Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses
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20.08.2019 |
Rasche A.
Lehmann F.
König A.
Goldmann N.
Corman V.
Moreira-Soto A.
Geipel A.
van Riel D.
Vakulenko Y.
Sander A.
Niekamp H.
Kepper R.
Schlegel M.
Akoua-Koffi C.
Souza B.
Sahr F.
Olayemi A.
Schulze V.
Petraityte-Burneikiene R.
Kazaks A.
Lowjaga K.
Geyer J.
Kuiken T.
Drosten C.
Lukashev A.
Fichet-Calvet E.
Ulrich R.
Glebe D.
Drexler J.
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Proceedings of the National Academy of Sciences of the United States of America |
10.1073/pnas.1908072116 |
0 |
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© 2019 National Academy of Sciences. All rights reserved. Shrews, insectivorous small mammals, pertain to an ancient mammalian order. We screened 693 European and African shrews for hepatitis B virus (HBV) homologs to elucidate the enigmatic genealogy of HBV. Shrews host HBVs at low prevalence (2.5%) across a broad geographic and host range. The phylogenetically divergent shrew HBVs comprise separate species termed crowned shrew HBV (CSHBV) and musk shrew HBV (MSHBV), each containing distinct genotypes. Recombination events across host orders, evolutionary reconstructions, and antigenic divergence of shrew HBVs corroborated ancient origins of mammalian HBVs dating back about 80 million years. Resurrected CSHBV replicated in human hepatoma cells, but human- and tupaia-derived primary hepatocytes were resistant to hepatitis D viruses pseudotyped with CSHBV surface proteins. Functional characterization of the shrew sodium taurocholate cotransporting polypeptide (Ntcp), CSHBV/MSHBV surface peptide binding patterns, and infection experiments revealed lack of Ntcp-mediated entry of shrew HBV. Contrastingly, HBV entry was enabled by the shrew Ntcp. Shrew HBVs universally showed mutations in their genomic preCore domains impeding hepatitis B e antigen (HBeAg) production and resembling those observed in HBeAg-negative human HBV. Deep sequencing and in situ hybridization suggest that HBeAg-negative shrew HBVs cause intense hepatotropic monoinfections and low within-host genomic heterogeneity. Geographical clustering and low MSHBV/CSHBV-specific seroprevalence suggest focal transmission and high virulence of shrew HBVs. HBeAg negativity is thus an ancient HBV infection pattern, whereas Ntcp usage for entry is not evolutionarily conserved. Shrew infection models relying on CSHBV/MSHBV revertants and human HBV will allow comparative assessments of HBeAg-mediated HBV pathogenesis, entry, and species barriers.
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Identification of surface epitopes associated with protection against highly immune-evasive VlsE-expressing Lyme disease spirochetes
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01.08.2018 |
Batool M.
Caoili S.
Dangott L.
Gerasimov E.
Ionov Y.
Piontkivska H.
Zelikovsky A.
Waghela S.
Rogovskyy A.
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Infection and Immunity |
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3 |
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© 2018 American Society for Microbiology. The tick-borne pathogen Borrelia burgdorferi is responsible for approximately 300,000 Lyme disease (LD) cases per year in the United States. Recent increases in the number of LD cases, in addition to the spread of the tick vector and a lack of a vaccine, highlight an urgent need for designing and developing an efficacious LD vaccine. Identification of protective epitopes that could be used to develop a second-generation (subunit) vaccine is therefore imperative. Despite the antigenicity of several lipoproteins and integral outer membrane proteins (OMPs) on the B. burgdorferi surface, the spirochetes successfully evade antibodies primarily due to the VlsE-mediated antigenic variation. VlsE is thought to sterically block antibody access to protective epitopes of B. burgdorferi. However, it is highly unlikely that VlsE shields the entire surface epitome. Thus, identification of subdominant epitope targets that induce protection when they are made dominant is necessary to generate an efficacious vaccine. Toward the identification, we repeatedly immunized immunocompetent mice with live-attenuated VlsE-deleted B. burgdorferi and then challenged the animals with the VlsE-expressing (host-adapted) wild type. Passive immunization and Western blotting data suggested that the protection of 50% of repeatedly immunized animals against the highly immune-evasive B. burgdorferi was antibody mediated. Comparison of serum antibody repertoires identified in protected and nonprotected animals permitted the identification of several putative epitopes significantly associated with the protection. Most linear putative epitopes were conserved between the main pathogenic Borrelia genospecies and found within known subdominant regions of OMPs. Currently, we are performing immunization studies to test whether the identified protection-associated epitopes are protective for mice.
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Genetic determinants of the development and course of membranous nephropathy
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01.01.2018 |
Kamyshova E.
Bobkova I.
Gorelova I.
Êàkhsurueva P.
Filatova E.
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Terapevticheskii Arkhiv |
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0 |
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© 2018 Media Sphera Publishing Group. All rights reserved. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and is classified as either primary (idiopatic) or secondary MN according to underlying etiology (the later result from some known disease such as systemic autoimmune diseases, infections, malignancies, drugs, etc). In recent years, phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as two major podocytic antigens involved in the pathogenesis of idiopatic MN (IMN). And the discovery of circulating antibodies specific for these target antigens has transformed the diagnostic workup and significally improved management of IMN. However why do such antibodies develop is not conclusively established. The role of underlying genetic factors is discussed. The review presents the results of recent studies, that have shown significant associations of specific genetic factors (particularly human leucocyte antigen class II and PLA2R1 genes) with IMN.
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Immune checkpoint inhibition and autoimmunity: Rheumatological problems
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01.01.2018 |
Nasonov E.
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Nauchno-Prakticheskaya Revmatologiya |
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1 |
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The paper deals with the mechanisms of a T-cell immune response, which depends on the balance between costimula-tory and coinhibitory signals that have been called as immune checkpoints (ICP). The imbalance of T-cell activation within ICTs (CTLA4/CD28 and PD1/PD1L) is considered to be a fundamental mechanism not only of autoimmune disease, but also impaired antitumor immunity underlying the development of malignant tumors. The use of monoclonal antibodies against negative regulatory ICTs (CTLA4, PD1, and PD1L) is a major achievement in the treatment of malignant neoplasms in the early 21st century. However, since CTLA4 and PD1 control the activation of auto-reactive T cells, the inhibition of these ICTs is associated with the development of autoimmune disease that is defined as immune-mediated adverse even. The paper considers the clinical manifestations of IMAR, primarily rheumatic ones and discusses the prospects of pharmacotherapy from the standpoint of achievements of modern rheumatology.
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