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Hamburg, Germany

Gabriel G.,Heinrich Pette Institute | Arck P.C.,University of Hamburg
Journal of Infectious Diseases | Year: 2014

Sex-specific endocrine and immune responses are widely recognized to account for differential disease outcomes between females and males. Surprisingly, sex-specific risk assessments for influenza, a viral pathogen that affects human populations worldwide through seasonal epidemics and irregular occurring pandemics, are sparse and - if available - ambiguous. To date, this precludes proposing an unequivocal sex-dependent susceptibility to influenza. However, one undisputable observation recurrently confirmed during influenza seasons of the last decades is the significantly increased risk for pregnant women. This increased risk is likely attributable to the contradictory demands for the maternal immune system to adapt to pregnancy and to simultaneously mount an immune response to clear the influenza virus infection. Here, we review published evidence on the potential association between sex on influenza risk and propose that future epidemiologic studies should carefully dissect surveillance data for sex-specific effects. Moreover, we propose potential mechanisms involved in enhanced risk for severe influenza during pregnancy that could be studied to identify causal pathways. © 2014 The Author.


Altfeld M.,Heinrich Pette Institute | Gale M.,University of Washington
Nature Immunology | Year: 2015

During acute HIV-1 infection, viral pathogen-associated molecular patterns are recognized by pathogen-recognition receptors (PRRs) of infected cells, which triggers a signaling cascade that initiates innate intracellular antiviral defenses aimed at restricting the replication and spread of the virus. This cell-intrinsic response propagates outward via the action of secreted factors such as cytokines and chemokines that activate innate immune cells and attract them to the site of infection and to local lymphatic tissue. Antiviral innate effector cells can subsequently contribute to the control of viremia and modulate the quality of the adaptive immune response to HIV-1. The concerted actions of PRR signaling, specific viral-restriction factors, innate immune cells, innate-adaptive immune crosstalk and viral evasion strategies determine the outcome of HIV-1 infection and immune responses.


Brune W.,Heinrich Pette Institute
Virus Research | Year: 2011

The elimination of infected cells by programmed cell death (PCD) is one of the most ancestral defense mechanisms against infectious agents. This mechanism should be most effective against intracellular parasites, such as viruses, which depend on the host cell for their replication. However, even large and slowly replicating viruses like the cytomegaloviruses (CMVs) can prevail and persist in face of cellular suicide programs and other innate defense mechanisms. During evolution, these viruses have developed an impressive set of countermeasures against premature demise of the host cell. In the last decade, several genes encoding suppressors of apoptosis and necrosis have been identified in the genomes of human and murine CMV (HCMV and MCMV). Curiously, most of the gene products are not homologous to cellular antiapoptotic proteins, suggesting that the CMVs did not capture the genes from the host cell genome. This review summarizes our current understanding of how the CMVs suppress PCD and which signaling pathways they target. © 2010 Elsevier B.V.


Gabriel G.,Heinrich Pette Institute | Czudai-Matwich V.,University of Marburg | Klenk H.-D.,University of Marburg
Virus Research | Year: 2013

Adaptation of the viral polymerase to host factors plays an important role in interspecies transmission of H5N1 viruses. Several adaptive mutations have been identified that, in general, determine not only host range, but also pathogenicity and transmissibility of the virus. The available evidence indicates that most of these mutations are found in the PB2 subunit of the polymerase. Particularly prominent mutations are located in the C-terminal domain of PB2 involving the amino acid exchanges E627K and D701N. Both mutations, that are also responsible for the adaptation of other avian viruses to mammalian hosts, have been described in human H5N1 isolates. In animal models, it could be demonstrated that they enhance pathogenicity in mice and induce contact transmission in guinea pigs. Mutation E627K has also been identified as a determinant of air-borne H5N1 transmission in ferrets. We are only beginning to understand the underlying mechanisms at the molecular level. Thus, mutation D701N promotes importin-α mediated nuclear transport in mammalian cells. Mutation E627K also enhances the replication rate in an importin-α dependent fashion in mammalian cells, yet without affecting nuclear entry of PB2. Numerous other adaptive mutations, some of which compensate for the lack of PB2 E627K, have been observed in PB2 as well as in the polymerase subunit PB1, the nucleoprotein NP, and the nuclear export protein NEP (NS2). © 2013 Elsevier B.V.


Niebuhr B.,Heinrich Pette Institute
Blood | Year: 2013

The t(12;21) chromosomal translocation, targeting the gene encoding the RUNX1 transcription factor, is observed in 25% of pediatric acute lymphoblastic leukemia (ALL) and is an initiating event in the disease. To elucidate the mechanism by which RUNX1 disruption initiates leukemogenesis, we investigated its normal role in murine B-cell development. This study revealed 2 critical functions of Runx1: (1) to promote survival and development of progenitors specified to the B-cell lineage, a function that can be substituted by ectopic Bcl2 expression, and (2) to enable the developmental transition through the pre-B stage triggered by the pre-B-cell antigen receptor (pre-BCR). Gene expression analysis and genomewide Runx1 occupancy studies support the hypothesis that Runx1 reinforces the transcription factor network governing early B-cell survival and development and specifically regulates genes encoding members of the Lyn kinase subfamily (key integrators of interleukin-7 and pre-BCR signaling) and the stage-specific transcription factors SpiB and Aiolos (critical downstream effectors of pre-BCR signaling). Interrogation of expression databases of 257 ALL samples demonstrated the specific down-regulation of the SPIB and IKZF3 genes (the latter encoding AIOLOS) in t(12;21) ALL, providing novel insight into the mechanism by which the translocation blocks B-cell development and promotes leukemia.

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