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1.
Arch Pediatr ; 28(7): 573-575, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1491712

ABSTRACT

In the context of the current coronavirus disease 2019 (COVID-19) pandemic, cutaneous lesions are being described. Here, we report on a 13-year-old girl with SARS-CoV-2-associated Henoch-Schönlein purpura and Epstein-Barr virus (EBV) infection. She presented without any respiratory symptoms, only a purpuric skin rash, abdominal pain, low-grade fever, and pharyngitis. Virology tests by polymerase chain reaction (PCR) were positive for SARS-CoV-2 and EBV. The potential association of Henoch-Schönlein purpura and SARS-CoV-2 should be kept in mind in order to reduce the spread of the virus, particularly in children with few respiratory symptoms.


Subject(s)
COVID-19/diagnosis , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human/isolation & purification , SARS-CoV-2/isolation & purification , Abdominal Pain/etiology , Adolescent , Epstein-Barr Virus Infections/complications , Exanthema/etiology , Female , Fever/etiology , Herpesvirus 4, Human/genetics , Humans , Pharyngitis/etiology , Polymerase Chain Reaction , SARS-CoV-2/genetics
2.
J Virol ; 95(13): e0019221, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1486499

ABSTRACT

Understanding factors that affect the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is central to combatting coronavirus disease 2019 (COVID-19). The virus surface spike protein of SARS-CoV-2 mediates viral entry into cells by binding to the ACE2 receptor on epithelial cells and promoting fusion. We found that Epstein-Barr virus (EBV) induces ACE2 expression when it enters the lytic replicative cycle in epithelial cells. By using vesicular stomatitis virus (VSV) particles pseudotyped with the SARS-CoV-2 spike protein, we showed that lytic EBV replication enhances ACE2-dependent SARS-CoV-2 pseudovirus entry. We found that the ACE2 promoter contains response elements for Zta, an EBV transcriptional activator that is essential for EBV entry into the lytic cycle of replication. Zta preferentially acts on methylated promoters, allowing it to reactivate epigenetically silenced EBV promoters from latency. By using promoter assays, we showed that Zta directly activates methylated ACE2 promoters. Infection of normal oral keratinocytes with EBV leads to lytic replication in some of the infected cells, induces ACE2 expression, and enhances SARS-CoV-2 pseudovirus entry. These data suggest that subclinical EBV replication and lytic gene expression in epithelial cells, which is ubiquitous in the human population, may enhance the efficiency and extent of SARS-CoV-2 infection of epithelial cells by transcriptionally activating ACE2 and increasing its cell surface expression. IMPORTANCE SARS-CoV-2, the coronavirus responsible for COVID-19, has caused a pandemic leading to millions of infections and deaths worldwide. Identifying the factors governing susceptibility to SARS-CoV-2 is important in order to develop strategies to prevent SARS-CoV-2 infection. We show that Epstein-Barr virus, which infects and persists in >90% of adult humans, increases susceptibility of epithelial cells to infection by SARS-CoV-2. EBV, when it reactivates from latency or infects epithelial cells, increases expression of ACE2, the cellular receptor for SARS-CoV-2, enhancing infection by SARS-CoV-2. Inhibiting EBV replication with antivirals may therefore decrease susceptibility to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Epithelial Cells/virology , Herpesvirus 4, Human/physiology , SARS-CoV-2/physiology , Virus Internalization , Virus Replication , Angiotensin-Converting Enzyme 2/metabolism , Cell Line , DNA Methylation , Epithelial Cells/metabolism , Gene Expression Regulation , Humans , Promoter Regions, Genetic , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Trans-Activators/metabolism , Virus Activation
3.
Biosens Bioelectron ; 195: 113672, 2022 Jan 01.
Article in English | MEDLINE | ID: covidwho-1439904

ABSTRACT

We present the first combination of a microfluidic polymerase chain reaction (PCR) with a gold nanoslit-based surface plasmon resonance (SPR) sensor for detecting the DNA sequence of latent membrane protein 1 (LMP1). The PCR microchannel was produced through a laser scribing technique, and the SPR nanoslit chip was manufactured via hot-embossing nanoimprinting lithography. Afterward, the LMP1 DNA probe was adsorbed onto the SPR chip of the integrated device through electrostatic interactions for further detection. The device can complete the analytical procedure in around 36 min, while the traditional machine requires 105 min to achieve similar signals under the same PCR thermal cycles. The calibration curve with serially diluted LMP1 DNA exhibited the accuracy (R2 > 0.99) and sensitivity (limit of detection: ∼10-11 g/mL) of the device. Moreover, extracted DNA from Epstein-Barr virus (EBV)-positive cells were directly detected through the integrated chip. In brief, this all-in-one chip can amplify gene fragments at the front-end and detect them at the back-end, decreasing the time required for the analysis without compromising accuracy or sensitivity. We believe this label-free, real-time, low-cost device has enormous potential for rapid detection of various viruses, such as EBV and COVID-19.


Subject(s)
Biosensing Techniques , COVID-19 , Epstein-Barr Virus Infections , Gold , Herpesvirus 4, Human/genetics , Humans , Microfluidics , Polymerase Chain Reaction , SARS-CoV-2 , Viral Matrix Proteins/genetics
4.
BMC Infect Dis ; 21(1): 955, 2021 Sep 15.
Article in English | MEDLINE | ID: covidwho-1414111

ABSTRACT

BACKGROUND: Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. METHOD: This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. RESULTS: Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. CONCLUSIONS: In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Critical Illness , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/epidemiology , Herpesvirus 4, Human , Humans , Retrospective Studies , SARS-CoV-2 , Virus Activation
5.
Virol J ; 18(1): 180, 2021 09 05.
Article in English | MEDLINE | ID: covidwho-1388778

ABSTRACT

BACKGROUND: Covid-19 has the respiratory tract as the main target of infection, and patients present mainly dyspnea, pneumonia, dry cough, and fever. Nevertheless, organs outside the respiratory tract had been reported in recent studies, including the gastrointestinal tract and liver. The host innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through their pattern recognition receptor (PRRs). Toll-like receptor 7 (TLR-7) is a pattern recognition receptor recognizing ssRNA (SARS-CoV-2 is an ssRNA). Polymorphisms are characterized by two or more alternative forms of a distinct phenotype in the same population. Polymorphisms in tlrs genes can negatively influence the immune response to infectious diseases. There are several references in the literature to non-synonymous single nucleotide (rs) polymorphisms related to several genes. Some of them are important for the innate immunity, as rs 179008 (tlr-7), rs3775291 (tlr3), rs8177374 (tir domain-containing adaptor protein, tirap), rs1024611 (monocyte chemoattractant protein-1, mcp-1) and rs61942233 (2'-5'-oligoadenylate synthase-3, oas-3). CASE PRESENTATION: We identified a 5-year-old-male child with gastrointestinal symptoms and fever presenting acholic stool and jaundice, who was positive for SARS-CoV-2 IgM, IgA, and IgG and presenting the Gln11Leu rs 179008 in tlr-7. The child presented high levels of aspartate aminotransferase, alanine aminotransferase, bilirubin, C-reactive protein, D-dimer, gamma-glutamyl transferase, alkaline phosphatase, and was negative for serological tests for hepatitis A, B, C, E, HIV 1 and 2, herpes virus, cytomegalovirus, Epstein-Barr virus, and negative for RTqPCR for Influenza A and B, RSV and SARS-CoV-2. We also investigated other SNPs in the tlr-3 (rs3775291), tirap (rs8177374), mcp-1 (rs1024611), and oas-3 (rs61942233) genes, and no mutation was detected. After an interview with the child's caregivers, any possible accidental ingestion of drugs or hepatotoxic substances was ruled out. CONCLUSION: To our knowledge, this is the first report of a SARS-CoV-2 caused hepatitis in a male child that has the tlr-7 Gln11Leu rs 179008, which could impair an efficient initial immune response. The knowledge of the patient's immune deficiency could improve the treatment to correct this deficiency with specific medications.


Subject(s)
COVID-19/genetics , COVID-19/virology , Hepatitis, Viral, Human/genetics , Hepatitis, Viral, Human/virology , Toll-Like Receptor 7/genetics , Antibodies, Viral/blood , COVID-19/immunology , Child, Preschool , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/virology , Feces/virology , Hepatitis, Viral, Human/immunology , Herpesvirus 4, Human/isolation & purification , Humans , Immunity, Innate , Influenza, Human , Male , Polymorphism, Single Nucleotide , SARS-CoV-2/isolation & purification
6.
J Investig Med High Impact Case Rep ; 9: 23247096211040626, 2021.
Article in English | MEDLINE | ID: covidwho-1371944

ABSTRACT

Epstein-Barr virus (EBV), a member of the herpes virus family, is a causative agent for infectious mononucleosis in young adults. It has an asymptomatic and subclinical distribution in about 90% to 95% of the world population based on seropositivity. EBV is associated with various lymphomas, nasopharyngeal carcinoma, and in immunocompromised states can give rise to aggressive lymphoproliferative disorders. Symptomatic patients mostly present with mild hepatitis, rash, oral symptoms, lymphadenopathy, and generalized malaise. Recently with the COVID-19 (coronavirus disease-2019) pandemic, hepatitis has been found to be related to acute EBV and cytomegalovirus reactivation versus acute infection in the absence of other major causes. We describe a case of EBV coinfection in a patient with resolving mild COVID-19 infection.


Subject(s)
COVID-19/complications , Coinfection , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human , SARS-CoV-2 , Herpesvirus 4, Human/pathogenicity , Humans , Male , Middle Aged
7.
Immun Inflamm Dis ; 9(4): 1563-1572, 2021 12.
Article in English | MEDLINE | ID: covidwho-1366235

ABSTRACT

INTRODUCTION: Although most patients recover within several weeks after acute COVID-19, some of them develop long-lasting clinical symptoms. Renal transplant recipients have an increased mortality risk from COVID-19. We aimed to describe complications occurring after COVID-19 in this group of patients. METHODS: A prospective single-center cohort study was conducted at University Hospital Centre Zagreb. Patients with two negative reverse transcriptase-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 after COVID-19 were eligible for further follow-up at our outpatient clinic. They underwent detailed clinical and laboratory assessments. The primary outcome was the development of complications after COVID-19. RESULTS: Only 11.53% of renal transplant recipients who survived acute COVID-19 were symptomless and free from new-onset laboratory abnormalities during the median follow-up of 64 days (range: 50-76 days). Three patients died from sepsis after discharge from the hospital. In 47 patients (45.2%), clinical complications were present, while 74 patients (71.2%) had one or more laboratory abnormalities. The most common clinical complications included shortness of breath (19.2%), tiredness (11.5%), peripheral neuropathy (7.7%), self-reported cognitive impairments (5.7%), and dry cough (7.7%). Most common laboratory abnormalities included shortened activated partial thromboplastin time (50%), elevated D-dimers (36.5%), elevated fibrinogen (30.16%), and hypogammaglobulinemia (24%). Positive RT-PCR for cytomegalovirus (8.7%), Epstein-Barr virus (26%), or BK virus (16.3%). Multivariate analysis identified the history of diabetes mellitus and eGFR CKD-EPI as predictors for the development of post-COVID clinical complications. Six months after acute COVID-19, elevated D-dimers persisted with normalization of other laboratory parameters. Twenty-nine patients were hospitalized, mostly with several concomitant problems. However, initially reported clinical problems gradually improved in the majority of patients. CONCLUSION: Post-COVID-19 clinical and laboratory complications are frequent in the renal transplant population, in some of them associated with significant morbidity. All patients recovered from acute COVID-19 should undergo long-term monitoring for evaluation and treatment of complications.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Kidney Transplantation , Cohort Studies , Follow-Up Studies , Herpesvirus 4, Human , Humans , Kidney Transplantation/adverse effects , Prospective Studies , SARS-CoV-2
8.
Arch Pediatr ; 28(7): 573-575, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1358159

ABSTRACT

In the context of the current coronavirus disease 2019 (COVID-19) pandemic, cutaneous lesions are being described. Here, we report on a 13-year-old girl with SARS-CoV-2-associated Henoch-Schönlein purpura and Epstein-Barr virus (EBV) infection. She presented without any respiratory symptoms, only a purpuric skin rash, abdominal pain, low-grade fever, and pharyngitis. Virology tests by polymerase chain reaction (PCR) were positive for SARS-CoV-2 and EBV. The potential association of Henoch-Schönlein purpura and SARS-CoV-2 should be kept in mind in order to reduce the spread of the virus, particularly in children with few respiratory symptoms.


Subject(s)
COVID-19/diagnosis , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human/isolation & purification , SARS-CoV-2/isolation & purification , Abdominal Pain/etiology , Adolescent , Epstein-Barr Virus Infections/complications , Exanthema/etiology , Female , Fever/etiology , Herpesvirus 4, Human/genetics , Humans , Pharyngitis/etiology , Polymerase Chain Reaction , SARS-CoV-2/genetics
10.
Nano Lett ; 21(11): 4643-4653, 2021 06 09.
Article in English | MEDLINE | ID: covidwho-1303734

ABSTRACT

DNA quantification is important for biomedical research, but the routinely used techniques rely on nucleic acid amplification which have inherent issues like cross-contamination risk and quantification bias. Here, we report a CRISPR-Cas12a-based molecular diagnostic technique for amplification-free and absolute quantification of DNA at the single-molecule level. To achieve this, we first screened out the optimal reaction parameters for high-efficient Cas12a assay, yielding over 50-fold improvement in sensitivity compared with the reported Cas12a assays. We further leveraged the microdroplet-enabled confinement effect to perform an ultralocalized droplet Cas12a assay, obtaining excellent specificity and single-molecule sensitivity. Moreover, we demonstrated its versatility and quantification capability by direct counting of diverse virus's DNAs (African swine fever virus, Epstein-Barr virus, and Hepatitis B virus) from clinical serum samples with a wide range of viral titers. Given the flexible programmability of crRNA, we envision this amplification-free technique as a versatile and quantitative platform for molecular diagnosis.


Subject(s)
African Swine Fever Virus , Epstein-Barr Virus Infections , African Swine Fever Virus/genetics , Animals , CRISPR-Cas Systems , DNA/genetics , Herpesvirus 4, Human , Swine
11.
Front Immunol ; 12: 677027, 2021.
Article in English | MEDLINE | ID: covidwho-1282385

ABSTRACT

Epstein-Barr virus (EBV) is a human herpesvirus that is common among the global population, causing an enormous disease burden. EBV can directly cause infectious mononucleosis and is also associated with various malignancies and autoimmune diseases. In order to prevent primary infection and subsequent chronic disease, efforts have been made to develop a prophylactic vaccine against EBV in recent years, but there is still no vaccine in clinical use. The outbreak of the COVID-19 pandemic and the global cooperation in vaccine development against SARS-CoV-2 provide insights for next-generation antiviral vaccine design and opportunities for developing an effective prophylactic EBV vaccine. With improvements in antigen selection, vaccine platforms, formulation and evaluation systems, novel vaccines against EBV are expected to elicit dual protection against infection of both B lymphocytes and epithelial cells. This would provide sustainable immunity against EBV-associated malignancies, finally enabling the control of worldwide EBV infection and management of EBV-associated diseases.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/physiology , Lymphoproliferative Disorders/immunology , SARS-CoV-2/physiology , Viral Vaccines/immunology , Animals , Epstein-Barr Virus Infections/prevention & control , Humans , Lymphoproliferative Disorders/prevention & control , Pre-Exposure Prophylaxis
12.
Acta Paediatr ; 110(10): 2729-2736, 2021 10.
Article in English | MEDLINE | ID: covidwho-1258900

ABSTRACT

Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Lymphohistiocytosis, Hemophagocytic , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/therapy , SARS-CoV-2
13.
Biomed J ; 44(3): 227-234, 2021 06.
Article in English | MEDLINE | ID: covidwho-1252506

ABSTRACT

This issue of the Biomedical Journal tells us about the risks of electronic cigarette smoking, variations of SARS-CoV-2 and ACE2, and how COVID-19 affects the gastrointestinal system. Moreover, we learn that cancer immunotherapy seems to work well in elderly patients, how thyroid hormones regulate noncoding RNAs in a liver tumour context, and that G6PD is a double-edged sword of redox signalling. We also discover that Perilla leaf extract could inhibit SARS-CoV-2, that artificial neural networks can diagnose COVID-19 patients and predict vaccine epitopes on the Epstein-Barr Virus, and that men and women have differential inflammatory responses to physical effort. Finally, the surgical strategies for drug-resistant epilepsy, computer-supervised double-jaw surgery, dental pulp stem cell motility, and the restitution of the brain blood supply after atherosclerotic stroke are discussed.


Subject(s)
COVID-19 , Electronic Nicotine Delivery Systems , Epstein-Barr Virus Infections , Aged , COVID-19/diagnosis , Exercise , Female , Herpesvirus 4, Human/immunology , Humans , Male , Neural Networks, Computer , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Smoke
14.
Transplant Proc ; 53(8): 2498-2501, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1246217

ABSTRACT

The coronavirus disease 2019 pandemic has made us adjust our standards and cope with unpredictable circumstances affecting the whole world, including the medical field. A 2-year-old boy diagnosed with X-linked lymphoproliferative disease type 2 with concomitant positive polymerase chain reaction test for Epstein-Barr virus-DNA was admitted to our transplant ward. His treatment scheme had to be modified at the last moment because of a donor disqualification due to a positive polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 just before the apheresis. We decided to perform salvage haploidentical bone marrow transplant from the patient's mother because it was the only possible option. Now, in a 5-month observation period after the hematopoietic stem cell transplantation, our patient is in good general condition. His case convinced us to redirect our approach to transplant procedure preparation. Following the European Group of Blood and Marrow Transplantation recommendations, we use cryopreserved apheresis materials to ensure the availability of stem cell products before the start of a conditioning regimen.


Subject(s)
Bone Marrow Transplantation , COVID-19 , Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Lymphohistiocytosis, Hemophagocytic , Salvage Therapy , COVID-19/diagnosis , Child, Preschool , Graft vs Host Disease , Herpesvirus 4, Human , Humans , Lymphohistiocytosis, Hemophagocytic/surgery , Male , Stem Cells , Transplantation Conditioning , Unrelated Donors
15.
Viruses ; 13(6)2021 05 26.
Article in English | MEDLINE | ID: covidwho-1244150

ABSTRACT

Due to the current, rapidly increasing Coronavirus disease 2019 (COVID-19) pandemic, efficient and highly specific diagnostic methods are needed. The receptor-binding part of the spike (S) protein, S1, has been suggested to be highly virus-specific; it does not cross-react with antibodies against other coronaviruses. Three recombinant partial S proteins of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) expressed in mammalian or baculovirus-insect cells were evaluated as antigens in a Luminex-based suspension immunoassay (SIA). The best performing antigen (S1; amino acids 16-685) was selected and further evaluated by serum samples from 76 Swedish patients or convalescents with COVID-19 (previously PCR and/or serologically confirmed), 200 pre-COVID-19 individuals (180 blood donors and 20 infants), and 10 patients with acute Epstein-Barr virus infection. All 76 positive samples showed detectable antibodies to S1, while none of the 210 negative controls gave a false positive antibody reaction. We further compared the COVID-19 SIA with a commercially available enzyme immunoassay and a previously evaluated COVID-19 rapid antibody test. The results revealed an overall assay sensitivity of 100%, a specificity of 100% for both IgM and IgG, a quantitative ability at concentrations up to 25 BAU/mL, and a better performance as compared to the commercial assays, suggesting the COVID-19 SIA as a most valuable tool for efficient laboratory-based serology.


Subject(s)
Antibodies, Viral/blood , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Immunoassay/methods , SARS-CoV-2/immunology , COVID-19/immunology , Herpesvirus 4, Human/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Reproducibility of Results , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology
16.
OMICS ; 25(6): 358-371, 2021 06.
Article in English | MEDLINE | ID: covidwho-1243453

ABSTRACT

About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.


Subject(s)
Epstein-Barr Virus Infections/virology , Neoplasms/virology , Papillomavirus Infections/virology , Retroviridae Infections/virology , Retroviridae/physiology , Sarcoma, Kaposi/virology , Tumor Virus Infections/virology , Alphapapillomavirus/physiology , Carcinogenesis , Cell Transformation, Viral , Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human/physiology , Herpesvirus 8, Human/physiology , Humans , Molecular Targeted Therapy , Neoplasms/pathology , Neoplasms/therapy , Papillomavirus Infections/pathology , Retroviridae Infections/pathology , Sarcoma, Kaposi/pathology , Signal Transduction , Tumor Microenvironment , Tumor Virus Infections/pathology
17.
Sci Rep ; 11(1): 10902, 2021 05 25.
Article in English | MEDLINE | ID: covidwho-1243311

ABSTRACT

The objective of this study was to detect the Epstein-Barr virus (EBV) coinfection in coronavirus disease 2019 (COVID-19). In this retrospective single-center study, we included 67 COVID-19 patients with onset time within 2 weeks in Renmin Hospital of Wuhan University from January 9 to February 29, 2020. Patients were divided into EBV/SARS-CoV-2 coinfection group and SARS-CoV-2 infection alone group according to the serological results of EBV, and the characteristics differences between the two groups were compared. The median age was 37 years, with 35 (52.2%) females. Among these COVID-19 patients, thirty-seven (55.2%) patients were seropositive for EBV viral capsid antigen (VCA) IgM antibody. EBV/SARS-CoV-2 coinfection patients had a 3.09-fold risk of having a fever symptom than SARS-CoV-2 infection alone patients (95% CI 1.11-8.56; P = 0.03). C-reactive protein (CRP) (P = 0.02) and the aspartate aminotransferase (AST) (P = 0.04) in EBV/SARS-CoV-2 coinfection patients were higher than that in SARS-CoV-2 infection alone patients. EBV/SARS-CoV-2 coinfection patients had a higher portion of corticosteroid use than the SARS-CoV-2 infection alone patients (P = 0.03). We find a high incidence of EBV coinfection in COVID-19 patients. EBV/SARS-CoV-2 coinfection was associated with fever and increased inflammation. EBV reactivation may associated with the severity of COVID-19.


Subject(s)
Antibodies, Viral/blood , COVID-19/pathology , Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human/isolation & purification , Adrenal Cortex Hormones/therapeutic use , Adult , Aspartate Aminotransferases/blood , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/virology , Capsid Proteins/immunology , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/virology , Female , Fever/etiology , Herpesvirus 4, Human/immunology , Herpesvirus 4, Human/metabolism , Humans , Immunoglobulin M/blood , Male , Middle Aged , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index
18.
PLoS Pathog ; 17(4): e1009041, 2021 04.
Article in English | MEDLINE | ID: covidwho-1231262

ABSTRACT

Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus with latent and lytic cycles. EBV replicates in the stratified epithelium but the nasopharynx is also composed of pseudostratified epithelium with distinct cell types. Latent infection is associated with nasopharyngeal carcinoma (NPC). Here, we show with nasopharyngeal conditionally reprogrammed cells cultured at the air-liquid interface that pseudostratified epithelial cells are susceptible to EBV infection. Donors varied in susceptibility to de novo EBV infection, but susceptible cultures also displayed differences with respect to pathogenesis. The cultures from one donor yielded lytic infection but cells from two other donors were positive for EBV-encoded EBERs and negative for other lytic infection markers. All cultures stained positive for the pseudostratified markers CK7, MUC5AC, α-tubulin in cilia, and the EBV epithelial cell receptor Ephrin receptor A2. To define EBV transcriptional programs by cell type and to elucidate latent/lytic infection-differential changes, we performed single cell RNA-sequencing on one EBV-infected culture that resulted in alignment with many EBV transcripts. EBV transcripts represented a small portion of the total transcriptome (~0.17%). All cell types in the pseudostratified epithelium had detectable EBV transcripts with suprabasal cells showing the highest number of reads aligning to many EBV genes. Several restriction factors (IRF1, MX1, STAT1, C18orf25) known to limit lytic infection were expressed at lower levels in the lytic subcluster. A third of the differentially-expressed genes in NPC tumors compared to an uninfected pseudostratified ALI culture overlapped with the differentially-expressed genes in the latent subcluster. A third of these commonly perturbed genes were specific to EBV infection and changed in the same direction. Collectively, these findings suggest that the pseudostratified epithelium could harbor EBV infection and that the pseudostratified infection model mirrors many of the transcriptional changes imposed by EBV infection in NPC.


Subject(s)
Epithelial Cells/virology , Epstein-Barr Virus Infections/virology , Host-Pathogen Interactions/immunology , Nasopharyngeal Neoplasms/virology , Carcinoma/metabolism , Carcinoma/virology , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/virology , Epstein-Barr Virus Infections/metabolism , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/pathogenicity , Humans , Nasopharyngeal Carcinoma/virology , RNA, Viral/genetics
19.
BMC Pediatr ; 20(1): 288, 2020 06 09.
Article in English | MEDLINE | ID: covidwho-1228992

ABSTRACT

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome that requires prompt diagnosis and appropriate treatment. A risk-stratification model that could be used to identify high-risk pediatric patients with HLH who should be considered for second-line therapies, including salvage regimens and allogeneic hematopoietic cell transplantation (HCT), was developed. METHODS: The medical records of 88 pediatric patients (median age 1.4 years, range 0.2-15 years) with non-malignancy associated secondary HLH were retrospectively reviewed. Treatment strategies included dexamethasone, etoposide, and cyclosporine. RESULTS: Survival analysis showed HLH patients with infections other than Epstein-Barr virus (EBV) and unknown causes experienced better 5-year overall survival (OS) than patients with HLH due to autoimmune disease, EBV or immunodeficiency (76% vs. 65, 33.3, 11%, p < 0.001). On multivariate analysis, among all patients, non-response at 8 weeks was the most powerful predictor of poor OS. When treatment response was excluded, hemoglobin < 60 g/L and albumin < 25 g/L at diagnosis were associated with poor OS. In patients with EBV-HLH, hemoglobin < 60 g/L at diagnosis was associated with poor OS. A prognostic risk score was established and weighted based on hazard ratios calculated for three parameters measured at diagnosis: hemoglobin < 60 g/L (2 points), platelets < 30 × 109/L (1 point), albumin < 25 g/L (2 points). Five-year OS of low-risk (score 0-1), intermediate-risk (score 2), and poor-risk (score ≥ 3) patients were 88, 38, and 22%, respectively (p < 0.001). CONCLUSIONS: These findings indicate that clinicians should be aware of predictive factors at diagnosis and consider 8-week treatment response to identify patients with high-risk of disease progression and the need for second-line therapy and allogeneic HCT.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Lymphohistiocytosis, Hemophagocytic , Neoplasms , Adolescent , Child , Child, Preschool , Herpesvirus 4, Human , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/therapy , Prognosis , Retrospective Studies , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , Treatment Outcome
20.
Vopr Virusol ; 66(2): 152-161, 2021 05 15.
Article in Russian | MEDLINE | ID: covidwho-1229649

ABSTRACT

INTRODUCTION: Immunodeficiency underlying the development of severe forms of new coronavirus infection may be the result of mixed infection with SARS-CoV-2 and other pathogens, including Epstein-Barr virus (EBV).The aim is to study the prevalence and epidemiological features of co-infection with SARS-CoV-2 and EBV. MATERIAL AND METHODS: A cross-sectional randomized study was conducted in Moscow region from March to May 2020. Two groups were examined for EBV-markers: hospital patients (n = 95) treated for SARS-CoV-2 infection and blood donors (n = 92). RESULTS: With equal EBV prevalence the detection of active infection markers in donors (10.9%) was noticeably lower than in SARS-CoV-2 patients (80%). Significant differences in this indicator were also found when patients from subgroups with interstitial pneumonia with the presence (96.6%) and absence (97.2%) of SARS-CoV-2 in the nasopharyngeal smear were compared with the subgroup of patients with mild COVID-19 (43.3%). The average IgG VCA and IgG EBNA positivity coefficients in donor group were higher than in patient group (p < 0.05). Patients with active EBV infection markers were significantly more likely to have pneumonia, exceeding the reference values of ALT and the relative number of monocytes (odds ratio - 23.6; 3.5; 9.7, respectively). DISCUSSION: The present study examined the incidence and analyzed epidemiological features of active EBV infection in patients with COVID-19. CONCLUSION: A significantly higher rate of detection of active EBV infection markers in hospital patients indicates a combined participation SARS-CoV-2 and EBV in the development of interstitial pneumonia. Low levels of specific IgG EBV serve as predictors of EBV reactivation. Exceeding the reference values of ALT and the relative number of monocytes in patients should serve as a reason for examination for active EBV infection markers.


Subject(s)
COVID-19/metabolism , Epstein-Barr Virus Infections/metabolism , Herpesvirus 4, Human/metabolism , SARS-CoV-2/metabolism , Virus Activation , Adolescent , Adult , COVID-19/epidemiology , COVID-19/pathology , Epstein-Barr Virus Infections/epidemiology , Epstein-Barr Virus Infections/pathology , Female , Humans , Male , Middle Aged
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