37 research outputs found
Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells
Background: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. Methods and Findings: Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. Conclusions: The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM+ memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens
ΠΠΈΠ½Π΅ΡΠΈΠΊΠ° Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΈΡ ΠΆΠ΅Π»Π΅Π·Π° ΠΏΡΠΈ Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²ΠΈΡΠ΅Π»ΡΠ½ΠΎΠΉ ΠΏΠ»Π°Π²ΠΊΠ΅ ΡΡΠ΄ΠΎΡΠ³ΠΎΠ»ΡΠ½ΡΡ ΠΎΠΊΠ°ΡΡΡΠ΅ΠΉ
ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΎ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΠΈΠ½ΡΠ΅Π½ΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΠ΅Π½Π° Π½Π° ΠΊΠΈΠ½Π΅ΡΠΈΠΊΡ Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΈΡ ΠΆΠ΅Π»Π΅Π·Π° Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΏΠ»Π°Π²ΠΊΠΈ ΡΡΠ΄ΠΎΡΠ³ΠΎΠ»ΡΠ½ΡΡ
ΠΎΠΊΠ°ΡΡΡΠ΅ΠΉ. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ Ρ ΡΠΎΡΡΠΎΠΌ ΠΈΠ½ΡΠ΅Π½ΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΠ΅Π½Π° ΠΏΠΎΠ²ΡΡΠ°Π΅ΡΡΡ ΡΠΊΠΎΡΠΎΡΡΡ Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²ΠΈΡΠ΅Π»ΡΠ½ΡΡ
ΠΏΡΠΎΡΠ΅ΡΡΠΎΠ². ΠΡΠ»Π΅Π΄ΡΡΠ²ΠΈΠ΅ ΡΠΎΡΡΠ° ΠΊΠΎΡΡΡΠΈΡΠΈΠ΅Π½ΡΠ° ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΠ΅Π½Π° ΡΠ²Π΅Π»ΠΈΡΠΈΠ²Π°Π΅ΡΡΡ Π³Π»ΡΠ±ΠΈΠ½Π° Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½Π½ΠΎΠ³ΠΎ ΡΠ»ΠΎΡ ΠΎΠΊΠ°ΡΡΡΠ°, ΡΡΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎ ΠΈΠ·ΠΌΠ΅Π½ΡΡΡΡΡ Π΅Π³ΠΎ ΡΡΡΡΠΊΡΡΡΠ° ΠΈ Ρ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΈΠΉ ΡΠΎΡΡΠ°Π² ΠΎΠ±ΡΠ°Π·ΡΡΡΠ΅ΠΉΡΡ ΠΌΠ΅ΡΠ°Π»Π»ΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΠ°Π·Ρ.ΠΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½ΠΎ Π²ΠΏΠ»ΠΈΠ² ΡΠ½ΡΠ΅Π½ΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΡΠ½Ρ Π½Π° ΠΊΡΠ½Π΅ΡΠΈΠΊΡ Π²ΡΠ΄Π½ΠΎΠ²Π»Π΅Π½Π½Ρ Π·Π°Π»ΡΠ·Π° Π² ΠΏΡΠΎΡΠ΅ΡΡ ΠΏΠ»Π°Π²ΠΊΠΈ ΡΡΠ΄ΠΎΠ²ΡΠ³ΡΠ»ΡΠ½ΠΈΡ
ΠΎΠΊΠ°ΡΠΈΡΡΠ². ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΠΎ ΠΏΡΠΈ Π·ΡΠΎΡΡΠ°Π½Π½Ρ ΡΠ½ΡΠ΅Π½ΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΡΠ½Ρ ΠΏΡΠ΄Π²ΠΈΡΡΡΡΡΡΡ ΡΠ²ΠΈΠ΄ΠΊΡΡΡΡ Π²ΡΠ΄Π½ΠΎΠ²Π»ΡΠ²Π°Π»ΡΠ½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΡΠ². ΠΠ½Π°ΡΠ»ΡΠ΄ΠΎΠΊ Π·ΡΠΎΡΡΠ°Π½Π½Ρ ΠΊΠΎΠ΅ΡΡΡΡΡΠ½ΡΡ ΡΠ΅ΠΏΠ»ΠΎΠΎΠ±ΠΌΡΠ½Ρ Π·Π±ΡΠ»ΡΡΡΡΡΡΡΡ Π³Π»ΠΈΠ±ΠΈΠ½Π° Π²ΡΠ΄Π½ΠΎΠ²Π»Π΅Π½ΠΎΠ³ΠΎ ΡΠ°ΡΡ ΠΎΠΊΠ°ΡΠΈΡΠ°, ΡΡΡΡΡΠ²ΠΎ Π·ΠΌΡΠ½ΡΡΡΡΡΡ ΠΉΠΎΠ³ΠΎ ΡΡΡΡΠΊΡΡΡΠ° ΡΠ° Ρ
ΡΠΌΡΡΠ½ΠΈΠΉ ΡΠΊΠ»Π°Π΄ ΠΌΠ΅ΡΠ°Π»Π΅Π²ΠΎΡ ΡΠ°Π·ΠΈ, ΡΠΎ ΡΡΠ²ΠΎΡΡΡΡΡΡΡ.Influence of intensity of heat exchange is investigational on kinetics reduction of iron in the process of melting ore-coal pellets. It is rotined that speed of reduction processes rises with growth of intensity of heat exchange. Because of growth of coefficient of heat exchange the depth of the recovered layer of pellet is increased, his structure and chemical composition of appearing metallic phase changes substantially
Computational Identification of Transcriptional Regulators in Human Endotoxemia
One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model. Given a high-dimensional transcriptional profiling dataset from human blood leukocytes, an elementary set of temporal dynamic responses which capture the essence of a pro-inflammatory phase, a counter-regulatory response and a dysregulation in leukocyte bioenergetics has been extracted. Upon identification of these expression patterns, fourteen inflammation-specific gene batteries that represent groups of hypothetically βcoregulatedβ genes are proposed. Subsequently, statistically significant cis-regulatory modules (CRMs) are identified and decomposed into a list of critical transcription factors (34) that are validated largely on primary literature. Finally, our analysis further allows for the construction of a dynamic representation of the temporal transcriptional regulatory program across the host, deciphering possible combinatorial interactions among factors under which they might be active. Although much remains to be explored, this study has computationally identified key transcription factors and proposed a putative time-dependent transcriptional regulatory program associated with critical transcriptional inflammatory responses. These results provide a solid foundation for future investigations to elucidate the underlying transcriptional regulatory mechanisms under the host inflammatory response. Also, the assumption that coexpressed genes that are functionally relevant are more likely to share some common transcriptional regulatory mechanism seems to be promising, making the proposed framework become essential in unravelling context-specific transcriptional regulatory interactions underlying diverse mammalian biological processes