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ABSTRACT: Astroviruses are small, nonenveloped, single-stranded RNA viruses that cause diarrhea in a wide variety of mammals and birds. On the surface of the viral capsid are globular spikes that are thought to be involved in attachment to host cells. To understand the basis of species-specificity, we investigated the structure of an avian astrovirus capsid spike and compared it to a previously-reported human astrovirus capsid spike structure. Here we report the crystal structure of the turkey astrovirus-2 (TAstV-2) capsid surface spike domain determined to 1.5 Å resolution and identify three conserved patches on the surface of the spike that are candidate avian receptor-binding sites. Surprisingly, the overall TAstV-2 capsid spike structure is unique, with only distant structural similarities to the human astrovirus capsid spike and other viral capsid spikes. There is an absence of conserved, putative receptor-binding site residues between the human and avian spikes. However, there is evidence for carbohydrate-binding sites in both human and avian spikes, and studies with the human astrovirus-1 (HAstV-1) suggest a minor role for chondroitin sulfate but not heparin in infection. Overall, our structural and functional studies provide new insights into astrovirus host cell entry, species-specificity, and evolution.
Journal of Virology 05/2013; · 5.40 Impact Factor
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Ron A M Fouchier,
Adolfo García-Sastre,
Yoshihiro Kawaoka,
Wendy S Barclay,
Nicole M Bouvier,
Ian H Brown,
Ilaria Capua,
Hualan Chen,
Richard W Compans,
Robert B Couch, [......],
Kanta Subbarao,
David E Swayne,
Toru Takimoto,
Masato Tashiro,
Jeffery K Taubenberger,
Paul G Thomas,
Ralph A Tripp,
Terrence M Tumpey,
Richard J Webby,
Robert G Webster
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ABSTRACT: In January 2012, influenza virus researchers from around the world announced a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. Now that the aims of the voluntary moratorium have been met in some countries and are close to being met in others, we declare an end to the voluntary moratorium on avian flu transmission studies.
Science 01/2013; · 31.20 Impact Factor
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ABSTRACT: Macrophages are known to be one of the first lines of defense against influenza virus infection. However, they may also contribute to severe disease caused by the highly pathogenic avian (HPAI) H5N1 influenza viruses. One reason for this may be the ability of certain influenza virus strains to productively replicate in macrophages. However, studies investigating the productive replication of influenza viruses in macrophages have been contradictory and results may depend on both the type of macrophages used and the specific viral strain. In this work, we investigated the ability of H1-H16 viruses to productively replicate in primary murine alveolar macrophages and RAW264.7 macrophages. We show that only a subset of HPAI H5N1 viruses, those that cause high morbidity and mortality in mammals, can productively replicate in macrophages, as measured by the release of newly synthesized virus particles into the cell supernatant. Mechanistically, we found that these H5 strains can overcome a block early in the viral lifecycle leading to efficient nuclear entry, viral transcription, translation, and ultimately replication. Studies with reassortant viruses demonstrated that expression of the hemagglutinin gene from an H5N1 virus rescued replication of H1N1 influenza virus in macrophages. This study is the first to characterize H5N1 influenza viruses as the only subtype of influenza virus capable of productive replication in macrophages and establishes the viral gene that is required for this characteristic. The ability to productively replicate in macrophages is unique to H5N1 influenza viruses and may contribute to their increased pathogenesis.
Journal of Virology 11/2012; · 5.40 Impact Factor
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Leticia Elizondo-Montemayor,
Martín Hernández-Torre,
Patricia A Ugalde-Casas,
Jesús Santos-Guzmán,
Mónica Serrano-González,
Norma G Gutiérrez,
Lorena Lam-Franco,
Daniela Tamargo-Barrera,
Ubaldo Martínez,
Humberto Bustamante-Careaga,
Mario M Alvarez, Stacey Schultz-Cherry
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ABSTRACT: Clinical features of pandemic H1N1 have been derived from lab-confirmed, hospitalized, or critically ill subjects. This report describes the clinical features of H1N1 and their prevalence from non-confirmed subjects according to seroprevalence status in México. The objective was to determine the prevalence of these clinical features from non-confirmed cases of pandemic H1N1 and to compare them according to seroprevalence status in northern Monterrey, México, during 2009, and to identify the predictive signs and symptoms; there have been no prior serologic studies in México.
During November-December 2009, 2,222 volunteers, ages 6-99 years, were categorized into 3 symptomatic groups: influenza-like illness, respiratory illness, and non-respiratory illness. Antibodies against influenza A/H1N1/2009 were determined by a virus-free enzyme-linked immunosorbent assay (ELISA) method. Demographics and clinical presentation were assessed through face-to-face questionnaire, and the association with seroprevalence status was determined and compared.
Overall seroprevalence was 39%. Of the seropositive subjects, 67% were symptomatic and 33% were asymptomatic. Seventy-one percent of seropositive symptomatic subjects reported respiratory illness, 17% reported non-respiratory symptoms, and 12% reported influenza-like illness. The most common symptoms were rhinorrhea/nasal congestion (93%) and headache (83%). No significant difference was found between the symptom profiles of the seropositive group, compared to the seronegative one, nor of the median duration of symptoms. The seropositive group had a significantly elevated proportion of influenza-like illness (12%), compared to the seronegative group (8%). The proportion of subjects who took days off and who sought medical attention was significantly higher in the seropositive group. No single symptom was associated as a predictor of seropositiveness.
One third of the seropositive subjects were asymptomatic, and few had an influenza-like illness. No difference was found in the symptom profiles of the seropositive and seronegative groups. No single symptom predicted seropositiveness. Large scale population studies are needed, especially in México, to characterize clinical syndromes.
Respiratory care 03/2012; 57(10):1586-93. · 2.01 Impact Factor
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ABSTRACT: Please cite this paper as: Karlsson et al. (2012) Review on the impact of pregnancy and obesity on influenza virus infection. Influenza and Other Respiratory Viruses 6(6), 449-460. A myriad of risk factors have been linked to an increase in the severity of the pandemic H1N1 2009 influenza A virus [A(H1N1)pdm09] including pregnancy and obesity where death rates can be elevated as compared to the general population. The goal of this review is to provide an overview of the influence of pregnancy and obesity on the reported cases of A(H1N1)pdm09 virus infection and of how the concurrent presence of these factors may have an exacerbating effect on infection outcome. Also, the hypothesized immunologic mechanisms that contribute to A(H1N1)pdm09 virus severity during pregnant or obese states are outlined. Identifying the mechanisms underlying the increased disease severity in these populations may result in improved therapeutic approaches and future pandemic preparedness.
Influenza and Other Respiratory Viruses 02/2012; 6(6):449-60. · 4.16 Impact Factor
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Ron A M Fouchier,
Adolfo García-Sastre,
Yoshihiro Kawaoka,
Wendy S Barclay,
Nicole M Bouvier,
Ian H Brown,
Ilaria Capua,
Hualan Chen,
Richard W Compans,
Robert B Couch, [......],
Kanta Subbarao,
David E Swayne,
Toru Takimoto,
Masato Tashiro,
Jeffery K Taubenberger,
Paul G Thomas,
Ralph A Tripp,
Terrence M Tumpey,
Richard J Webby,
Robert G Webster
Science 01/2012; 335(6067):400-1. · 31.20 Impact Factor
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ABSTRACT: For the first time, obesity appeared as a risk factor for developing severe 2009 pandemic influenza infection. Given the increase in obesity, there is a need to understand the mechanisms underlying poor outcomes in this population. In these studies, we examined the severity of pandemic influenza virus in obese mice and evaluated antiviral effectiveness. We found that genetically and diet-induced obese mice challenged with either 2009 influenza A virus subtype H1N1 or 1968 subtype H3N2 strains were more likely to have increased mortality and lung pathology associated with impaired wound repair and subsequent pulmonary edema. Antiviral treatment with oseltamivir enhanced survival of obese mice. Overall, these studies demonstrate that impaired wound lung repair in the lungs of obese animals may result in severe influenza virus infection. Alternative approaches to prevention and control of influenza may be needed in the setting of obesity.
The Journal of Infectious Diseases 12/2011; 205(2):252-61. · 6.41 Impact Factor
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ABSTRACT: A novel H1N1 influenza virus emerged in 2009 (pH1N1) to become the first influenza pandemic of the 21st century. This virus is now cocirculating with highly pathogenic H5N1 avian influenza viruses in many parts of the world, raising concerns that a reassortment event may lead to highly pathogenic influenza strains with the capacity to infect humans more readily and cause severe disease. To investigate the virulence of pH1N1-H5N1 reassortant viruses, we created pH1N1 (A/California/04/2009) viruses expressing individual genes from an avian H5N1 influenza strain (A/Hong Kong/483/1997). Using several in vitro models of virus replication, we observed increased replication for a reassortant CA/09 virus expressing the hemagglutinin (HA) gene of HK/483 (CA/09-483HA) relative to that of either parental CA/09 virus or reassortant CA/09 expressing other HK/483 genes. This increased replication correlated with enhanced pathogenicity in infected mice similar to that of the parental HK/483 strain. The serial passage of the CA/09 parental virus and the CA/09-483HA virus through primary human lung epithelial cells resulted in increased pathogenicity, suggesting that these viruses easily adapt to humans and become more virulent. In contrast, serial passage attenuated the parental HK/483 virus in vitro and resulted in slightly reduced morbidity in vivo, suggesting that sustained replication in humans attenuates H5N1 avian influenza viruses. Taken together, these data suggest that reassortment between cocirculating human pH1N1 and avian H5N1 influenza strains will result in a virus with the potential for increased pathogenicity in mammals.
Journal of Virology 09/2011; 85(23):12262-70. · 5.40 Impact Factor
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ABSTRACT: Outbreaks of influenza A viruses are associated with significant human morbidity worldwide. Given the increasing resistance to the available influenza drugs, new therapies for the treatment of influenza virus infection are needed. An alternative approach is to identify products that enhance a protective immune response. In these studies, we demonstrate that infecting mice with the Th1-inducing parasite Toxoplasma gondii prior to highly pathogenic avian H5N1 influenza virus infection led to decreased lung viral titers and enhanced survival. A noninfectious fraction of T. gondii soluble antigens (STAg) elicited an immune response similar to that elicited by live parasites, and administration of STAg 2 days after H5N1 influenza virus infection enhanced survival, lowered viral titers, and reduced clinical disease. STAg administration protected H5N1 virus-infected mice lacking lymphocytes, suggesting that while the adaptive immune response was not required for enhanced survival, it was necessary for STAg-mediated viral clearance. Mechanistically, we found that administration of STAg led to increased production of gamma interferon (IFN-γ) from natural killer (NK) cells, which were both necessary and sufficient for survival. Further, administration of exogenous IFN-γ alone enhanced survival from H5N1 influenza virus infection, although not to the same level as STAg treatment. These studies demonstrate that a noninfectious T. gondii extract enhances the protective immune response against severe H5N1 influenza virus infections even when a single dose is administered 2 days postinfection.
Journal of Virology 09/2011; 85(17):8680-8. · 5.40 Impact Factor
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Leticia Elizondo-Montemayor,
Mario M Alvarez,
Martín Hernández-Torre,
Patricia A Ugalde-Casas,
Lorena Lam-Franco,
Humberto Bustamante-Careaga,
Fernando Castilleja-Leal,
Julio Contreras-Castillo,
Héctor Moreno-Sánchez,
Daniela Tamargo-Barrera,
Felipe López-Pacheco,
Pamela J Freiden, Stacey Schultz-Cherry
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ABSTRACT: No serological studies have been performed in Mexico to assess the seroprevalence of influenza A/H1N1/2009 in groups of people according to the potential risk of transmission. The aim of this study was to determine the seroprevalence of antibodies against influenza A/H1N1/2009 in subjects in Mexico grouped by risk of transmission.
Two thousand two hundred and twenty-two subjects were categorized into one of five occupation groups according to the potential risk of transmission: (1) students, (2) teachers, (3) healthcare workers, (4) institutional home residents aged >60 years, and (5) general population. Seroprevalence by potential transmission group and by age grouped into decades was determined by a virus-free ELISA method based on the recombinant receptor-binding domain of the hemagglutinin of influenza A/H1N1/2009 virus as antigen (85% sensitivity; 95% specificity). The Wilson score, Chi-square test, and logistic regression models were used for the statistical analyses.
Seroprevalence for students was 47.3%, for teachers was 33.9%, for older adults was 36.5%, and for the general population was 33.0%, however it was only 24.6% for healthcare workers (p=0.011). Of the students, 56.6% of those at middle school, 56.4% of those at high school, 52.7% of those at elementary school, and 31.1% of college students showed positive antibodies (p<0.001). Seroprevalence was 44.6% for college teachers, 31.6% for middle school teachers, and 29.8% for elementary school teachers, but was only 20.3% for high school teachers (p=0.002).
The student group was the group most affected by influenza A/H1N1/2009, while the healthcare worker group showed the lowest prevalence. Students represent a key target for preventive measures.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 08/2011; 15(11):e781-6. · 2.17 Impact Factor
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ABSTRACT: Given the poor immunogenicity of current H5N1 influenza vaccines, additives and adjuvants remain a viable solution for increasing efficacy. Here, we demonstrate that a 20-amino acid peptide (EB) possessing influenza antiviral activity also enhances the immune response to H5N1 vaccination in mice. The addition of EB to formalin-inactivated whole-virus vaccine induced virion aggregation and these aggregates were readily engulfed by phagocytic cells in vitro. In vivo, mice vaccinated with a suboptimal dose of inactivated vaccine containing EB peptide had reduced morbidity, improved viral clearance, and faster recovery than mice receiving vaccine alone. This phenomenon was not accompanied by an increase in virus-specific antibodies. Instead, cell-mediated immunity was enhanced as demonstrated by increased interferon-γ production from splenocytes. This data demonstrates that the EB peptide may a useful adjuvant for boosting the efficacy of poorly immunogenic influenza vaccines.
Vaccine 08/2011; 29(44):7696-703. · 3.77 Impact Factor
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ABSTRACT: Highly pathogenic H5N1 influenza infections are associated with enhanced inflammatory and cytokine responses, severe lung damage, and an overall dysregulation of innate immunity. C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. However, the role of this protein in the pathogenesis of H5N1 infection is unknown. Here we demonstrate that H5N1 influenza virus infected mice had increased levels of C5a and C3 activation byproducts as compared to mice infected with either seasonal or pandemic 2009 H1N1 influenza viruses. We hypothesized that the increased complement was associated with the enhanced disease associated with the H5N1 infection. However, studies in knockout mice demonstrated that C3 was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. These studies suggest that although the levels of complement activation may differ depending on the influenza virus subtype, complement is an important host defense mechanism.
PLoS ONE 01/2011; 6(3):e17377. · 4.09 Impact Factor
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ABSTRACT: The antiviral peptide, entry blocker (EB), inhibits influenza virus replication by preventing attachment to cells. Here, we identified the minimal and optimal EB sequence that retained antiviral activity with a 50% inhibitory concentration (IC(50)) and 50% effective concentration (EC(50)) similar to those of the full-length EB peptide and several truncated variants that possessed up to 10-fold lower IC(50)s. These data have implications for improving the antiviral efficacy of EB-derived peptides while decreasing production costs and easing synthesis.
Antimicrobial Agents and Chemotherapy 01/2011; 55(4):1810-3. · 4.84 Impact Factor
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ABSTRACT: The hemagglutinin (HA) surface glycoprotein promotes influenza virus entry and is the key protective antigen in natural immunity and vaccines. The HA protein is a trimeric envelope glycoprotein consisting of a globular receptor-binding domain (HA-RBD) that is inserted into a membrane fusion-mediating stalk domain. Similar to other class I viral fusion proteins, the fusogenic stalk domain spontaneously refolds into its postfusion conformation when expressed in isolation, consistent with this domain being trapped in a metastable conformation. Using X-ray crystallography, we show that the influenza virus HA-RBD refolds spontaneously into its native, immunogenic structure even when expressed in an unglycosylated form in Escherichia coli. In the 2.10-Å structure of the HA-RBD, the receptor-binding pocket is intact and its conformational epitopes are preserved. Recombinant HA-RBD is immunogenic and protective in ferrets, and the protein also binds with specificity to sera from influenza virus-infected humans. Overall, the data provide a structural basis for the rapid production of influenza vaccines in E. coli. From an evolutionary standpoint, the ability of the HA-RBD to refold spontaneously into its native conformation suggests that influenza virus acquired this domain as an insertion into an ancestral membrane-fusion domain. The insertion of independently folding domains into fusogenic stalk domains may be a common feature of class I viral fusion proteins.
Journal of Virology 11/2010; 85(2):865-72. · 5.40 Impact Factor
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ABSTRACT: Infection of domestic cats with pandemic H1N1 influenza virus has recently been documented. We conducted a seroprevalence survey and found that 17 of 78 (21.8%) cats sampled during the 2009-2010 influenza season had antibody titers ≥40 against the novel H1N1 strain by hemagglutinin-inhibition assay, compared to only 1 of 39 (2.6%) sampled in 2008 prior to emergence of the pandemic (p = 0.006). Seroprevalance of seasonal H1N1 (41.9%) and H3N2 (25.6%) viruses was similarly high. These data reflecting past infection of household cats raise the possibility that they may act as a vector of influenza transmission within households.
Archives of Virology 09/2010; 156(1):117-20. · 2.11 Impact Factor
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ABSTRACT: Outbreaks of influenza A viruses continue to cause morbidity and mortality worldwide. The global disease burden of influenza is substantial. While antiviral therapies are available, influenza vaccines are the mainstay of efforts to reduce the substantial health burden from seasonal influenza. Inactivated influenza vaccines have been available since the 1940s, with live attenuated, cold-adapted vaccines becoming available in the United States in 2003. In spite of the successes, more research is needed to develop more effective seasonal influenza vaccines that provide long-lasting immunity and broad protection against strains that differ antigenically from vaccine viruses. This review introduces the virus and its disease, the current state of seasonal and pandemic influenza vaccines, and the challenges we face in the future.
Advances in Virus Research 01/2010; 77:63-84. · 3.97 Impact Factor
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Mario M Alvarez,
Felipe López-Pacheco,
José M Aguilar-Yañez,
Roberto Portillo-Lara,
Gonzalo I Mendoza-Ochoa,
Sergio García-Echauri,
Pamela Freiden, Stacey Schultz-Cherry,
Manuel I Zertuche-Guerra,
David Bulnes-Abundis,
Johari Salgado-Gallegos,
Leticia Elizondo-Montemayor,
Martín Hernández-Torre
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ABSTRACT: Although it has been estimated that pandemic Influenza A H1N1/2009 has infected millions of people from April to October 2009, a more precise figure requires a worldwide large-scale diagnosis of the presence of Influenza A/H1N1/2009 antibodies within the population. Assays typically used to estimate antibody titers (hemagglutination inhibition and microneutralization) would require the use of the virus, which would seriously limit broad implementation.
An ELISA method to evaluate the presence and relative concentration of specific Influenza A/H1N1/2009 antibodies in human serum samples is presented. The method is based on the use of a histidine-tagged recombinant fragment of the globular region of the hemagglutinin (HA) of the Influenza A H1N1/2009 virus expressed in E. coli.
The ELISA method consistently discerns between Inf A H1N1 infected and non-infected subjects, particularly after the third week of infection/exposure. Since it does not require the use of viral particles, it can be easily and quickly implemented in any basic laboratory. In addition, in a scenario of insufficient vaccine availability, the use of this ELISA could be useful to determine if a person has some level of specific antibodies against the virus and presumably at least partial protection.
PLoS ONE 01/2010; 5(4):e10176. · 4.09 Impact Factor
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Christina M Carlson,
Elizabeth A Turpin,
Lindsey A Moser,
Kevin B O'Brien,
Troy D Cline,
Jeremy C Jones,
Terrence M Tumpey,
Jacqueline M Katz,
Laura A Kelley,
Jack Gauldie, Stacey Schultz-Cherry
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ABSTRACT: Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis.
PLoS Pathogens 01/2010; 6(10):e1001136. · 9.13 Impact Factor
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José M Aguilar-Yáñez,
Roberto Portillo-Lara,
Gonzalo I Mendoza-Ochoa,
Sergio A García-Echauri,
Felipe López-Pacheco,
David Bulnes-Abundis,
Johari Salgado-Gallegos,
Itzel M Lara-Mayorga,
Yenny Webb-Vargas,
Felipe O León-Angel,
Ramón E Rivero-Aranda,
Yuriana Oropeza-Almazán,
Guillermo M Ruiz-Palacios,
Manuel I Zertuche-Guerra,
Rebecca M DuBois,
Stephen W White, Stacey Schultz-Cherry,
Charles J Russell,
Mario M Alvarez
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ABSTRACT: The A/H1N1/2009 influenza pandemic made evident the need for faster and higher-yield methods for the production of influenza vaccines. Platforms based on virus culture in mammalian or insect cells are currently under investigation. Alternatively, expression of fragments of the hemagglutinin (HA) protein in prokaryotic systems can potentially be the most efficacious strategy for the manufacture of large quantities of influenza vaccine in a short period of time. Despite experimental evidence on the immunogenic potential of HA protein constructs expressed in bacteria, it is still generally accepted that glycosylation should be a requirement for vaccine efficacy.
We expressed the globular HA receptor binding domain, referred to here as HA(63-286)-RBD, of the influenza A/H1N1/2009 virus in Escherichia coli using a simple, robust and scalable process. The recombinant protein was refolded and purified from the insoluble fraction of the cellular lysate as a single species. Recombinant HA(63-286)-RBD appears to be properly folded, as shown by analytical ultracentrifugation and bio-recognition assays. It binds specifically to serum antibodies from influenza A/H1N1/2009 patients and was found to be immunogenic, to be capable of triggering the production of neutralizing antibodies, and to have protective activity in the ferret model.
Projections based on our production/purification data indicate that this strategy could yield up to half a billion doses of vaccine per month in a medium-scale pharmaceutical production facility equipped for bacterial culture. Also, our findings demonstrate that glycosylation is not a mandatory requirement for influenza vaccine efficacy.
PLoS ONE 01/2010; 5(7):e11694. · 4.09 Impact Factor
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ABSTRACT: Human astroviruses are nonenveloped, positive-sense single-strand RNA viruses associated with self-limiting diarrhea. Although they are recognized as a leading cause of disease in young children, the cellular factors involved in astrovirus replication are not well defined. The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate many viral infections, but its role during astrovirus infection is unknown. In this report, we show that astrovirus activates ERK1/2 early in infection independently of replication. Inhibition of ERK activation with U0126, a specific ERK inhibitor, significantly reduced viral production. Investigations into the mechanism of ERK1/2 regulation revealed that all steps of the viral life cycle, including early and late protein expression as well as subgenomic and genomic RNA transcription, were diminished during U0126 treatment of monolayers. These data support a role for ERK1/2 in a postattachment step, although the precise mechanism remains under investigation.
Journal of Virology 09/2008; 82(15):7475-82. · 5.40 Impact Factor
