Synergistic adaptive mutations in the hemagglutinin and polymerase acidic protein lead to increased virulence of pandemic 2009 H1N1 influenza A virus in mice.

Influenza impressively reflects the paradigm of a viral disease in which continued evolution of the virus is of paramount importance for annual epidemics and occasional pandemics in humans. Because of the continuous threat of novel influenza outbreaks, it is essential to gather further knowledge about viral pathogenicity determinants. Here, we explored the adaptive potential of the influenza A virus subtype H1N1 variant isolate A/Hamburg/04/09 (HH/04) by sequential passaging in mice lungs.

Improvement of H5N1 influenza vaccine viruses: influence of internal gene segments of avian and human origin on production and hemagglutinin content.

The H5N1-clade 1 influenza vaccine strain NIBRG-14 produces exceptionally low amounts of antigen, a problem recently encountered also for initial pandemic H1N1-2009 vaccine seeds. Here, we report on a strategy that may contribute to overcome this obstacle. Influenza vaccine viruses usually consist of two segments coding for the antigenic HA and NA proteins of a wild-type strain and the six residual internal gene segments of the vaccine donor strain A/PR/8/34 (PR8).

Measles virus modulates chemokine release and chemotactic responses of dendritic cells.

Interference with dendritic cell (DC) maturation and function is considered to be central to measles virus (MV)-induced immunosuppression. Temporally ordered production of chemokines and switches in chemokine receptor expression are essential for pathogen-driven DC maturation as they are prerequisites for chemotaxis and T cell recruitment. We found that MV infection of immature monocyte-derived DCs induced transcripts specific for CCL-1, -2, -3, -5, -17 and -22, CXCL-10 and CXCL-11, yet did not induce CXCL-8 (interleukin-8) and CCL-20 at the mRNA and protein level.

Sabotage of antiviral signaling and effectors by influenza viruses.

Vertebrate cells activate multiple signaling modules upon virus infection to eliminate the invading pathogen and to prevent the establishment of a persistent infection. A major immediate response pathway is controlled by the RNA helicases RIG-I and MDA5, which, after recognition of viral nucleic acids, signal induction of the interferon (IFN)-alpha/beta cytokine family that upregulates numerous antiviral effector proteins. Virulent viruses, in contrast, have learned during co-evolution with their hosts to manipulate or avoid this response in order to prevail in a repulsive environment.

Measles virus targets DC-SIGN to enhance dendritic cell infection.

Dendritic cells (DCs) are involved in the pathogenesis of measles virus (MV) infection by inducing immune suppression and possibly spreading the virus from the respiratory tract to lymphatic tissues. It is becoming evident that DC function can be modulated by the involvement of different receptors in pathogen interaction. Therefore, we have investigated the relative contributions of different MV-specific receptors on DCs to MV uptake into and infection of these cells.

Impact of measles virus dendritic-cell infection on Th-cell polarization in vitro.

Interference of measles virus (MV) with dendritic-cell (DC) functions and deregulation of T-cell differentiation have been proposed to be central to the profound suppression of immune responses to secondary infections up to several weeks after the acute disease. To address the impact of MV infection on the ability of DCs to promote Th-cell differentiation, an in vitro system was used where uninfected, tumour necrosis factor alpha/interleukin (IL) 1 beta-primed DCs were co-cultured with CD45RO(-) T cells in the presence of conditioned media from MV-infected DCs primed under neutral or DC-polarizing conditions. It was found that supernatants of DCs infected with an MV vaccine strain strongly promoted Th1 differentation, whereas those obtained from wild-type MV-infected DCs generated a mixed Th1/Th0 response, irrespective of the conditions used for DC priming.