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1.
Nature ; 617(7961): 574-580, 2023 May.
Article in English | MEDLINE | ID: covidwho-2326179

ABSTRACT

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.


Subject(s)
Adenovirus Infections, Human , Coinfection , Dependovirus , Hepatitis , Child , Humans , Acute Disease , Adenovirus Infections, Human/epidemiology , Adenovirus Infections, Human/virology , Coinfection/epidemiology , Coinfection/virology , Dependovirus/genetics , Dependovirus/isolation & purification , Epstein-Barr Virus Infections/epidemiology , Epstein-Barr Virus Infections/virology , Hepatitis/epidemiology , Hepatitis/virology , Herpesvirus 4, Human/isolation & purification , Herpesvirus 6, Human/isolation & purification , Enterovirus A, Human/isolation & purification , Helper Viruses/isolation & purification
2.
Blood ; 141(17): 2062-2074, 2023 04 27.
Article in English | MEDLINE | ID: covidwho-2313904

ABSTRACT

Preventing viral infections at an early stage is a key strategy for successfully improving transplant outcomes. Preemptive therapy and prophylaxis with antiviral agents have been successfully used to prevent clinically significant viral infections in hematopoietic cell transplant recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors, as well as the introduction of novel antiviral agents and advances in immunotherapy. High-quality evidence exists for the effective prevention of herpes simplex virus, varicella-zoster virus, and cytomegalovirus infection and disease. Few data are available on the effective prevention of human herpesvirus 6, Epstein-Barr virus, adenovirus, and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity and cases that feature differences in approaches, reflecting distinct hematopoietic cell transplant practices, such as ex vivo T-cell depletion.


Subject(s)
Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Virus Diseases , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/prevention & control , Herpesvirus 4, Human , Virus Diseases/prevention & control , Virus Diseases/etiology , Antiviral Agents/therapeutic use
3.
Int J Mol Sci ; 24(9)2023 Apr 25.
Article in English | MEDLINE | ID: covidwho-2313827

ABSTRACT

Some viruses are known to be associated with the onset of specific cancers. These microorganisms, oncogenic viruses or oncoviruses, can convert normal cells into cancer cells by modulating the central metabolic pathways or hampering genomic integrity mechanisms, consequently inhibiting the apoptotic machinery and/or enhancing cell proliferation. Seven oncogenic viruses are known to promote tumorigenesis in humans: human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), Epstein-Barr virus (EBV), human T-cell leukemia virus 1 (HTLV-1), Kaposi sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCPyV). Recent research indicates that SARS-CoV-2 infection and COVID-19 progression may predispose recovered patients to cancer onset and accelerate cancer development. This hypothesis is based on the growing evidence regarding the ability of SARS-CoV-2 to modulate oncogenic pathways, promoting chronic low-grade inflammation and causing tissue damage. Herein, we summarize the main relationships known to date between virus infection and cancer, providing a summary of the proposed biochemical mechanisms behind the cellular transformation. Mechanistically, DNA viruses (such as HPV, HBV, EBV, and MCPyV) encode their virus oncogenes. In contrast, RNA viruses (like HCV, HTLV-1) may encode oncogenes or trigger host oncogenes through cis-/-trans activation leading to different types of cancer. As for SARS-CoV-2, its role as an oncogenic virus seems to occur through the inhibition of oncosuppressors or controlling the metabolic and autophagy pathways in the infected cells. However, these effects could be significant in particular scenarios like those linked to severe COVID-19 or long COVID. On the other hand, looking at the SARS-CoV-2─cancer relationship from an opposite perspective, oncolytic effects and anti-tumor immune response were triggered by SARS-CoV-2 infection in some cases. In summary, our work aims to recall comprehensive attention from the scientific community to elucidate the effects of SARS-CoV-2 and, more in general, ß-coronavirus infection on cancer susceptibility for cancer prevention or supporting therapeutic approaches.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Hepatitis C , Neoplasms , Papillomavirus Infections , Humans , SARS-CoV-2 , Epstein-Barr Virus Infections/complications , Papillomavirus Infections/complications , Post-Acute COVID-19 Syndrome , Herpesvirus 4, Human , COVID-19/complications , Neoplasms/pathology , Oncogenic Viruses/genetics , Cell Transformation, Neoplastic , Hepatitis C/complications
4.
Rinsho Ketsueki ; 64(4): 277-282, 2023.
Article in Japanese | MEDLINE | ID: covidwho-2319751

ABSTRACT

Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) is a rare disease characterized by persistent or recurrent inflammation accompanied by EBV infection of T or NK cells that is not self-limiting, and it is fatal, if untreated. After receiving the first dose of the BNT162b2 mRNA COVID-19 vaccine, a 79-year-old male presented to the hospital with a 2-week history of fever. Laboratory results indicated pancytopenia, elevated liver transaminase levels, hyperferritinemia, and hypofibrinogenemia. Computed tomography revealed hepatosplenomegaly, but lymphadenopathy was not observed. A bone marrow biopsy, a random skin biopsy, and a liver biopsy revealed no malignancy, but an infectious evaluation revealed EBV viremia (5.19 Log IU/ml). Flow cytometry and RT-PCR revealed that the EBV genome was localized in NK cells, suggesting the diagnosis of EBV-NK-LPD. We administered prednisolone, intravenous immunoglobulin, and etoposide, but the EBV-DNA load failed to decrease, and he died 2 months later. Recently, case reports of COVID-19 vaccination-related hemophagocytic lymphohistiocytosis have been published. Although the mechanisms and risk factors for EBV-LPD after BNT162b2 mRNA COVID-19 vaccination remain unknown, it is important to note the possibility of reactivation of EBV after COVID-19 vaccination to initiate early and targeted therapy.


Subject(s)
COVID-19 Vaccines , COVID-19 , Epstein-Barr Virus Infections , Lymphoproliferative Disorders , Aged , Humans , Male , BNT162 Vaccine , COVID-19/prevention & control , COVID-19/complications , COVID-19 Vaccines/adverse effects , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human/genetics , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/diagnosis
5.
Front Immunol ; 14: 1087996, 2023.
Article in English | MEDLINE | ID: covidwho-2318168

ABSTRACT

Background: To evaluate the benefits of SARS-CoV-2 vaccination in cancer patients it is relevant to understand the adaptive immune response elicited after vaccination. Patients affected by hematologic malignancies are frequently immune-compromised and show a decreased seroconversion rate compared to other cancer patients or controls. Therefore, vaccine-induced cellular immune responses in these patients might have an important protective role and need a detailed evaluation. Methods: Certain T cell subtypes (CD4, CD8, Tfh, γδT), including cell functionality as indicated by cytokine secretion (IFN, TNF) and expression of activation markers (CD69, CD154) were assessed via multi-parameter flow cytometry in hematologic malignancy patients (N=12) and healthy controls (N=12) after a second SARS-CoV-2 vaccine dose. The PBMC of post-vaccination samples were stimulated with a spike-peptide pool (S-Peptides) of SARS-CoV-2, with CD3/CD28, with a pool of peptides from the cytomegalovirus, Epstein-Barr virus and influenza A virus (CEF-Peptides) or left unstimulated. Furthermore, the concentration of spike-specific antibodies has been analyzed in patients. Results: Our results indicate that hematologic malignancy patients developed a robust cellular immune response to SARS-CoV-2 vaccination comparable to that of healthy controls, and for certain T cell subtypes even higher. The most reactive T cells to SARS-CoV-2 spike peptides belonged to the CD4 and Tfh cell compartment, being median (IQR), 3.39 (1.41-5.92) and 2.12 (0.55-4.14) as a percentage of IFN- and TNF-producing Tfh cells in patients. In this regard, the immunomodulatory treatment of patients before the vaccination period seems important as it was strongly associated with a higher percentage of activated CD4 and Tfh cells. SARS-CoV-2- and CEF-specific T cell responses significantly correlated with each other. Compared to lymphoma patients, myeloma patients had an increased percentage of SARS-CoV-2-specific Tfh cells. T-SNE analysis revealed higher frequencies of γδT cells in patients compared to controls, especially in myeloma patients. In general, after vaccination, SARS-CoV-2-specific T cells were also detectable in patients without seroconversion. Conclusion: Hematologic malignancy patients are capable of developing a SARS-CoV-2-specific CD4 and Tfh cellular immune response after vaccination, and certain immunomodulatory therapies in the period before vaccination might increase the antigen-specific immune response. A proper response to recall antigens (e.g., CEF-Peptides) reflects immune cellular functionality and might be predictive for generating a newly induced antigen-specific immune response as is expected after SARS-CoV-2 vaccination.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Hematologic Neoplasms , Multiple Myeloma , Humans , COVID-19 Vaccines , SARS-CoV-2 , Leukocytes, Mononuclear , COVID-19/prevention & control , Herpesvirus 4, Human , Hematologic Neoplasms/therapy , Vaccination
6.
BMJ Open ; 13(2): e068877, 2023 02 27.
Article in English | MEDLINE | ID: covidwho-2317984

ABSTRACT

OBJECTIVES: Infectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV). DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17-39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA. MAIN OUTCOME MEASURES: Regression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort. RESULTS: In the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62-0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67-0.72) and good calibration. CONCLUSIONS: The alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings.


Subject(s)
Epstein-Barr Virus Infections , Infectious Mononucleosis , Pharyngitis , Young Adult , Humans , Adult , Adolescent , Infectious Mononucleosis/diagnosis , Herpesvirus 4, Human , Clinical Decision Rules , Prospective Studies , Retrospective Studies , Antigens, Viral , Pain
7.
Cell Commun Signal ; 21(1): 103, 2023 05 08.
Article in English | MEDLINE | ID: covidwho-2317587

ABSTRACT

Hematopoietic stem cells (HSCs) are known for their significant capability to reconstitute and preserve a functional hematopoietic system in long-term periods after transplantation into conditioned hosts. HSCs are thus crucial cellular targets for the continual repair of inherited hematologic, metabolic, and immunologic disorders. In addition, HSCs can undergo various fates, such as apoptosis, quiescence, migration, differentiation, and self-renewal. Viruses continuously pose a remarkable health risk and request an appropriate, balanced reaction from our immune system, which as well as affects the bone marrow (BM). Therefore, disruption of the hematopoietic system due to viral infection is essential. In addition, patients for whom the risk-to-benefit ratio of HSC transplantation (HSCT) is acceptable have seen an increase in the use of HSCT in recent years. Hematopoietic suppression, BM failure, and HSC exhaustion are all linked to chronic viral infections. Virus infections continue to be a leading cause of morbidity and mortality in HSCT recipients, despite recent advancements in the field. Furthermore, whereas COVID-19 manifests initially as an infection of the respiratory tract, it is now understood to be a systemic illness that significantly impacts the hematological system. Patients with advanced COVID-19 often have thrombocytopenia and blood hypercoagulability. In the era of COVID-19, Hematological manifestations of COVID-19 (i.e., thrombocytopenia and lymphopenia), the immune response, and HSCT may all be affected by the SARS-CoV-2 virus in various ways. Therefore, it is important to determine whether exposure to viral infections may affect HSCs used for HSCT, as this, in turn, may affect engraftment efficiency. In this article, we reviewed the features of HSCs, and the effects of viral infections on HSCs and HSCT, such as SARS-CoV-2, HIV, cytomegalovirus, Epstein-Barr virus, HIV, etc. Video Abstract.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , HIV Infections , Thrombocytopenia , Virus Diseases , Humans , SARS-CoV-2 , Herpesvirus 4, Human , Hematopoietic Stem Cells
8.
Semin Hematol ; 60(1): 10-19, 2023 01.
Article in English | MEDLINE | ID: covidwho-2317424

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) has been used as a curative standard of care for moderate to severe primary immunodeficiency disorders as well as relapsed hematologic malignancies for over 50 years [1,2]. However, chronic and refractory viral infections remain a leading cause of morbidity and mortality in the immune deficient period following HSCT, where use of available antiviral pharmacotherapies is limited by toxicity and emerging resistance [3]. Adoptive immunotherapy using virus-specific T cells (VSTs) has been explored for over 2 decades [4,5] in patients post-HSCT and has been shown prior phase I-II studies to be safe and effective for treatment or preventions of viral infections including cytomegalovirus, Epstein-Barr virus, BK virus, and adenovirus with minimal toxicity and low risk of graft vs host disease [6-9]. This review summarizes methodologies to generate VSTs the clinical results utilizing VST therapeutics and the challenges and future directions for the field.


Subject(s)
Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Virus Diseases , Humans , T-Lymphocytes/transplantation , Herpesvirus 4, Human , Neoplasm Recurrence, Local , Virus Diseases/therapy , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods
9.
BMJ Case Rep ; 16(5)2023 May 09.
Article in English | MEDLINE | ID: covidwho-2317052

ABSTRACT

A man in his 60s presented with intermittent constitutional symptoms along with waxing and waning chest radiographic abnormalities, eventually leading to a diagnosis of lymphomatoid granulomatosis (LYG). LYG is a rare, progressive Epstein-Barr virus (EBV)-driven lymphoproliferative disease associated with immune dysregulation most commonly involving the lungs. The diagnosis requires tissue biopsy; thus, the decision to pursue tissue sampling with histopathology examination in a timely manner is essential. Currently, there are no established guidelines regarding the treatment of LYG, which varies from cessation of immunosuppressants to immunochemotherapy and usually requires multidisciplinary team discussion.


Subject(s)
Epstein-Barr Virus Infections , Lymphomatoid Granulomatosis , Male , Humans , Tumor Necrosis Factor-alpha , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Lymphomatoid Granulomatosis/chemically induced , Lymphomatoid Granulomatosis/diagnosis , Lymphomatoid Granulomatosis/drug therapy , Herpesvirus 4, Human , Immunologic Factors
10.
BMJ Case Rep ; 16(5)2023 May 03.
Article in English | MEDLINE | ID: covidwho-2315734

ABSTRACT

The heterophile antibody (also known as the Monospot) test is a useful screening tool for infectious mononucleosis (IM) resulting from primary Epstein-Barr virus (EBV) infection. However, up to 10% of patients with IM are heterophile negative. Heterophile-negative patients who have lymphocytosis or atypical lymphocytes on peripheral blood smear should be further tested for EBV serologies, which include testing for specific IgM and IgG antibodies against viral capsid antigens, early antigens and EBV nuclear antigen proteins. A diagnostic dilemma arises when the patient has clinical and laboratory features of IM, but is both heterophile negative and seronegative for IM, as illustrated in this case presentation. To avoid missed diagnoses of IM, misdiagnosis of mononucleosis-like illnesses and unnecessary testing, knowledge of test characteristics and the evolving course of EBV serologies is important to assure and inform both the physician and the patient.


Subject(s)
Epstein-Barr Virus Infections , Infectious Mononucleosis , Lymphocytosis , Humans , Herpesvirus 4, Human , Lymphocytosis/diagnosis , Infectious Mononucleosis/diagnosis , Antigens, Viral , Fever , Antibodies, Viral
11.
Vopr Virusol ; 67(4): 265-273, 2022 09 10.
Article in Russian | MEDLINE | ID: covidwho-2319449

ABSTRACT

The number of studies devoted to Epstein-Barr viral infection (EBV infection) has been growing in recent years. However, they all relate to the clinical aspects of this problem. Epidemiology issues remain practically unexplored. A review of domestic and foreign publications has shown that at the present stage there is a high intensity of the epidemic process of EBV infection both in Russia and abroad. The main indicators of unfavorable epidemiological situation are the ubiquitous spread of the pathogen and the increase in the incidence of infectious mononucleosis in recent years. The deterioration of the epidemic situation of EBV infection is influenced by changes in the immunological reactivity of various population groups due to the spread of HIV, HBV, HCV, the causative agent of tuberculosis and SARS-CoV-2. The above makes it possible to classify the problem as a global one and determines the need for the rapid implementation of the system of epidemiological surveillance of EBV infection and optimization of the complex of preventive and anti-epidemic measures. Reducing the burden of EBV is possible only with the consolidated participation of specialists of various profiles.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Infectious Mononucleosis , COVID-19/epidemiology , Epstein-Barr Virus Infections/epidemiology , Herpesvirus 4, Human , Humans , SARS-CoV-2
12.
Viruses ; 15(4)2023 04 12.
Article in English | MEDLINE | ID: covidwho-2302776

ABSTRACT

Recent studies have strengthened the evidence for Epstein-Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood-brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Multiple Sclerosis , Humans , Herpesvirus 4, Human , Epstein-Barr Virus Infections/complications , COVID-19/complications , SARS-CoV-2 , Inflammation/complications , Disease Progression
13.
Curr Microbiol ; 80(6): 195, 2023 Apr 27.
Article in English | MEDLINE | ID: covidwho-2294094

ABSTRACT

Chronic inflammatory gastrointestinal diseases such as Crohn's disease (CD) and ulcerative colitis (UC) are known as inflammatory bowel disorders (IBD). Patients with inflammatory bowel illnesses are more susceptible to viral infections. In people with IBD, viral infections have emerged as a significant issue. Viral infections are often difficult to identify and have a high morbidity and fatality rate. We reviewed studies on viral infections and IBD, concentrating on Cytomegalovirus (CMV), SARS-CoV-2, Epstein-Barr virus (EBV), enteric viruses, and hepatitis B virus (HBV). Also, the effect of IBD on these viral infections is discussed. These data suggest that patients with IBD are more likely to get viral infections. As a result, practitioners should be aware of the increased risk of viral infections in inflammatory bowel disease patients.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Inflammatory Bowel Diseases , Virus Diseases , Humans , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human , SARS-CoV-2 , Inflammatory Bowel Diseases/complications , Virus Diseases/complications
14.
Cells ; 12(5)2023 02 21.
Article in English | MEDLINE | ID: covidwho-2259004

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally transmissible and pathogenic coronavirus that appeared at the end of 2019 and triggered a pandemic of acute respiratory disease, known as coronavirus disease 2019 (COVID-19). COVID-19 can evolve into a severe disease associated with immediate and delayed sequelae in different organs, including the central nervous system (CNS). A topic that deserves attention in this context is the complex relationship between SARS-CoV-2 infection and multiple sclerosis (MS). Here, we initially described the clinical and immunopathogenic characteristics of these two illnesses, accentuating the fact that COVID-19 can, in defined patients, reach the CNS, the target tissue of the MS autoimmune process. The well-known contribution of viral agents such as the Epstein-Barr virus and the postulated participation of SARS-CoV-2 as a risk factor for the triggering or worsening of MS are then described. We emphasize the contribution of vitamin D in this scenario, considering its relevance in the susceptibility, severity and control of both pathologies. Finally, we discuss the experimental animal models that could be explored to better understand the complex interplay of these two diseases, including the possible use of vitamin D as an adjunct immunomodulator to treat them.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Multiple Sclerosis , Animals , SARS-CoV-2 , Herpesvirus 4, Human , Vitamin D
15.
Proc Natl Acad Sci U S A ; 120(12): e2220320120, 2023 03 21.
Article in English | MEDLINE | ID: covidwho-2263575

ABSTRACT

Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (ß-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein-Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Child, Preschool , Adult , Child , Humans , Middle Aged , Aged , Aged, 80 and over , SARS-CoV-2 , T-Lymphocytes , Herpesvirus 4, Human , CD4-Positive T-Lymphocytes , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Cross Reactions
16.
BMC Biotechnol ; 23(1): 7, 2023 03 07.
Article in English | MEDLINE | ID: covidwho-2261238

ABSTRACT

BACKGROUND: Mammalian cell lines are frequently used as protein expression hosts because of their ability to correctly fold and assemble complex proteins, produce them at high titers, and confer post-translational modifications (PTMs) critical to proper function. Increasing demand for proteins with human-like PTMs, particularly viral proteins and vectors, have made human embryonic kidney 293 (HEK293) cells an increasingly popular host. The need to engineer more productive HEK293 platforms and the ongoing nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study strategies to improve viral protein expression in transient and stable HEK293 platforms. RESULTS: Initial process development was done at 24 deep well plate (DWP) -scale to screen transient processes and stable clonal cell lines for recombinant SARS-CoV-2 receptor binding domain (rRBD) titer. Nine DNA vectors that drove rRBD production under different promoters and optionally contained Epstein-Barr virus (EBV) elements to promote episomal expression were screened for transient rRBD production at 37 °C or 32 °C. Use of the cytomegalovirus (CMV) promoter to drive expression at 32 °C led to the highest transient protein titers, but inclusion of episomal expression elements did not augment titer. In parallel, four clonal cell lines with titers higher than that of the selected stable pool were identified in a batch screen. Flask-scale transient transfection and stable fed-batch processes were then established that produced rRBD up to 100 mg/L and 140 mg/L, respectively. While a bio-layer interferometry (BLI) assay was crucial for efficiently screening DWP batch titers, an enzyme-linked immunosorbent assay (ELISA) was used to compare titers from the flask-scale batches due to varying matrix effects from different cell culture media compositions. CONCLUSION: Comparing yields from the flask-scale batches revealed that stable fed-batch cultures produced up to 2.1x more rRBD than transient processes. The stable cell lines developed in this work are the first reported clonal, HEK293-derived rRBD producers and have titers up to 140 mg/L. As stable production platforms are more economically favorable for long-term protein production at large scales, investigation of strategies to increase the efficiency of high-titer stable cell line generation in Expi293F or other HEK293 hosts is warranted.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Animals , Humans , SARS-CoV-2/genetics , HEK293 Cells , Herpesvirus 4, Human , Kidney , Mammals
17.
Iran J Allergy Asthma Immunol ; 22(1): 110-118, 2023 Feb 20.
Article in English | MEDLINE | ID: covidwho-2260833

ABSTRACT

CD27 is a costimulatory receptor involved in the maturation of the innate and adaptive immunity. CD27, through interaction with CD70, plays a role in the control of Epstein-Barr virus (EBV) infection. CD27 deficiency leads to an immune dysregulation disease characterized by EBV susceptibility. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might put patients with primary immunodeficiency at risk for adverse outcomes. Chromogenic in situ hybridization (CISH) study was performed to detect EBV in the lymphoma tissue. Genetic analysis of the patient was done with Whole Exome Sequencing and detected variant was confirmed with PCR-Sanger sequencing. Here we report a 20-month-old boy with CD27 deficiency who developed lymphoma and coronary artery ectasia and had been infected with SARS-CoV-2. Clinical and laboratory findings were incompatible with atypical Kawasaki syndrome or multisystem inflammatory syndrome in children (MIS-C). As CD27 deficiency is a rare immune defect, publishing clinical data about the identified patient(s) can shed light on our knowledge about the related phenotype and the spectrum of clinical manifestations associated with CD27 deficiency. Thus, our findings expanded the spectrum of manifestations beyond EBV infection, highlighting this unusual cardiac sequela that could be related to EBV infection, lymphoma, or an underlying disease.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Lymphoma , Humans , Herpesvirus 4, Human , Dilatation, Pathologic/complications , SARS-CoV-2 , Lymphoma/complications
18.
Melanoma Res ; 33(2): 136-148, 2023 04 01.
Article in English | MEDLINE | ID: covidwho-2259451

ABSTRACT

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.


Subject(s)
COVID-19 , Clostridioides difficile , Epstein-Barr Virus Infections , Melanoma , Skin Neoplasms , Humans , Fecal Microbiota Transplantation/adverse effects , Donor Selection , Epstein-Barr Virus Infections/etiology , Seroepidemiologic Studies , SARS-CoV-2 , Melanoma/etiology , Herpesvirus 4, Human , Skin Neoplasms/etiology
19.
Rev Med Virol ; 33(3): e2437, 2023 05.
Article in English | MEDLINE | ID: covidwho-2280697

ABSTRACT

To provide a comprehensive systematic review and meta-analysis regarding the cumulative incidence (incidence proportion) of human herpesvirus (HHV) reactivation among patients with coronavirus disease 2019 (COVID-19), we searched PubMed/MEDLINE, Web of Science, and EMBASE up to 25 September 2022, with no language restrictions. All interventional and observational studies enrolling patients with confirmed COVID-19 and providing data regarding HHV reactivation were included. The random-effects model was used in the meta-analyses. We included information from 32 studies. HHV reactivation was considered a positive polymerase chain reaction result taken at the time of COVID-19 infection. Most of the included patients were severe COVID-19 cases. The pooled cumulative incidence estimate was 38% (95% Confidence Intervals [CI], 28%-50%, I2  = 86%) for herpes simplex virus (HSV), 19% (95% CI, 13%-28%, I2  = 87%) for cytomegalovirus (CMV), 45% (95% CI, 28%-63%, I2  = 96%) for Epstein-Barr virus (EBV), 18% (95% CI, 8%-35%) for human herpesvirus 6 (HHV-6), 44% (95% CI, 32%-56%) for human herpesvirus 7 (HHV-7), and 19% (95% CI, 14%-26%) for human herpesvirus 8 (HHV-8). There was no evidence of funnel plot asymmetry based on visual inspection and Egger's regression test for the results of HSV (p = 0.84), CMV (p = 0.82), and EBV (p = 0.27) reactivation. In conclusion, the identification of HHV reactivation in severe COVID-19 patients is helpful in the management of patients as well as the prevention of complications. Further research is required to elucidate the interaction between HHVs and COVID-19. Systematic review registration: PROSPERO CRD42022321973.


Subject(s)
COVID-19 , Cytomegalovirus Infections , Epstein-Barr Virus Infections , Herpesviridae Infections , Herpesviridae , Herpesvirus 6, Human , Humans , Herpesviridae Infections/complications , Herpesviridae Infections/epidemiology , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/physiology , COVID-19/complications , Simplexvirus , Cytomegalovirus/physiology , Herpesvirus 6, Human/genetics
20.
Acta Dermatovenerol Croat ; 30(4): 265-266, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2277052

ABSTRACT

Dear Editor, Pityriasis rosea (PR) is a common, self-limited erythematous papulosquamous dermatosis that mainly affects young adults. It is believed to represent a delayed reaction to viral infections and is usually associated with endogenous systemic reactivation of human herpesvirus (HHV) 6 and / or 7 (1). A 46-year-old man presented to our Department with a two-week history of skin rash associated with mild pruritus. He described the appearance of an erythematous centrally scaled lesion at the right part of his abdomen, followed by the spreading of red oval mildly scaling lesions on the trunk, neck, and proximal parts of the upper extremities, which showed in the physical examination (Figure 1, a and b). He was otherwise healthy and taking no medications. Six weeks prior to the appearance of the initial skin lesion, the patient had coronavirus disease 2019 (COVID-19) infection with mild clinical presentation (fever up to 38 °C lasting for four days and mild headache) and with symptoms of post COVID-19 syndrome (excessive tiredness). He denied oropharyngeal lesions. Potassium hydroxide, syphilis, and laboratory tests were within normal limits. Within two weeks of topical betamethasone dipropionate treatment, the lesions disappeared completely. In addition to reactivation of HHV-6 or HHV-7, PR can be triggered by some drugs (like angiotensin-converting enzyme inhibitors alone or in combination with hydrochlorothiazide, sartans plus hydrochlorothiazide, allopurinol, nimesulide, and acetyl salicylic acid (2) and vaccines (such as smallpox, poliomyelitis, influenza, human papillomavirus, diphtheria, tuberculosis, hepatitis B, pneumococcus, and yellow fever vaccines) (3). There is a growing number of published cases that link PR to COVID-19 infection, with PR appearing either in the acute phase of COVID-19 or, as in our patient, in the post COVID-19 period (4-9). Unlike in our patient, oropharyngeal lesions were observed in approximately 16% of patients with typical PR (10). It has been suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces reactivation of other viruses, such as HHV-6, HHV-7, varicella zoster virus, and Epstein-Barr virus (5). PR has also been reported to follow COVID-19 vaccination (11). As our patient did not receive a COVID-19 vaccine, we cannot evaluate the latter based on the present case. We speculate that PR could be a delayed skin manifestation of COVID-19 infection, triggered either by SARS-CoV-2 immediately or indirectly by the reactivation of other viruses such as HHV-6 or HHV-7. However, the etiopathogenetic mechanisms remain largely unknown and further studies are needed in order to clarify the correlation between SARS-CoV-2 and PR.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Herpesvirus 6, Human , Herpesvirus 7, Human , Pityriasis Rosea , Male , Young Adult , Humans , Middle Aged , Pityriasis Rosea/diagnosis , Pityriasis Rosea/etiology , Pityriasis Rosea/pathology , COVID-19 Vaccines , COVID-19/complications , Post-Acute COVID-19 Syndrome , SARS-CoV-2 , Herpesvirus 4, Human , Herpesvirus 7, Human/physiology , Hydrochlorothiazide
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