Dana G Wolf

Publications of Dana G Wolf

• Modeling of human cytomegalovirus maternal-fetal transmission in a novel decidual organ culture.

  Authors: Yiska Weisblum, Amos Panet, Zichria Zakay-Rones, Ronit Haimov-Kochman, Debra Goldman-Wohl, Ilana Ariel, Haya Falk, Shira Natanson-Yaron, Miri D Goldberg, Ronit Gilad, Nell S Lurain, Caryn Greenfield, Simcha Yagel, Dana G Wolf

  Journal of virology. 12/2011; 85(24):13204-13.

  Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via theHuman cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the ex vivo modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3- to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection-providing a mechanistic basis for their clinical use in prenatal prevention. The ex vivo-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.

• Increased extent of and risk factors for pandemic (H1N1) 2009 and seasonal influenza among children, Israel.

  Authors: Dan Engelhard, Michal Bromberg, Diana Averbuch, Ariel Tenenbaum, Daniele Goldmann, Marina Kunin, Einat Shmueli, Ido Yatsiv, Michael Weintraub, Michal Mandelboim, Nurith Strauss-Liviatan, Emilia Anis, Ella Mendelson, Tamy Shohat, Dana G Wolf, Mervyn Shapiro, Itamar Grotto

  Emerging infectious diseases. 09/2011; 17(9):1740-3.

  During the pandemic (H1N1) 2009 outbreak in Israel, incidence rates among children were 2× higher than that of the previous 4 influenza seasons; hospitalization rates were 5× higher. ChildrenDuring the pandemic (H1N1) 2009 outbreak in Israel, incidence rates among children were 2× higher than that of the previous 4 influenza seasons; hospitalization rates were 5× higher. Children hospitalized for pandemic (H1N1) 2009 were older and had more underlying chronic diseases than those hospitalized for seasonal influenza.

• An outbreak of adenovirus type 7 in a residential facility for severely disabled children.

  Authors: Hammam Ghanaiem, Diana Averbuch, Benjamin Z Koplewitz, Ido Yatsiv, Jackues Braun, Natali Dehtyar, Dana G Wolf, Michal Mandelboim, Dan Engelhard

  The Pediatric infectious disease journal. 06/2011; 30(11):948-52.

  Adenoviruses cause a variety of clinical symptoms, involving the respiratory, gastrointestinal, urogenital, and neurologic systems. Only a few of the 55 known serotypes of adenovirus that affectAdenoviruses cause a variety of clinical symptoms, involving the respiratory, gastrointestinal, urogenital, and neurologic systems. Only a few of the 55 known serotypes of adenovirus that affect humans can cause outbreaks of respiratory tract infection. To describe the characteristics and clinical manifestations of severe respiratory disease contracted by 8 physically and cognitively disabled children during a very short outbreak of adenovirus serotype 7 infection in a residential facility. The clinical, imaging, and laboratory findings of the patients who were hospitalized with severe respiratory symptoms were retrospectively reviewed. Molecular typing of the adenovirus was performed. During 10 days in February 2010, 8 severely disabled children, 9 months to 5 years of age (median 22.5 months), from the same residential facility, were hospitalized due to severe acute respiratory disease with hypoxemia. Four of them (50%) needed mechanical ventilation for 2 to 8 days and one developed multisystem failure, including acute renal failure. Adenovirus serotype 7 was detected in the respiratory specimens of all 8 children. Two patients were treated with intravenous cidofovir. All 8 patients survived and were discharged after hospitalization of 6 to 15 (median: 11.5) days. The epidemiologic investigation revealed that all the 8 affected children shared a playroom and a caregiver worked with them while suffering fever, sore throat, and conjunctivitis before the onset of the outbreak. Adenovirus type 7 may cause short outbreaks of infection in institutions, causing children to develop life-threatening disease. Early detection of pathogens causing respiratory infections in institutions, isolation, and other preventive precautions are advocated. Moreover, vaccination of health care providers in institutions with the currently available live, oral adenovirus vaccine for types 4 and 7 should be considered.

• Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation.

  Authors: Dana G Wolf, Avichai Shimoni, Igor B Resnick, Thomas Stamminger, Avidan U Neumann, Sunwen Chou, Thomas Efferth, Orit Caplan, Jessica Rose, Arnon Nagler, Manfred Marschall

  Antiviral research. 03/2011; 90(3):183-6.

  The anti-malaria drug artesunate has been shown to be an effective inhibitor of cytomegalovirus (CMV) in vitro, in an experimental animal model, and in a recent single-case clinical use. In thisThe anti-malaria drug artesunate has been shown to be an effective inhibitor of cytomegalovirus (CMV) in vitro, in an experimental animal model, and in a recent single-case clinical use. In this first case-series of 6 stem cell transplant recipients who received preemptive artesunate treatment for CMV infection, we have examined the viral kinetics following institution of artesunate, and employed first-phase viral kinetics studies to calculate its antiviral effectiveness. Two patients demonstrated a rapid 0.8-2.1 log viral load decline by 7 days, with a viral decay half-live of 0.9-1.9 days. Four patients demonstrated a continued yet stalled viral growth slope during treatment. No adverse events were noted in treatment courses of up to 28 days. Overall, a divergent antiviral efficacy was revealed, ranging from 43% to 90%, which appeared to be primarily dependent on the virus baseline growth dynamics. Further dose escalation studies are needed to examine the role of artesunate in the treatment of CMV infection in the transplantation setting.

• The humoral immune response of hematopoietic stem cell transplantation recipients to AS03-adjuvanted A/California/7/2009 (H1N1)v-like virus vaccine during the 2009 pandemic.

  Authors: Dan Engelhard, Zichria Zakay-Rones, Michael Y Shapira, Igor Resnick, Diana Averbuch, Sigal Grisariu, Lillian Dray, Esther Djian, Nurith Strauss-Liviatan, Itamar Grotto, Dana G Wolf, Reuven Or

  Vaccine. 02/2011; 29(9):1777-82.

  We evaluated the formation of hemagglutination-inhibition (HI) antibodies in response to vaccination of 55 allogeneic and 23 autologous hematopoietic stem cell transplantation (HSCT) recipients withWe evaluated the formation of hemagglutination-inhibition (HI) antibodies in response to vaccination of 55 allogeneic and 23 autologous hematopoietic stem cell transplantation (HSCT) recipients with 3.75 μg inactivated influenza A/California/7/2009 (H1N1)v-like virus adjuvanted with AS03, given towards the end of the 2009 influenza pandemic. The 78 HSCT recipients, aged 11-72 (median 50) years, were vaccinated 1-290 (median 27) months post-HSCT. Of the 55 allogeneic HSCT recipients, 50.9% received reduced intensity conditioning, 74.5% had a sibling donor, 67.2% had active graft-versus-host disease and 43.6% were on steroid therapy. At baseline, 14/78 (17.9%) had HI titers ≥ 1:40. Blood samples of 77 patients were available post-1st vaccination; of these, 34 (44.2%) patients had HI titers ≥ 1:40. Blood samples of 43 patients were available post-2nd vaccination; of these, 21 (48.8%) had HI titers ≥ 1:40. There was a significant increase in HI titers ≥ 1:40 from baseline to both post-1st and 2nd vaccinations (p<0.001 each), and also from 1st to 2nd vaccination (p=0.008). In seronegative (HI titers <1:10) patients, whose sera were available before, after one dose, and after 2 doses of vaccine, seroconversion (to ≥ 1:40) occurred in 4/24 (16.7%) after 1-dose and in a total of 10/24 (41.7%) after 2-dose vaccination (p=0.031). Logistic regression analysis revealed that ≥ 1:40 HI titers were significantly associated with higher lymphocyte counts and higher HI baseline titers and, in allogeneic HSCT, with having a sibling donor and higher baseline titers. In conclusion, 2-dose vaccination with AS03-adjuvanted vaccine containing 3.75 μg antigen resulted in a statistically significant, yet limited, serological response. Therefore, additional precautions should be taken during influenza outbreaks.

• Human cytomegalovirus UL97 kinase and nonkinase functions mediate viral cytoplasmic secondary envelopment.

  Authors: Miri D Goldberg, Alik Honigman, Jacob Weinstein, Sunwen Chou, Albert Taraboulos, Alexander Rouvinski, Vera Shinder, Dana G Wolf

  Journal of virology. 01/2011; 85(7):3375-84.

  Previous studies have revealed critical roles for the human cytomegalovirus (HCMV) UL97 kinase in viral nuclear maturation events. We have shown recently that UL97 affects the morphology of the viralPrevious studies have revealed critical roles for the human cytomegalovirus (HCMV) UL97 kinase in viral nuclear maturation events. We have shown recently that UL97 affects the morphology of the viral cytoplasmic assembly compartment (AC) (M. Azzeh, A. Honigman, A. Taraboulos, A. Rouvinski, and D. G. Wolf, Virology 354:69-79, 2006). Here, we employed a comprehensive ultrastructural analysis to dissect the impact of UL97 on cytoplasmic steps of HCMV assembly. Using UL97 deletion (ΔUL97) and kinase-null (K355M) mutants, as well as the UL97 kinase inhibitor NGIC-I, we demonstrated that the loss of UL97 kinase activity resulted in a unique combination of cytoplasmic features: (i) the formation of pp65-rich aberrant cytoplasmic tegument aggregates, (ii) distorted intracytoplasmic membranes, which replaced the normal architecture of the AC, and (iv) a paucity of cytoplasmic tegumented capsids and dense bodies (DBs). We further showed that these abnormal assembly intermediates did not result from impaired nuclear capsid maturation and egress per se by using 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl) benzimidizole (BDCRB) to induce the artificial inhibition of nuclear maturation and the nucleocytoplasmic translocation of capsids. The specific abrogation of UL97 kinase activity under low-multiplicity-of-infection conditions resulted in the improved release of extracellular virus compared to that of ΔUL97, despite similar rates of viral DNA accumulation and similar effects on nuclear capsid maturation and egress. The only ultrastructural correlate of the growth difference was a higher number of cytoplasmic DBs, tegumented capsids, and clustered viral particles observed upon the specific abrogation of UL97 kinase activity compared to that of ΔUL97. These combined findings reveal a novel role for UL97 in HCMV cytoplasmic secondary envelopment steps, with a further distinction of kinase-mediated function in the formation of the virus-induced AC and a nonkinase function enhancing the efficacy of viral tegumentation and release.

• Influenza A infection in young infants.

  Authors: David Rekhtman, Dana G Wolf, Floris Levy-Khademi, Diana Averbuch, Eitan Kerem, Isaiah D Wexler

  Archives of disease in childhood. 10/2010; 96(11):1085-7.

  To determine the clinical characteristics of infants ≤2 months old hospitalised with influenza A. The study was a retrospective analysis of infants ≤2 months old hospitalised with fever, respiratoryTo determine the clinical characteristics of infants ≤2 months old hospitalised with influenza A. The study was a retrospective analysis of infants ≤2 months old hospitalised with fever, respiratory distress and/or sepsis. Clinical signs, laboratory values, hospital duration and outcome were compared between children with influenza A and other viruses. The charts of 268 infants were reviewed. 29 (11%) children had laboratory-confirmed influenza A infection. Unique features associated with influenza infection included the high number presenting with fever (97%) and a history of exposure to family members with a flu-like illness (69%). A significantly lower rate of respiratory distress was observed in the influenza group compared with respiratory syncytial virus (RSV) (24% vs 89%, p≤0.001). Median duration of hospitalisation for influenza was shorter than RSV (4 days vs 6 days, p<0.001). In young infants, influenza A is a relatively mild disease compared to RSV and is primarily associated with upper respiratory tract manifestations.

• The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination.

  Authors: Daphna Nachmani, Dikla Lankry, Dana G Wolf, Ofer Mandelboim

  Nature immunology. 09/2010; 11(9):806-13.

  Although approximately 200 viral microRNAs are known, only very few share similar targets with their host's microRNAs. A notable example of this is the stress-induced ligand MICB, which is targetedAlthough approximately 200 viral microRNAs are known, only very few share similar targets with their host's microRNAs. A notable example of this is the stress-induced ligand MICB, which is targeted by several distinct viral and cellular microRNAs. Through the investigation of the microRNA-mediated immune-evasion strategies of herpesviruses, we initially identified two new cellular microRNAs that targeted MICB and were expressed differently both in healthy tissues and during melanocyte transformation. We show that coexpression of various pairs of cellular microRNAs interfered with the downregulation of MICB, whereas the viral microRNAs optimized their targeting ability to efficiently downregulate MICB. Moreover, we demonstrate that through site proximity and possibly inhibition of translation, a human cytomegalovirus (HCMV) microRNA acts synergistically with a cellular microRNA to suppress MICB expression during HCMV infection.

• Cytomegalovirus infection in pediatric rheumatic diseases: a review.

  Authors: Eli M Eisenstein, Dana G Wolf

  Pediatric rheumatology online journal. 01/2010; 8:17.

  Human cytomegalovirus (HCMV) is familiar to pediatric rheumatologists mainly as a cause of opportunistic disease in pharmacologically immune suppressed patients. However, HCMV also has a variety ofHuman cytomegalovirus (HCMV) is familiar to pediatric rheumatologists mainly as a cause of opportunistic disease in pharmacologically immune suppressed patients. However, HCMV also has a variety of immuno-modulatory effects, through which it may influence the course of rheumatic conditions. In this article we discuss the interplay between HCMV and the immune system, and review the clinical manifestations, diagnosis, and treatment of HCMV infection in children with rheumatic disease.

• Analysis of human cytomegalovirus encoded-microRNAs activity during infection.

  Authors: Noam Stern-Ginossar, Niveen Saleh, Miri D Goldberg, Mark Prichard, Dana G Wolf, Ofer Mandelboim

  Journal of virology. 09/2009;

  MicroRNAs (miRNAs) are expressed in a wide variety of organisms ranging from plants to animals and are key posttranscriptional regulators of gene expression. Virally-encoded miRNAs are unique as theyMicroRNAs (miRNAs) are expressed in a wide variety of organisms ranging from plants to animals and are key posttranscriptional regulators of gene expression. Virally-encoded miRNAs are unique as they could potentially target both viral and host genes. Indeed, we have previously demonstrated that a human cytomegalovirus (HCMV) encoded miRNA, miR-UL112 downregulates the expression of a host immune gene, MICB. Remarkably, it was shown that the same miRNA also downregulates immediate early viral genes and its ectopic expression resulted in reduced viral replication and viral titers. The targets for most of the viral miRNAs and hence their function, are still unknown. Here, we demonstrate that miR-UL112 also targets the UL114 gene and present evidence that the reduction of UL114 by miR-UL112 reduces its activity as uracil DNA glycosylase but only minimally affects virus growth. In addition, we show that two additional HCMV encoded miRNAs, miR-US25-1 and miR-US25-2, reduce viral replication and DNA synthesis not only of HCMV but also of other viruses, suggesting that these two miRNAs target cellular genes which are essential for virus growth. Thus, we demonstrate that in addition to miR-UL112, two additional HCMV miRNAs control the life cycle of the virus.

• Association of Human Metapneumovirus with Radiologically Diagnosed Community-Acquired Alveolar Pneumonia in Young Children.

  Authors: Dana G Wolf, David Greenberg, Yonat Shemer-Avni, Noga Givon-Lavi, Jacob Bar-Ziv, Ron Dagan

  The Journal of pediatrics. 09/2009;

  OBJECTIVES: To determine the involvement of human metapneumovirus (HMPV) in childhood community-acquired alveolar pneumonia (CAAP) and compare the demographic, clinical, and laboratory features ofOBJECTIVES: To determine the involvement of human metapneumovirus (HMPV) in childhood community-acquired alveolar pneumonia (CAAP) and compare the demographic, clinical, and laboratory features of HMPV-associated CAAP and CAAP associated with other respiratory viruses. STUDY DESIGN: Nasopharyngeal wash specimens obtained prospectively over a 4-year period from children age < 5 years evaluated in the emergency department with radiologically diagnosed CAAP and from healthy controls were tested for HMPV by reverse-transcriptase polymerase chain reaction and for respiratory syncytial virus (RSV), adenovirus, influenza and parainfluenza viruses by direct immunofluorescence and culture. RESULTS: HMPV was detected in 108 of 1296 patients (8.3%) versus RSV in 23.1%, adenovirus in 3.4%, influenza A virus in 2.9%, and parainfluenza viruse in 2.9%. During the period of peak activity (November to May), HMPV was detected in 95 of 1017 patients (9.3%) and in 3 of 136 controls (2.2%) (P = .005). The patients with HMPV were older than those with RSV (P < .001) with a more common history of acute otitis media requiring tympanocentesis (P = .032), wheezing (P = .001) and gastrointestinal symptoms (P < .001) and a lower hospitalization rate (P = .005). CONCLUSIONS: The high detection rate suggests an important role for HMPV in childhood CAAP. Our findings identify demographic and clinical features of HMPV-positive CAAP and its age-related impact on hospital admissions.

• Epstein Barr virus - related diarrhea or exacerbation of inflammatory bowel disease: A diagnostic dilemma.

  Authors: Ido Weinberg, Tzahi Neuman, Maya Margalit, Fadeela Ayman, Dana G. Wolf, Arie Ben-Yehuda

  Journal of clinical microbiology. 04/2009;

  While the presence of Epstein Barr virus (EBV) in colonic specimens from patients with inflammatory bowel disease (IBD) has been documented, diarrhea secondary to gastrointestinal (GI) involvement byWhile the presence of Epstein Barr virus (EBV) in colonic specimens from patients with inflammatory bowel disease (IBD) has been documented, diarrhea secondary to gastrointestinal (GI) involvement by EBV in the context of primary EBV infection in patients with IBD has not been reported. We describe a patient with IBD who presented with diarrhea and primary EBV infection and propose a role for colonic involvement by EBV in the pathogenesis of his symptoms.

• Emergence of oseltamivir-resistant influenza A/H3N2 virus with altered hemagglutination pattern in a hematopoietic stem cell transplant recipient.

  Authors: Leonor Cohen-Daniel, Zichria Zakay-Rones, Igor B Resnick, Michael Y Shapira, Marina Dorozhko, Nurith Mador, Evgenia Greenbaum, Dana G Wolf

  Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 02/2009;

  BACKGROUND: Persistent influenza virus replication during antiviral therapy in patients undergoing hematopoietic stem cell transplantation (HSCT) could promote the emergence of antiviral drugBACKGROUND: Persistent influenza virus replication during antiviral therapy in patients undergoing hematopoietic stem cell transplantation (HSCT) could promote the emergence of antiviral drug resistance. OBJECTIVES: To follow the viral genotypic and drug susceptibility changes in a patient who developed progressive influenza A/H3N2 pneumonia despite oseltamivir therapy after haploidentical HSCT. STUDY DESIGN: Direct genotypic analysis of the neuraminidase (NA) and hemagglutinin (HA) genes in successive bronchoalveolar lavage specimens was employed in combination with hemagglutination and NA enzymatic activity assays of the corresponding viral isolates. RESULTS: The emergence of NA oseltamivir-resistance mutation R292K was detected by 12 days of oseltamivir treatment with 44,286-fold increase in oseltamivir IC(50). Resurgence of wild type viral population was identified by 7 days after cessation of oseltamivir. Sequential HA mutations R228S and A138S were identified and associated with a shift in the HA receptor binding pattern reflected by loss of the ability to agglutinate chicken erythrocytes. CONCLUSIONS: These rapid evolutionary changes warrant close virologic monitoring of immunocompromised patients treated for influenza infection, and raise concern about the efficacy of mono-drug therapy for influenza-associated disease in HSCT recipients.

• The antiviral activities of artemisinin and artesunate.

  Authors: Thomas Efferth, Marta R Romero, Dana G Wolf, Thomas Stamminger, Jose J G Marin, Manfred Marschall

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 10/2008; 47(6):804-11.

  Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicineTraditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.

• Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation.

  Authors: Michael Y Shapira, Igor B Resnick, Sunwen Chou, Avidan U Neumann, Nell S Lurain, Thomas Stamminger, Orit Caplan, Niveen Saleh, Thomas Efferth, Manfred Marschall, Dana G Wolf

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 06/2008; 46(9):1455-7.

  This is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with a newly identified foscarnet-resistant and ganciclovir-resistant DNAThis is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with a newly identified foscarnet-resistant and ganciclovir-resistant DNA polymerase L776M mutation. Artesunate treatment resulted in a 1.7-2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9-1.9 days, indicating a highly effective block in viral replication.

• Severe Epstein-Barr virus-associated hemophagocytic syndrome in six adult patients.

  Authors: Anat Scheiman Elazary, Dana G Wolf, Gail Amir, Batia Avni, Deborah Rund, Dina Ben-Yehuda, Sigal Sviri

  Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 11/2007; 40(2):156-9.

  BACKGROUND: EBV associated hemophagocytic syndrome (HPS) is an aggressive and potentially life-threatening condition. So far, most EBV associated HPS has been characterized mainly in infants andBACKGROUND: EBV associated hemophagocytic syndrome (HPS) is an aggressive and potentially life-threatening condition. So far, most EBV associated HPS has been characterized mainly in infants and children in Asian countries. RESULTS: Here, we report six cases of EBV associated HPS occurring in previously healthy adults in a non-endemic area within a short period of 3 years. All patients presented with fever, hepatosplenomegaly and pancytopenia as well as disturbed liver function tests and coagulopathy. Half were diagnosed as having lymphoma. While EBV-specific serological assays were non-diagnostic in four of the six patients, the presence of EBV DNA in plasma allowed the diagnosis of EBV associated HPS in all patients. CONCLUSION: EBV associated HPS may be more prevalent in non-Japanese adults than was previously considered. Screening for hemophagocytic syndrome, in adults as well as in children, should include real-time PCR for EBV.

• Steroids for deteriorating herpes simplex virus encephalitis.

  Authors: Banan Musallam, Israel Matoth, Dana G Wolf, Dan Engelhard, Diana Averbuch

  Pediatric neurology. 10/2007; 37(3):229-32.

  A 16-month-old girl presented with herpes simplex virus type 1 encephalitis with involvement of bilateral parietofrontal lobes, left thalamus and cerebellum. She was treated with intravenousA 16-month-old girl presented with herpes simplex virus type 1 encephalitis with involvement of bilateral parietofrontal lobes, left thalamus and cerebellum. She was treated with intravenous acyclovir. As her condition deteriorated, high-dose methylprednisolone was administered, resulting in remarkable improvement. This case suggests considering a short course of high-dose steroid therapy in severe herpes simplex encephalitis when there is clinical and radiologic deterioration in spite of appropriate antiviral therapy and decreasing viral load in the cerebrospinal fluid.

• Host immune system gene targeting by a viral miRNA.

  Authors: Noam Stern-Ginossar, Naama Elefant, Albert Zimmermann, Dana G Wolf, Nivin Saleh, Moshe Biton, Elad Horwitz, Zafnat Prokocimer, Mark Prichard, Gabriele Hahn, Debra Goldman-Wohl, Caryn Greenfield, Simcha Yagel, Hartmut Hengel, Yael Altuvia, Hanah Margalit, Ofer Mandelboim

  Science (New York, N.Y.). 08/2007; 317(5836):376-81.

  Virally encoded microRNAs (miRNAs) have recently been discovered in herpesviruses. However, their biological roles are mostly unknown. We developed an algorithm for the prediction of miRNA targetsVirally encoded microRNAs (miRNAs) have recently been discovered in herpesviruses. However, their biological roles are mostly unknown. We developed an algorithm for the prediction of miRNA targets and applied it to human cytomegalovirus miRNAs, resulting in the identification of the major histocompatibility complex class I-related chain B (MICB) gene as a top candidate target of hcmv-miR-UL112. MICB is a stress-induced ligand of the natural killer (NK) cell activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. We show that hcmv-miR-UL112 specifically down-regulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. Our results reveal a miRNA-based immunoevasion mechanism that appears to be exploited by human cytomegalovirus.

• NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome.

  Authors: Roi Gazit, Memet Aker, Moran Elboim, Hagit Achdout, Gil Katz, Dana G Wolf, Shulamit Katzav, Ofer Mandelboim

  Blood. 06/2007; 109(10):4306-12.

  Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GSGriscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primer-polymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors.

• Enterovirus, cytomegalovirus, and Epstein-Barr virus infection screening in idiopathic sudden sensorineural hearing loss.

  Authors: Menachem Gross, Dana G Wolf, Josef Elidan, Ron Eliashar

  Audiology & neuro-otology. 02/2007; 12(3):179-82.

  Sudden sensorineural hearing loss (SSNHL) is frequently classified as 'idiopathic' since the causative factor is not identified in most cases. In the present study we determined whether SSNHL isSudden sensorineural hearing loss (SSNHL) is frequently classified as 'idiopathic' since the causative factor is not identified in most cases. In the present study we determined whether SSNHL is associated with common viral infections, namely enterovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Between April 2004 and March 2005, we conducted a prospective cohort study on 48 unselected patients with unilateral idiopathic SSNHL. Plasma samples obtained at presentation were analyzed for the presence of enterovirus RNA by reverse-transcription polymerase chain reaction (RT-PCR). Recent occurrence of CMV and EBV infection was determined by serological tests. Among 23 men and 25 women aged 18-84 years (mean age 51.67 years), none presented with clinical symptoms of a viral infection compatible with preceding or concurrent viral infection. One patient (2.08%) had evidence of enterovirus infection by RT-PCR, 3 patients (6.25%) had EBV IgM, and none were positive for CMV IgM. The majority of SSNHL patients (91.67%) did not have evidence of any of the three common viral infections upon presentation. The present study failed to identify recent or concurrent systemic viral infections among SSNHL patients, except for a small proportion who demonstrated recent viral infection. Therefore the theory that viral infection is a factor in SSNHL pathogenesis is not supported by this study. Further studies in larger patient populations and different epidemiological settings are required in order to verify the true role of viral infections in SSNHL.