Antiviral Response in Pandemic Influenza Viruses

The regulatory activities of the nonstructural protein 1 appear to affect the ability of influenza viruses to infect multiple animal species

Antibodies targeting epitopes on the cell-surface form of NS1 protect against Zika virus infection during pregnancy

Zika virus is an arthropod-transmitted flavivirus that can cause microcephaly and other fetal abnormalities during pregnancy. Here Wessel et al. develop antibodies against the Zika virus nonstructural protein 1 that protect non-pregnant and pregnant mice against infection, and define particular antibody epitopes and mechanisms underlying this protection

Rotavirus NSP1 contributes to intestinal viral replication, pathogenesis, and transmission

Rotavirus (RV)-encoded nonstructural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of the simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infectio

Cluster analysis of the origins of the new influenza A(H1N1) virus

In March and April 2009, a new strain of influenza A(H1N1) virus has been isolated in Mexico and the United States. Since the initial reports more than 10,000 cases have been reported to the World Health Organization, all around the world. Several hundred isolates have already been sequenced and deposited in public databases. We have studied the genetics of the new strain and identified its closest relatives through a cluster analysis approach. We show that the new virus combines genetic information related to different swine influenza viruses. Segments PB2, PB1, PA, HA, NP and NS are related to swine H1N2 and H3N2 influenza viruses isolated in North America. Segments NA and M are related to swine influenza viruses isolated in Eurasia

Expression of influenza virus nonstructural protein 1 (NS1)

Avian influenza poses a threat to many species including man, as shown by the current scenario in Southeast Asia. It appears that this particular type of influenza virus can spread to many species causing severe disease in these new species. For example, from 258 human cases 154 were fatal (WHO, 2006-11-29). Why some avian influenza virus have the ability to infect other species remains to be understood. One viral gene, coding for the non-structural protein 1 (NS1), appears to be an important factor for successfully transmission into a new host, by counteracting the new host’s immune system. The exact mechanism of action of NS1 is still unclear, but leads to down-regulation of various pathways of the immune defence. The aim of this study was to express NS1 proteins of influenza viruses originating from different hosts, including highly pathogenic avian influenza viruses, for use in investigations on the mechanism used by NS1 to interfere with the immune system of various hosts. In particular, studies on the interaction of NS1 with the RNA dependent protein kinase (PKR) were initiated, to determine differences in this interaction between high and low pathogenic influenza viruses from different hosts. By establishing tools and optimised assays, the work enables further studies on the role NS1 in immune evasion

Análise molecular dos vírus dengue tipo 1 e 2 no Brasil, baseada nas seqüências da região da junção dos genes do envelope e da proteína não estrutural 1

The genomic sequences of the Envelope-Non-Structural protein 1 junction region (E/NS1) of 84 DEN-1 and 22 DEN-2 isolates from Brazil were determined. Most of these strains were isolated in the period from 1995 to 2001 in endemic and regions of recent dengue transmission in São Paulo State. Sequence data for DEN-1 and DEN-2 utilized in phylogenetic and split decomposition analyses also include sequences deposited in GenBank from different regions of Brazil and of the world. Phylogenetic analyses were done using both maximum likelihood and Bayesian approaches. Results for both DEN-1 and DEN-2 data are ambiguous, and support for most tree bipartitions are generally poor, suggesting that E/NS1 region does not contain enough information for recovering phylogenetic relationships among DEN-1 and DEN-2 sequences used in this study. The network graph generated in the split decomposition analysis of DEN-1 does not show evidence of grouping sequences according to country, region and clades. While the network for DEN-2 also shows ambiguities among DEN-2 sequences, it suggests that Brazilian sequences may belong to distinct subtypes of genotype III.Foram determinadas as seqüências nucleotídicas da junção dos genes do envelope e da proteína não estrutural 1 (E/NS1) de 84 cepas de DEN-1 e 22 cepas de DEN-2 do Brasil. A maioria dessas cepas foi isolada no período de 1995-2001, em regiões endêmicas e de transmissão recente no Estado de São Paulo. Seqüências da junção E/NS1 de DEN-1 e DEN-2 de outras regiões geográficas brasileiras e mundiais, obtidas do GenBank, foram também utilizadas neste estudo. As análises foram efetuadas utilizando-se as técnicas de Verossimilhança Máxima e Bayesiana de inferência filogenética. Os resultados das análises das seqüências de DEN-1 e DEN-2 são ambíguos e o suporte para a maioria dos grupos é baixo, sugerindo que a região E/NS1 não é filogeneticamente informativa. O gráfico gerado na análise de decomposição dos grupos de DEN-1 não mostrou evidências de agrupamento das seqüências de acordo com os países, as regiões ou clados. No entanto, para DEN-2 evidenciou a existência de ambigüidades entre as seqüências, sugerindo que as brasileiras pertencem a subtipos distintos do genotipo III

The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker

The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first reported in 1970 as a viral antigen circulating in the sera of dengue-infected patients. All flavivirus NS1 genes share a high degree of homology, encoding a 352-amino-acid polypeptide that has a molecular weight of 46-55. kDa, depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found in different cellular locations: a cell membrane-bound form in association with virus-induced intracellular vesicular compartments, on the cell surface and as a soluble secreted hexameric lipoparticle. Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays an essential cofactor role in replication. Although this makes NS1 an ideal target for inhibitor design, the precise nature of its cofactor function has yet to be elucidated. A plethora of potential interacting partners have been identified, particularly for the secreted form of NS1, with many being implicated in immune evasion strategies. Secreted and cell-surface-associated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host. Finally, NS1 is also an important biomarker for early diagnosis of disease. In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40. years of study of this fascinating protein

Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

<p>Abstract</p> <p>Background</p> <p>The nonstructural protein 1 (NSP1) of rotavirus has been reported to block interferon (IFN) signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs) and (or) the β-transducin repeat containing protein (β-TrCP). However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms.</p> <p>Results</p> <p>The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s) other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I), but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS), indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way.</p> <p>Conclusions</p> <p>Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.</p

A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Non-Structural Protein 1

ABSTRACT Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signaling and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) nonstructural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a three-dimensional (3D) microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue and thus show that pericytes can play a critical role in the etiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue. IMPORTANCE The World Health Organization considers dengue one of the top 10 global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signaling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue and potentially other infectious vascular leakage syndromes