infection with RVA was associated with acute diarrhea (26.5 % vs. 5.8 %, P < 0.05). The prevalence of a single infection with B. hominis in diarrhea cases was higher than in healthy controls (3.1 % vs. 0.5 %, OR = 4.7, 95 % CI: 1.01-112.0). Single infection with NoV GII was not associated with diarrhea (4.4 % vs. 3.5 %, OR = 1.2, 95 % CI: 0.5-3.3). Single infections with bacterial species were not observed. The prevalence of co-infections with two enteric pathogens in diarrhea cases was higher than in asymptomatic children (20.1 % vs. 5.3 %, P < 0.05). RVA-NoV GII was the most common co-infection in symptomatic children (4.4 %), with it aggravating the severity of diarrhea.Although it is clear that RVA has an overwhelming impact on diarrhea illnesses in children, co-infection with other enteric pathogens appears to also aggravate diarrhea severity. These findings should serve as evidence for public health services when planning and developing intervention programs.
- An overview of infectious complications after allogeneic hematopoietic stem cell transplantation. [REVIEW, JOURNAL ARTICLE]
- J Infect Chemother 2016 Jun 22.
Infections are the most common and significant cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The presence of neutropenia and mucosal damage are the leading risk factors in the early pre-engraftment phase. In the early post-engraftment phase, graft versus host disease (GvHD) induced infection risk is increased in addition to catheter related infections. In the late phase, in which reconstitution of cellular and humoral immunity continues, as well as the pathogens seen during the early post-engraftment phase, varicella-zoster virus and encapsulated bacterial infections due to impaired opsonization are observed. An appropriate vaccination schedule following the cessation of immunosuppressive treatment after transplantation, intravenous immunoglobulin administration, and antimicrobial prophylaxis with penicillin or macrolide antibiotics during immunosuppressive treatment for GvHD might decrease the risk of bacterial infections. Older age, severe mucositis due to toxicity of chemotherapy, gastrointestinal tract colonization, prolonged neutropenia, unrelated donor and cord blood originated transplantations, acute and chronic GvHD are among the most indicative clinical risk factors for invasive fungal infections. Mold-active anti-fungal prophylaxis is suggested regardless of the period of transplantation among high risk patients. The novel serological methods, including Aspergillus galactomannan antigen and beta-D-glucan detection and computed tomography are useful in surveillance. Infections due to adenovirus, influenza and respiratory syncytial virus are encountered in all phases after allo-HSCT, including pre-engraftment, early post-engraftment and late phases. Infections due to herpes simplex virus-1 and -2 are mostly seen during the pre-engraftment phase, whereas, infections due to cytomegalovirus and human herpesvirus-6 are seen in the early post-engraftment phase and Epstein-Barr virus and varicella-zoster virus infections often after +100th day. In order to prevent mortality and morbidity of infections after allo-HSCT, the recipients should be carefully followed-up with appropriate prophylactic measures in the post-transplant period.
- Nitrogen Gas Plasma Generated by a Static Induction Thyristor as a Pulsed Power Supply Inactivates Adenovirus. [Journal Article]
- PLoS One 2016; 11(6):e0157922.
Adenovirus is one of the most important causative agents of iatrogenic infections derived from contaminated medical devices or finger contact. In this study, we investigated whether nitrogen gas plasma, generated by applying a short high-voltage pulse to nitrogen using a static induction thyristor power supply (1.5 kilo pulse per second), exhibited a virucidal effect against adenoviruses. Viral titer was reduced by one log within 0.94 min. Results from detection of viral capsid proteins, hexon and penton, by Western blotting and immunochromatography were unaffected by the plasma treatment. In contrast, analysis using the polymerase chain reaction suggested that plasma treatment damages the viral genomic DNA. Reactive chemical products (hydrogen peroxide, nitrate, and nitrite), ultraviolet light (UV-A) and slight temperature elevations were observed during the operation of the gas plasma device. Viral titer versus intensity of each potential virucidal factor were used to identify the primary mechanism of disinfection of adenovirus. Although exposure to equivalent levels of UV-A or heat treatment did not inactivate adenovirus, treatment with a relatively low concentration of hydrogen peroxide efficiently inactivated the virus. Our results suggest the nitrogen gas plasma generates reactive chemical products that inactivate adenovirus by damaging the viral genomic DNA.
- Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. [JOURNAL ARTICLE]
- Hepatology 2016 Jun 16.
Hepatitis B virus (HBV) is a major human pathogen and about one third of the global population will be exposed to the virus in their life time. HBV infects hepatocytes where it replicates its DNA and infection can lead to acute and chronic hepatitis with high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type I IFN production, and this occurs through a pathway dependent on the DNA sensor cGAS and the downstream adaptor protein STING. In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type I IFN in response to foreign DNA or HBV infection and mice lacking STING or cGAS exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possess anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. In conclusion, the lack of a functional innate DNA sensing pathway in hepatocytes hampers efficient innate control of HBV infection. This may explain why HBV has adapted to specifically replicate in hepatocytes, and could contribute to the weak capacity of this cell type to clear HBV infection. This article is protected by copyright. All rights reserved.
- Mouse Adenovirus Type 1 Early Region 1A Effects on the Blood-Brain Barrier. [Journal Article]
- mSphere 2016 Mar-Apr; 1(2)
Mouse adenovirus type 1 (MAV-1) infects endothelial cells and disrupts the blood-brain barrier (BBB), causing encephalitis in inbred and outbred mice. Using a virus mutant that does not produce the early region 1A protein E1A, we investigated whether the activity of this known viral transcriptional regulator is needed for BBB disruption and other phenotypes associated with encephalitis. The wild-type (wt) virus and E1A mutant virus caused similar levels of permeability of sodium fluorescein in brains of infected mice. In an in vitro assay of BBB integrity, wt and mutant virus caused similar decreases in transendothelial electrical resistance in primary mouse brain endothelial cell monolayers. These results indicate that E1A protein does not contribute to disruption of BBB integrity in animals or cultured cells. Both wt and E1A mutant virus infection of mice led to similar increases in the activity of two matrix metalloproteinases known to correlate with BBB disruption, MMP2 and MMP9, while causing no increase in the steady-state expression of MMP2 or MMP9 mRNA. In contrast, the amount of MMP3 transcripts increased upon infection by both viruses and to a higher level in infections by the mutant virus lacking E1A protein production. There was no difference in the levels of steady-state expression of mRNA for tight junction proteins among mock virus, wt virus, and mutant virus infections. Thus, the MAV-1 E1A protein does not measurably affect BBB integrity in the parameters assayed, although it reduces the amount of MMP3 mRNA steady-state expression induced in brains upon infection. IMPORTANCE Encephalitis can be caused by viruses, and it is potentially life-threatening because of the vital nature of the brain and the lack of treatment options. MAV-1 produces viral encephalitis in its natural host, providing a model for investigating factors involved in development of encephalitis. MAV-1 infection disrupts the BBB and increases activity of matrix metalloproteinases in brains of infected mice. We investigated whether the major transcriptional regulator of adenoviruses, E1A protein, is responsible for any of the specific phenotypes that result from MAV-1 infection. For some of the functions assayed, an E1A mutant virus behaved like wild-type virus. However, expression of mRNA for one matrix metalloproteinase was higher in the virus lacking E1A protein production. This highlights the complex nature of encephalitis and suggests that E1A may have transcriptional effects on host genes important for the development of encephalitis.
- Epidemic Keratoconjunctivitis-Causing Adenoviruses Induce MUC16 Ectodomain Release To Infect Ocular Surface Epithelial Cells. [Journal Article]
- mSphere 2016 Jan-Feb; 1(1)
Human adenoviruses (HAdV), species D in particular (HAdV-D), are frequently associated with epidemic keratoconjunctivitis (EKC). Although the infection originates at the ocular surface epithelium, the mechanisms by which HAdV-Ds bypass the membrane-associated mucin (MAM)-rich glycocalyx of the ocular surface epithelium to trigger infection and inflammation remain unknown. Here, we report that an EKC-causing adenovirus (HAdV-D37), but not a non-EKC-causing one (HAdV-D19p), induces ectodomain release of MUC16-a MAM with barrier functions at the ocular surface-from cultured human corneal and conjunctival epithelial cells. HAdV-D37, but not HAdV-D19p, is also found to decrease the glycocalyx barrier function of corneal epithelial cells, as determined by rose bengal dye penetrance assays. Furthermore, results from quantitative PCR (qPCR) amplification of viral genomic DNA using primers specific to a conserved region of the E1B gene show that, in comparison to infection by HAdV-D19p, infection by HAdV-D37 is significantly increased in corneal epithelial cells. Collectively, these results point to a MUC16 ectodomain release-dependent mechanism utilized by the EKC-causing HAdV-D37 to initiate infection at the ocular surface. These findings are important in terms of understanding the pathogenesis of adenoviral keratoconjunctivitis. Similar MAM ectodomain release mechanisms may be prevalent across other mucosal epithelia in the body (e.g., the airway epithelium) that are prone to adenoviral infection. IMPORTANCE Human adenoviruses (HAdVs) are double-stranded DNA viruses that cause infections across all mucosal tissues in the body. At the ocular surface, HAdVs cause keratoconjunctivitis (E. Ford, K. E. Nelson, and D. Warren, Epidemiol Rev 9:244-261, 1987, and C. M. Robinson, D. Seto, M. S. Jones, D. W. Dyer, and J. Chodosh, Infect Genet Evol 11:1208-1217, 2011, doi:10.1016/j.meegid.2011.04.031)-a highly contagious infection that accounts for nearly 60% of conjunctivitis cases in the United States (R. P. Sambursky, N. Fram, and E. J. Cohen, Optometry 78:236-239, 2007, doi:10.1016/j.optm.2006.11.012, and A. M. Pihos, J Optom 6:69-74, 2013, doi:10.1016/j.optom.2012.08.003). The infection begins with HAdV entry within ocular surface epithelial cells; however, the mechanisms used by HAdVs to transit the otherwise protective mucosal barrier of ocular surface epithelial cells prior to entry remain unknown. Here, we report that the highly virulent keratoconjunctivitis-causing HAdV-D37 induces release of the extracellular domain (ectodomain) of MUC16, a major component of the mucosal barrier of ocular surface epithelial cells, prior to infecting underlying cells. Currently, there is no specific treatment for controlling this infection. Understanding the early steps involved in the pathogenesis of keratoconjunctivitis and using this information to intercept adenoviral entry within cells may guide the development of novel strategies for controlling the infection.
- Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia. [JOURNAL ARTICLE]
- Respirology 2016 Jun 15.
Limited data exist regarding factors predicting respiratory failure (RF) in non-immunocompromised patients with adenovirus (AdV) pneumonia.We described characteristics of AdV pneumonia (n = 91) versus non-AdV pneumonia (n = 55) and compared clinico-laboratory and radiological characteristics in patient groups categorized by RF.All 91 AdV pneumonia patients presented with acute respiratory symptoms and radiological infiltrations and had significantly lower levels of white blood cell counts and platelet counts compared with non-AdV pneumonia. Of them, 67 patients had mild pneumonia without RF (non-RF), 14 patients had no RF at admission but progressed to RF during hospitalization (progressed to RF) and 10 patients had RF at admission (initial RF). Initial monocyte percentage and absolute monocyte counts in RF patient groups (progressed to RF and initial RF) were significantly lower than those of non-RF patients (both P < 0.001), and the differences among progressed to RF and initial RF patients were not significant. Chest computed tomography findings such as dominant pattern or distribution, clinical symptoms, and bacterial or viral co-infections other than AdV were not discriminable between patients who had RF and those who did not. On univariate analysis, initial monocytopenia, multilobar infiltrations and pleural effusion were associated with RF. However, on multivariable analysis, only initial monocytopenia remained significant (P = 0.004) for predicting RF.Our data suggest that initial monocytopenia may help to predict RF during the course of AdV pneumonia in non-immunocompromised patients.
- Molecular epidemiological study of adenovirus infecting western lowland gorillas and humans in and around Moukalaba-Doudou National Park (Gabon). [JOURNAL ARTICLE]
- Virus Genes 2016 Jun 11.
Adenoviruses are widespread in human population as well as in great apes, although the data about the naturally occurring adenovirus infections remain rare. We conducted the surveillance of adenovirus infection in wild western lowland gorillas in Moukalaba-Doudou National Park (Gabon), in order to investigate naturally occurring adenovirus in target gorillas and tested specifically a possible zoonotic transmission with local people inhabiting the vicinity of the park. Fecal samples were collected from western lowland gorillas and humans, and analyzed by PCR. We detected adenoviral genes in samples from both gorillas and the local people living around the national park, respectively: the overall prevalence rates of adenovirus were 24.1 and 35.0 % in gorillas and humans, respectively. Sequencing revealed that the adenoviruses detected in the gorillas were members of Human mastadenovirus B (HAdV-B), HAdV-C, or HAdV-E, and those in the humans belonged to HAdV-C or HAdV-D. Although HAdV-C members were detected in both gorillas and humans, phylogenetic analysis revealed that the virus detected in gorillas are genetically distinct from those detected in humans. The HAdV-C constitutes a single host lineage which is compatible with the host-pathogen divergence. However, HAdV-B and HAdV-E are constituted by multiple host lineages. Moreover, there is no evidence of zoonotic transmission thus far. Since the gorilla-to-human transmission of adenovirus has been shown before, the current monitoring should be continued in a broader scale for getting more insights in the natural history of naturally occurring adenoviruses and for the safe management of gorillas' populations.