Schmitz, Herbert
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Schmitz, Herbert
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Schmitz, Herbert
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Item-typ:Veröffentlichung, Entwicklung eines enzymatischen Testes zum Nachweis von Antikörpern gegen Lassavirus in menschlichen Seren unter Berücksichtigung verschiedener Lassavirus Serotypen(2006-02-02); ; Two highly sensitive and specific reverse enzyme- immunoassays were developed, to detect Lassa virus antibodies. IgG and IgM antibodies of the human sera were bound to microtiter plates coated either with Rheumatoid factor or with anti-human à µ-chain antibodies, respectively. For both tests a crude antigen extracted from Lassa virus infected tissue cultures cells was used. This antigen was in turn reacted with a labeled monoclonal antibody to Lassa virus nucleocapsid. The reverse Elisa turned out to detect IgG in serum samples of West African patients with recent Lassa fever and in 76 sera of healthy seropositive (IIF) West Africans with a sensitivity of 100. In 1031 controls samples of healthy Africans, who were negative for IgG and IgM antibodies by indirect immunofluorescence (IIF), also no IgM antibodies could by found by Elisa. Compared to IIF, the specificity of the reverse Elisa for IgG antibodies was only 95%. But upon retesting the 19 discrepant samples with three different Lassa virus antigens by IIF, 14 samples turned out to react positively (titer ≥20) with at least one antigen in IIF. When all 1107 West African serum samples were tested in the Elisa for IgG antibodies to the three different Lassa virus antigen, in about 30% strictly strain-specific reactions were seen.Dissertation275 96 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Inhibition zellulärer antiviraler Abwehrmechanismen durch das Hepatitis A-Virus - eine Analyse der beteiligten viralen Faktoren: Inhibition des IRF-3 -vermittelten Signalweges durch das Nichtstrukturprotein 2B des Hepatitis A-Virus(2007-12-19); ; ; Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of Newcastle disease virus (NDV)- or dsRNA-mediated interferon-beta (IFN-beta) gene expression. The aim of this dissertation was to investigate which viral properties or factors are involved in this suppression. It could be demonstrated that the nonstructural protein HAV-2B correlates with the ability of HAV to suppress the NDV- or dsRNA-mediated interferon-beta (IFN-beta) gene expression. Further investigations supported this finding that HAV-2B is involved in inhibition of activation of transcription factor IRF-3 by HAV. As IRF-3 is necessary for IFN-beta transcription, inhibition of this factor results in efficient suppression of IFN-beta synthesis. This ability might be of vital importance for HAV, which is an exceptionally slowly growing virus sensitive to IFN-beta, as it allows this virus to establish infection and maintain viral replication for a longer time.Dissertation221 115 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Wirkung von Cytokinen und cytokininduzierten Proteinen auf die Replikation von Lassa-Virus und Lymphocytärem Choriomeningitis Virus(2003-07-24); ; ; Lassa virus is thought to be resistent to the effects of interferon (IFN). This study demonstrates that Lassa virus replication is inhibited by IFN-alpha and IFN-gamma, but not tumor necosis factor alpha (TNF-alpha), in Huh7and Vero cells. However, the effects were orders of magnitudes smaller compared to vesicular stomatitis virus. Lassa virus AV, which had causeda fulminant Lassa fever, was somewhat more inhibited than Lassa virus NL and CSF, which had been associated with less severe disease. Mostimportantly, there were no clear differences in response to IFN-alpha, IFN-gamma, and TNF-alpha between the Lassa virus strains and the strains CH-5692, Armstrong, and WE of lymphocytic choriomeningitis virus (LCMV),a related Old World arenavirus which is less pathogenic to humans than Lassa virus. Using inducible overexpression cell lines, no evidence for a role of the IFN-stimulated proteins promyelocytic leukemia protein(PML) and Sp100 in the IFN-mediated inhibition of Lassa virus and LCMV replication was found. This and the previous finding that PML knockout facilitates LCMV replication in vitro and in vivo (M. Djavani et al., J.Virol. 75:6204-6208; W. V. Bonilla et al., J. Virol. 76:3810-3818) would fit with the hypothesis that PML is a mediator in the antiviral pathway rather than a direct effector protein. In conclusion, the data show thatLassa virus is susceptible to IFN-alpha and IFN-gamma which is of relevance for the design of antiviral strategies against Lassa fever, aiming at enhancing the IFN response. In contrast to influenza A viruses (S. H.Seo et al., Nat. Med. 8:950-954), there appears to be no correlation between the pathogenicity of Old World arenaviruses and their sensitivity to IFN.Dissertation241 130 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Untersuchung und Identifizierung von Faktoren, die an der Hemmung der IFN-beta-Induktion bei einer Hepatitis A-Virusinfektion beteiligt sind(2008-09-16); ; ; Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of retinoic acid-inducible gene I (RIG-I)- and melanoma differentiation-associated gene 5 (MDA-5)-mediated interferon-beta gene expression. We show that this is due to an interaction of HAV with the signaling pathway component MAVS (mitochondrial antiviral signaling protein), in which the viral nonstructural protein 2B seems to be involved. In consequence, interferon regulatory factor 3 (IRF-3) is not activated. This resulzs in efficient suppression of IFN-beta synthesis.Dissertation221 145 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Untersuchungen zur Blockade zellulärer antiviraler Mechanismen durch das Hepatitis A-Virus unter besonderer Berücksichtigung der Proteinkinase R und des Transkriptionsfaktors NF-kappaB(2003-12-17); ; ; Virus infection normally induces expression and secretion of type I interferon (IFN), leading to the establishment of an antiviral state in adjacent cells. In rhesus monkey kidney cells, hepatitis A virus (HAV) suppresses induction of IFN-b on the level of transcription, even after transfection with poly(IC), a dsRNA analogon. Furthermore, HAV is able to establish a persistent infection in cell culture and to suppress apoptosis. The objectives of this work were 1) to transfer the above results into a human cell culture system and 2) to examine possible cellular targets of HAV. Human MRC-5 fibroblasts were infected with HAV, and results show that IFN-b is not induced by infection and that after poly(IC) transfection HAV actively suppresses IFN-b production (determined by plaque reduction assay). Suppression of IFN-b expression occurs on the level of mRNA, as detected by RT-PCR suggesting one or more proteins of dsRNA-dependent signalling pathways to be affected by HAV. Protein kinase R (PKR) is involved in dsRNA-induced apoptosis and furthermore, PKR has been described to be involved in the activation of NF-kB, a transcription factor participating in induction of IFN-b. Autophosphorylation is a hallmark of PKR-activation and therefore, phosphorylation of PKR on Thr-451 was analysed by immunoblotting. In HAV-infected cells, PKR-phosphorylation appeared to be generally reduced, whereas a degradation of PKR could not be detected. When cellular localization of NF-kB was examined by immunofluorescence, poly(IC)-induced nuclear translocation of NF-kB was found to be unaffected and even enhanced by HAV, excluding a role for NF-kB in HAV-mediated suppression of IFN-b. However, HAV-induced activation of anti-apoptotic NF-kB may contribute to survival of HAV-infected cells. The suppression of IFN-b and the influence on PKR, NF-kB and cell vitality may allow HAV to establish a persistent infection in cell culture and might be a prerequisite for successful replication in vivo.Dissertation214 171