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Siegmund B. Cytomegalovirus infection associated with inflammatory bowel disease. Lancet Gastroenterol Hepatol 2018; 2:369-376. [PMID: 28397701 DOI: 10.1016/s2468-1253(16)30159-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/18/2022]
Abstract
Refractory colitis in patients with inflammatory bowel disease is a complicated clinical disorder that might, in some patients, even necessitate surgery. Hence the diagnosis of additional complications is of utmost importance. Colitis mediated by cytomegalovirus is one such complication. The high seroprevalence and latent nature of cytomegalovirus, with the possibility of viral replication without mediating disease, poses a real challenge for the diagnosis of cytomegalovirus-mediated colitis. The challenge in daily clinical practice is to distinguish cytomegalovirus replication from cytomegalovirus-mediated colitis in patients with inflammatory bowel disease who have refractory colitis. This Review discusses the scientific literature and provides a diagnostic and therapeutic algorithm for clinical practice.
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Affiliation(s)
- Britta Siegmund
- Medizinische Klinik für Gastroenterologie, Infektiologie, Rheumatologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Nowacki TM, Bettenworth D, Meister T, Heidemann J, Lenze F, Schmidt HH, Heinzow HS. Novel score predicts risk for cytomegalovirus infection in ulcerative colitis. J Clin Virol 2018; 105:103-108. [PMID: 29940421 DOI: 10.1016/j.jcv.2018.06.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/04/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is associated with relapse and exacerbation of ulcerative colitis (UC), especially in immunosuppressed patients. OBJECTIVES The aim of this study was to identify risk factors for CMV colitis and to develop a predictive risk score to estimate the probability of CMV colitis in UC patients supporting clinical decision making. STUDY DESIGN A cohort of 239 UC-patients was retrospectively analyzed. Univariate and multivariate regression analysis identified several independent risk factors for CMV colitis and a predictive risk score was established using ROC analysis. RESULTS CMV colitis is common in patients with severe ulcerative colitis. Clinical UC activity, disease duration and extent as well as the use of steroids and anti-TNF-α agents were identified as risk factors (p < 0.05 each). Based on five predictive parameters, a web-based risk score was developed. A strong correlation between the predicted and actual rates of CMV colitis was found (AUC: 0.855; 95% CI 0.79-0.92; p < 0.0001). CONCLUSIONS Our study supports the pathogenic relevance of CMV in UC. The predictive risk score estimates the risk of CMV colitis and might aid in clinical decision making, especially when timely modifications of therapeutic regimens are needed and reliable diagnostic tools are not readily available.
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Affiliation(s)
- Tobias M Nowacki
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Tobias Meister
- Department of Gastroenterology, HELIOS Albert-Schweitzer Hospital, Northeim, Germany
| | - Jan Heidemann
- Department of Gastroenterology, Klinikum Bielefeld, Bielefeld, Germany
| | - Frank Lenze
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Hartmut H Schmidt
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Hauke S Heinzow
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
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3
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Detecting all Immunoglobulin Classes and Subclasses in a Multiplex 7 Color ImmunoSpot ® Assay. Methods Mol Biol 2018; 1808:85-94. [PMID: 29956176 DOI: 10.1007/978-1-4939-8567-8_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
Antibody molecules in peripheral blood have a relatively short half-life of roughly 20 days, and therefore their persistence in the serum depends on continuous replenishment by plasma cells. Serum antibody titers are thus indirect and unreliable indicators of immunological memory. In contrast, memory B cells persist in peripheral blood for decades, and enumerating these cells provides direct evidence of having developed an immune response to a given antigen. ELISPOT is an ideal research tool for enumerating antigen-specific memory B cells. Traditionally, B cell ELISPOT assays have been performed for detecting a single class of immunoglobulin (Ig), using a single colorimetric substrate. For comprehensive monitoring of B cell memory, however, all immunoglobulin classes and subclasses need to be assessed. Thus, seven single color assays would need to be performed to measure the numbers of antigen-specific B cells producing IgM, IgA, IgE, IgG1, IgG2, IgG3, and IgG4. We report here the development of a multiplex seven color B cell ImmunoSpot® assay in which the number of antigen-specific B cells can be established simultaneously for all major antibody classes and subclasses, requiring the PBMC, antigen, and labor corresponding to a single color assay.
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4
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Direct Detection of T- and B-Memory Lymphocytes by ImmunoSpot® Assays Reveals HCMV Exposure that Serum Antibodies Fail to Identify. Cells 2018; 7:cells7050045. [PMID: 29783767 PMCID: PMC5981269 DOI: 10.3390/cells7050045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/13/2018] [Accepted: 05/15/2018] [Indexed: 01/04/2023] Open
Abstract
It is essential to identify donors who have not been infected with human cytomegalovirus (HCMV) in order to avoid transmission of HCMV to recipients of blood transfusions or organ transplants. In the present study, we tested the reliability of seronegativity as an indicator for the lack of HCMV exposure in healthy human blood donors. Eighty-two HCMV seronegative individuals were identified, and their peripheral blood mononuclear cells (PBMC) were tested in ImmunoSpot® assays for the presence of HCMV-specific T- and B-memory lymphocytes. Eighty-two percent (67 of 82) of these HCMV seronegative individuals featured at least one memory cell that was lineage specific for HCMV, with the majority of these subjects possessing CD4+ and CD8+ T cells, as well as B cells, providing three independent lines of evidence for having developed immunity to HCMV. Only 15 of these 82 donors (18%) showed neither T- nor B-cell memory to HCMV, consistent with immunological naïveté to the virus. The data suggest that measurements of serum antibodies frequently fail to reveal HCMV exposure in humans, which may be better identified by direct detection of HCMV-specific memory lymphocytes.
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Landsman MJ, Sultan M, Stevens M, Charabaty A, Mattar MC. Diagnosis and management of common gastrointestinal tract infectious diseases in ulcerative colitis and Crohn's disease patients. Inflamm Bowel Dis 2014; 20:2503-2510. [PMID: 25208106 DOI: 10.1097/mib.0000000000000140] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Management of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, stretches beyond control of flares. Some infections of the gastrointestinal tract are more commonly seen in patients with IBD. Work from the Human Microbiome Project has been instrumental in our understanding of the interplay between the vast gut microbiota and host immune responses. Patients with IBD may be more prone to infectious complications based on their underlying inflammatory disease and variations in their microbiome. Immunosuppressant medications commonly used to treat patients with Crohn's and colitis also play a role in predisposing these patients to acquire these infections. Here, we present a detailed review of the data focusing on the most common infections of the gastrointestinal tract in patients with IBD: Clostridium difficile infections (CDI) and cytomegalovirus (CMV). We will discuss appropriate diagnostic tools and treatment options for these infections. Other less common infections will also be reviewed briefly. Studying the various infections of the gastrointestinal tract in these patients could enhance our understanding of the pathophysiology of IBD.
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Affiliation(s)
- Marc J Landsman
- *Internal Medicine, Georgetown University Hospital, Washington, DC; †Division of Gastroenterology, Georgetown University Hospital, Washington, DC; and ‡Division of Infectious Diseases, Virginia Commonwealth University Medical Center, Richmond, Virginia
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In Vitro Treatment with Ganciclovir Restores the Functionality of Exhausted T Cells from Cancer Patients. INT J GERONTOL 2013. [DOI: 10.1016/j.ijge.2012.11.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Garrido E, Carrera E, Manzano R, Lopez-Sanroman A. Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease. World J Gastroenterol 2013; 19:17-25. [PMID: 23326158 PMCID: PMC3545225 DOI: 10.3748/wjg.v19.i1.17] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 08/03/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
Cytomegalovirus (CMV) infection is common in humans. The virus then enters a “latency phase” and can reactivate to different stimuli such as immunosuppression. The clinical significance of CMV infection in inflammatory bowel disease is different in Crohn’s disease (CD) and ulcerative colitis (UC). CMV does not interfere in the clinical course of CD. However, CMV reactivation is frequent in severe or steroid-resistant UC. It is not known whether the virus exacerbates the disease or simply appears as a bystander of a severe disease. Different methods are used to diagnose CMV colitis. Diagnosis is classically based on histopathological identification of viral-infected cells or CMV antigens in biopsied tissues using haematoxylin-eosin or immunohistochemistry, other tests on blood or tissue samples are currently being investigated. Polymerase chain reaction performed in colonic mucosa has a high sensitivity and a positive result could be associated with a worse prognosis disease; further studies are needed to determine the most appropriate strategy with positive CMV-DNA in colonic mucosa. Specific endoscopic features have not been described in active UC and CMV infection. CMV colitis is usually treated with ganciclovir for several weeks, there are different opinions about whether or not to stop immunosuppressive therapy. Other antiviral drugs may be used. Multicenter controlled studies would needed to determine which subgroup of UC patients would benefit from early antiviral treatment.
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Nowacki TM, Bettenworth D, Ross M, Heidemann J, Lehmann PV, Lügering A. Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease. Cells 2012; 1:35-50. [PMID: 24710412 PMCID: PMC3901090 DOI: 10.3390/cells1020035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/12/2012] [Accepted: 04/16/2012] [Indexed: 12/19/2022] Open
Abstract
The role of cytomegalovirus (CMV) infection in the pathogenesis and exacerbation of Inflammatory Bowel Disease (IBD) has been unresolved. Typically, the CMV genome remains dormant in infected cells, but a breakdown of immune surveillance can lead to re-activation of viral replication in the gut mucosa, which is not necessarily associated with viremia or changes in antibody titers. We hypothesized that the detection of CMV-specific CD8 effector T cells should permit the distinction between dormant and active CMV infection. As CD8 effector T cells, unlike memory CD8 T cells, have perforin (PFN) and granzyme B (GzB) preformed in their cytoplasmic granules, we employed single cell resolution ELISPOT assays to measure the CMV antigen-triggered release of these molecules by CD8 T cells isolated from subjects with IBD, and age-matched healthy controls. The frequencies of CMV-specific (GzB) and PFN-producing CD8 T cells were increased in IBD patients compared to healthy controls. Furthermore, the increased CMV reactivity was associated with active IBD disease and with longer disease duration. Notably, PCR on serum frequently failed to detect CMV DNA during flares. The data show that during active IBD there is a flare of CD8 T cell activity against CMV in a substantial proportion of IBD patients, suggesting CMV reactivation that serum PCR does not detect. While it remains open whether CMV reactivation is a cause or consequence of IBD, our data suggest that monitoring CMV antigen-specific effector CD8 T cells with GzB and PFN ELISPOT analysis can provide novel insights into the role of CMV infection in IBD. Additionally, our data have implications for the fields of transplantation, HIV, cancer, and autoimmune diseases, in all of which patient care critically depends on sensitive and reliable detection of a reactivation of CMV infection.
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Affiliation(s)
- Tobias M Nowacki
- Department of Medicine B, University of Münster, Münster 48149, Germany.
| | | | - Matthias Ross
- Department of Medicine B, University of Münster, Münster 48149, Germany.
| | - Jan Heidemann
- Department of Medicine B, University of Münster, Münster 48149, Germany.
| | - Paul V Lehmann
- Cellular Technology Limited, Shaker Heights, OH 44122-5350, USA.
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Bertagnon JRD, Rossi S. Congenital cytomegalovirus infection. EINSTEIN-SAO PAULO 2011; 9:550-1. [DOI: 10.1590/s1679-45082011ai1687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Accepted: 08/08/2011] [Indexed: 11/21/2022] Open
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Abstract
Ulcerative colitis (UC) patients are believed to have an increased risk for the colonic reactivation of cytomegalovirus (CMV) infection due to both inherent and iatrogenic factors. Numerous studies and case reports have described CMV infection as complicating the disease course of ulcerative colitis patients; the existing evidence suggests an association between the presence of CMV infection and increased colectomy and mortality rates in UC patients. Whether CMV is nonpathogenic with a tropism towards areas of dysplasia and inflammation in the colon of UC or plays an active role in pathogenesis is still debated. In this paper, we examine the existing evidence for the diagnosis and management of CMV infection in UC patients.
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12
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Utility of newborn screening cards for detecting CMV infection in cases of stillbirth. J Clin Virol 2009; 44:215-8. [DOI: 10.1016/j.jcv.2008.12.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Revised: 12/17/2008] [Accepted: 12/18/2008] [Indexed: 11/23/2022]
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Palafox Sánchez CA, Satoh M, Chan EK, Carcamo WC, Muñoz Valle JF, Orozco Barocio G, Oregon Romero E, Navarro Hernández RE, Salazar Páramo M, Cabral Castañeda A, Vázquez Del Mercado M. Reduced IgG anti-small nuclear ribonucleoprotein autoantibody production in systemic lupus erythematosus patients with positive IgM anti-cytomegalovirus antibodies. Arthritis Res Ther 2009; 11:R27. [PMID: 19232124 PMCID: PMC2688261 DOI: 10.1186/ar2621] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2008] [Revised: 01/26/2009] [Accepted: 02/20/2009] [Indexed: 01/29/2023] Open
Abstract
Introduction Systemic lupus erythematosus is characterized by production of autoantibodies to RNA or DNA–protein complexes such as small nuclear ribonucleoproteins (snRNPs). A role of Epstein–Barr virus in the pathogenesis has been suggested. Similar to Epstein–Barr virus, cytomegalovirus (CMV) infects the majority of individuals at a young age and establishes latency with a potential for reactivation. Homology of CMV glycoprotein B (UL55) with the U1snRNP-70 kDa protein (U1–70 k) has been described; however, the role of CMV infection in production of anti-snRNPs is controversial. We investigated the association of CMV serology and autoantibodies in systemic lupus erythematosus. Methods Sixty-one Mexican patients with systemic lupus erythematosus were tested for CMV and Epstein–Barr virus serology (viral capsid antigen, IgG, IgM) and autoantibodies by immunoprecipitation and ELISA (IgG and IgM class, U1RNP/Sm, U1–70 k, P peptide, rheumatoid factor, dsDNA, β2-glycoprotein I). Results IgG anti-CMV and IgM anti-CMV were positive in 95% (58/61) and 33% (20/61), respectively, and two cases were negative for both. Clinical manifestation and autoantibodies in the IgM anti-CMV(+) group (n = 20) versus the IgM anti-CMV(-)IgG (+) (n = 39) group were compared. Most (19/20) of the IgM anti-CMV(+) cases were IgG anti-CMV(+), consistent with reactivation or reinfection. IgM anti-CMV was unrelated to rheumatoid factor or IgM class autoantibodies and none was positive for IgM anti-Epstein–Barr virus–viral capsid antigen, indicating that this is not simply due to false positive results caused by rheumatoid factor or nonspecific binding by certain IgM. The IgM anti-CMV(+) group has significantly lower levels of IgG anti-U1RNP/Sm and IgG anti-U1–70 k (P = 0.0004 and P = 0.0046, respectively). This finding was also confirmed by immunoprecipitation. Among the IgM anti-CMV(-) subset, anti-Su was associated with anti-U1RNP and anti-Ro (P < 0.05). High levels of IgG anti-CMV were associated with production of lupus-related autoantibodies to RNA or DNA–protein complex (P = 0.0077). Conclusions Our findings suggest a potential role of CMV in regulation of autoantibodies to snRNPs and may provide a unique insight to understand the pathogenesis.
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Affiliation(s)
- Claudia Azucena Palafox Sánchez
- Instituto de Investigación en Reumatología y del Sistema Músculo Esquelético (IIRSME), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, Guadalajara, Jalisco, CP 44340, México.
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Systematic review: cytomegalovirus infection in inflammatory bowel disease. J Gastroenterol 2009; 43:735-40. [PMID: 18958541 DOI: 10.1007/s00535-008-2246-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Accepted: 07/01/2008] [Indexed: 02/04/2023]
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Abstract
When patients with inflammatory bowel disease (IBD) are admitted to the hospital with a flare of acute severe colitis, the possibility of a concurrent cytomegalovirus (CMV) infection causing or worsening the colitis is often considered. IBD patients are usually immunosuppressed, and therefore presumably at increased risk for active CMV infection and disease. Multiple techniques are used to diagnose CMV infection, including endoscopy, histology, serology, viral culture, CMV antigen testing, and CMV DNA testing. Immunohistochemistry (IHC) performed on colon biopsy specimens with monoclonal antibodies directed against CMV immediate early antigen is considered by most to be the current gold standard for diagnosis. The prevalence of CMV infection in acute severe colitis appears to be 21-34%, and the prevalence of CMV infection in the steroid refractory subgroup of these patients is 33-36%. After antiviral therapy, colitis remission rates in IBD patients with CMV infection range from 67% to 100%, though CMV histological infection or the presence of circulating virus alone is not always associated with steroid resistance, and may not require antiviral therapy.
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Affiliation(s)
- Ahmed Kandiel
- Center for Inflammatory Bowel Disease, Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Zhang Y, Wen L, Cheng B. Effect of [Ca2+]i and neuronal mitochondria transmembrane potentials in hippocampus of murine cytomegalovirus infected mice. JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY. MEDICAL SCIENCES = HUA ZHONG KE JI DA XUE XUE BAO. YI XUE YING DE WEN BAN = HUAZHONG KEJI DAXUE XUEBAO. YIXUE YINGDEWEN BAN 2006; 26:211-2. [PMID: 16850749 DOI: 10.1007/bf02895818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
To explore the effect of [Ca2+]i and neuronal mitochondria transmembrane potentials in hippocampus of murine cytomegalovirus (MCMV) infected mice, newborn Balb/c mice were randomly divided into two groups: a virus inoculated group and a control group. After 56 days, single cell of hippocampus was isolated, and mitochondria transmembrane potentials and the intracellular free calcium level [Ca2+]i in hippocampus were measured by means of flow cytometry (FCM). Compared with the control group, the mitochondria transmembrane potentials was decreased (P<0.01) and the intracellular free calcium level [Ca2+]i was increased (P<0.01) in inoculated group. The dysfunction of [Ca2+]i and mitochondria transmembrane potentials in hippocampus may play an important role in the functional disorders in CMV-infected CNS.
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Affiliation(s)
- Ying Zhang
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Loh HS, Mohd-Lila MA, Abdul-Rahman SO, Kiew LJ. Pathogenesis and vertical transmission of a transplacental rat cytomegalovirus. Virol J 2006; 3:42. [PMID: 16737550 PMCID: PMC1500997 DOI: 10.1186/1743-422x-3-42] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Accepted: 06/01/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) congenital infection is the major viral cause of well-documented birth defects in human. Because CMV is species-specific, the main obstacle to developing animal models for congenital infection is the difference in placental architecture, which preludes virus transmission across the placenta. The rat placenta, resembling histologically to that of human, could therefore facilitate the study of CMV congenital infection in human. RESULTS In this report, we present clear evidences of the transplacental property of a new rat CMV (RCMV), namely ALL-03, which had been isolated from placenta and uterus of the house rat. Our study signifies the detection of infectious virus, virus particles, viral protein and DNA as well as immune response to demonstrate a natural model of acute CMV infection including the immunocompetent and immunocompromised host associated with or without pregnancy. It is characterized by a full range of CMV related clinical signs; lesions and anatomical virus distribution to uterus, placenta, embryo, fetus, neonate, lung, kidney, spleen, liver and salivary gland of the infected rats in addition to the virus-specific seroconversion. The preference of the virus for different organs mimics the situation in immunocompromised man. Most interestingly, the placenta was observed to be involved in the maternofetal infection and hence confirmed the hypothesis that the RCMV strain ALL-03 is capable to cross the placenta and infect the offsprings congenitally. CONCLUSION The maternal viremia leading to uterine infection which subsequently infecting to the fetus through the placenta is the most likely phenomenon of CMV vertical transmission in our study.
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Affiliation(s)
- Hwei-San Loh
- Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Mohd-Azmi Mohd-Lila
- Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Sheikh-Omar Abdul-Rahman
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Lik-Jun Kiew
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
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Ilies MA, Supuran CT, Scozzafava A. Therapeutic applications of serine protease inhibitors. Expert Opin Ther Pat 2005. [DOI: 10.1517/13543776.12.8.1181] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Casini A, Scozzafava A, Supuran CT. Sulfonamide derivatives with protease inhibitory action as anticancer, anti-inflammatory and antiviral agents. Expert Opin Ther Pat 2005. [DOI: 10.1517/13543776.12.9.1307] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Scott GM, Isaacs MA, Zeng F, Kesson AM, Rawlinson WD. Cytomegalovirus antiviral resistance associated with treatment induced UL97 (protein kinase) and UL54 (DNA polymerase) mutations. J Med Virol 2005; 74:85-93. [PMID: 15258973 DOI: 10.1002/jmv.20150] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
HCMV-related illness due to infections with antiviral resistant virus was verified by phenotypic and genotypic assays in 17% (8/47) of high-risk immunocompromised Australian patients. Selective PCR-sequencing of UL97 (protein kinase; PK) and UL54 (DNA polymerase; DNApol) regions important for antiviral sensitivity, identified the majority (6/8) of resistant strains through detection of mutations known to confer antiviral resistance. Additionally, eight UL54 (DNApol) mutations (N408K, T691S, A692V, S695T, L737M, A834P, V955I, and A972V) of unknown phenotype were identified in six specimens from patients with clinical evidence of antiviral resistant infections. One isolate was resistant to ganciclovir (GCV) and another resistant to PFA on phenotypic testing where mutations in UL97 (PK) or UL54 (DNApol) were not detected, suggesting a loss of correlation between phenotype and genotype. Selective PCR-sequencing of UL97 (PK) and UL54 (DNApol) provided rapid and comprehensive results, but missed some resistance detected by phenotypic assays. A combination of phenotypic and genotypic assays is recommended for complete analysis of CMV antiviral resistance, as well as further definition of the clinical relationship between novel UL54 (DNApol) mutations and antiviral resistance.
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Affiliation(s)
- G M Scott
- Virology Division, Department of Microbiology, SEALS, Prince of Wales Hospital, Randwick, and School of Medicial Sciences, University of New South Wales, Kensington, Australia
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de Souza S, Bonon SHA, Costa SCB, Rossi CL. Evaluation of an in-house specific immunoglobulin G (IgG) avidity ELISA for distinguishing recent primary from long-term human cytomegalovirus (HCMV) infection. Rev Inst Med Trop Sao Paulo 2004; 45:323-6. [PMID: 14762632 DOI: 10.1590/s0036-46652003000600005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This article describes the standardization and evaluation of an in-house specific IgG avidity ELISA for distinguishing recent primary from long-term human cytomegalovirus (HCMV) infection. The test was standardized with the commercial kit ETI-CYTOK G Plus (Sorin Biomedica, Italy) using 8 M urea in phosphate-buffered saline to dissociate low-avidity antibodies after the antigen-antibody interaction. The performance of the in-house assay was compared to that of the commercial automated VIDAS CMV IgG avidity test (bioM rieux, France). Forty-nine sera, 24 from patients with a recent primary HCMV infection and 25 from patients with a long-term HCMV infection and a sustained persistence of specific IgM antibodies, were tested. Similar results were obtained with the two avidity methods. All 24 sera from patients with recently acquired infection had avidity indices compatible with acute HCMV infection by the VIDAS method, whereas with the in-house method, one serum sample had an equivocal result. In the 25 sera from patients with long-term infection, identical results were obtained with the two methods, with only one serum sample having an incompatible value. These findings suggest that our in-house avidity test could be a potentially useful tool for the immunodiagnosis of HCMV infection.
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Affiliation(s)
- Silmara de Souza
- Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, S.P., Brasil
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Supuran CT, Casini A, Scozzafava A. Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents. Med Res Rev 2003; 23:535-58. [PMID: 12789686 DOI: 10.1002/med.10047] [Citation(s) in RCA: 310] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.
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Affiliation(s)
- Claudiu T Supuran
- Università degli Studi di Firenze, Dipartimento di Chimica, Via della Lastruccia, 3, Rm. 188, I-50019 Sesto Fiorentino (Florence), Italy.
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Jones CA, Walker KS, Henderson-Smart DJ. Antiviral therapy for symptomatic congenital cytomegalovirus infection in neonates and infants up to 3 months of age. Hippokratia 2003. [DOI: 10.1002/14651858.cd004340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Cheryl A Jones
- The University of Sydney; Discipline of Paediatrics and Child Health; Locked Bag 4001 Westmead NSW Australia 2145
| | - Karen S Walker
- The Children's Hospital at Westmead; Grace Neonatal Services; PO Box 4001 Sydney NSW Australia 2115
| | - David J Henderson-Smart
- Queen Elizabeth II Research Institute; NSW Centre for Perinatal Health Services Research; Building DO2 University of Sydney Sydney NSW Australia 2006
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Affiliation(s)
- Cheryl A Jones
- Children's Hospital at Westmead, Discipline of Pediatrics and Child Health, University of Sydney, Sydney, Australia
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Lee SH, Webb JR, Vidal SM. Innate immunity to cytomegalovirus: the Cmv1 locus and its role in natural killer cell function. Microbes Infect 2002; 4:1491-503. [PMID: 12505521 DOI: 10.1016/s1286-4579(02)00032-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The identification and characterization of genetic loci that contribute to patterns of susceptibility/resistance to infection provide important insights into the mechanisms of innate and adaptive immunity. Genetic heterogeneity across the population makes the characterization of such traits in humans technically difficult; however, inbred animal models represent an ideal tool for such analyses. This review illustrates the power of mouse genetics as utilized for the identification and characterization of the locus conferring early resistance to murine cytomegalovirus infection, Cmv1. This locus encodes an activating C-type lectin receptor of the Ly49 family that promotes natural killer (NK) cell cytolysis of infected cells. Although NK cells are usually able to detect and destroy virally infected cells via recognition of the downregulation of MHC class I molecules, the Cmv1 locus provides the first example of an NK receptor that is able to mediate clearance of viral infection via direct recognition of a virally encoded protein.
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Affiliation(s)
- Seung Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, room 4207, 451 Smyth Road, Ont., K1H 8M5, Ottawa, Canada
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Webb JR, Lee SH, Vidal SM. Genetic control of innate immune responses against cytomegalovirus: MCMV meets its match. Genes Immun 2002; 3:250-62. [PMID: 12140743 DOI: 10.1038/sj.gene.6363876] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2002] [Revised: 02/22/2002] [Accepted: 02/22/2002] [Indexed: 11/08/2022]
Abstract
Cytomegalovirus (CMV) is a widespread pathogen that is responsible for severe disease in immunocompromised individuals and probably, associated with vascular disease in the general population. There is increasing evidence that cells of the innate immune system play a key role in controlling this important pathogen. This is particularly evident in the experimental murine CMV (MCMV) model of infection which has revealed an important role for natural killer (NK) cells in controlling early viral replication after infection with MCMV. In this model, different strains of inbred mice exhibit striking differences in their level of susceptibility to MCMV infection. Genetic studies, performed almost 10 years ago, revealed that this pattern of susceptibility/resistance can be attributed to a single genetic locus termed Cmv1 and recently several groups that have been working on the mapping and identification of Cmv1 have met with success. Interestingly, Cmv1 is allelic to a member of the Ly49 gene family, which encode activating or inhibitory transmembrane receptors present on the surface of NK cells. All Ly49 receptors characterized to date interact with MHC class I molecules on potential target cells, resulting in the accumulation of signals to the NK to either 'kill' or 'ignore' the cell based upon the repertoire of MHC class I molecules expressed. The identification of Cmv1 as Ly49H, a stimulatory member of the Ly49 family, adds an interesting twist to the Ly49 story. Although the ligand of Ly49H is not yet known, there is already compelling evidence that the ligand is upregulated on virally infected cells, resulting in specific activation of Ly49H-expressing NK cells. This review provides an historical perspective of the MCMV infection model from its inception to the discovery of the gene responsible for the phenotype and provides a basis for further experiments aimed at understanding the role of NK cells, in general, and Ly49H, in particular, in mediating resistance to cytomegalovirus.
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Affiliation(s)
- J R Webb
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, K1H 8M5, Canada
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27
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Yan S, Fedorko DP. Recent advances in laboratory diagnosis of human cytomegalovirus infection. ACTA ACUST UNITED AC 2002. [DOI: 10.1016/s1529-1049(02)00045-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Dakin J, Griffiths M. The pulmonary physician in critical care 1: pulmonary investigations for acute respiratory failure. Thorax 2002; 57:79-85. [PMID: 11809996 PMCID: PMC1746170 DOI: 10.1136/thorax.57.1.79] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
This is the first in a series of reviews of the role of the pulmonary physician in critical care medicine. The investigation of mechanically ventilated patients is discussed, with particular reference to those presenting with acute respiratory failure and diffuse pulmonary infiltrates.
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Affiliation(s)
- J Dakin
- Unit of Critical Care, NHLI Division, Imperial College of Science, Technology & Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
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29
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Belouchi A, Vidal SM. Identification du locus Cmv1 : bases génétiques de la susceptibilité aux cytomégalovirus. Med Sci (Paris) 2001. [DOI: 10.1051/medsci/200117121349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Magalhães SM, Duarte FB, Vassallo J, Costa SC, Lorand-Metze I. Multiple lymphoid nodules in bone marrow biopsy in immunocompetent patient with cytomegalovirus infection: an immunohistochemical analysis. Rev Soc Bras Med Trop 2001; 34:365-8. [PMID: 11562730 DOI: 10.1590/s0037-86822001000400009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In Brazil, a high prevalence of cytomegalovirus (CMV) infection has been documented. In immunocompetent adults CMV infection is usually asymptomatic and therefore morphologic and immunophenotypic bone marrow changes have rarely been described. The authors report the case of a previously healthy patient who developed fever of undetermined origin. The diagnosis of acute CMV infection was based on serological testing. A computed tomographic scan showed mediastinal lymphadenopathy. A bone marrow biopsy revealed a hypercellular haematopoiesis with eosinophilia and large mixed T- and B-cell lymphoid aggregates. In spite of bcl-2 positivity, their reactive nature was demonstrated. Polymerase chain reaction (PCR) and immunohistochemistry were unable to detect CMV-DNA in paraffin-embedded bone marrow sections. Much like in other systemic disorders, the lymphoid nodules in this case seemed to be caused by immunological mechanisms, possibly due to cytokines released in response to the systemic infectious process.
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Affiliation(s)
- S M Magalhães
- Department of Clinical Medicine, HEMOCE, Federal University of Ceará, Fortaleza, CE, Brasil
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Abstract
Congenital cytomegalovirus (CMV) infections remain the leading viral cause of congenital malformations in the developed world. Despite advances in our knowledge, the epidemiology and natural history of congenital CMV infection are still poorly understood, particularly in Australia. Congenital CMV causes illness ranging from no clinical disease (asymptomatic, but infected) through to prematurity, encephalitis, deafness and haematological disorders and death. Perinatal CMV acquisition usually results in less severe illness including asymptomatic infection, acute infection with hepatitis, fever, and pneumonitis. CMV infects only humans, and in vitro and in vivo models for intrauterine infection are required in order to test new treatments, and better describe the pathogenesis of congenital CMV. Using new knowledge of the epidemiology and natural history of CMV, treatment regimens during late pregnancy are currently undergoing clinical trial although no definitive recommendations are available.
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Affiliation(s)
- D E Trincado
- Virology Division, Department of Microbiology, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Randwick, New South Wales, Australia
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32
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Affiliation(s)
- D P Lynch
- Department of Biologic and Diagnostic Sciences, College of Dentistry The University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA
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