Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
Records 1-30 (of 35 Records) |
Query Trace: Ruben W [original query] |
---|
A Public Health Research Agenda for Managing Infodemics: Methods and Results of the First WHO Infodemiology Conference.
Calleja N , AbdAllah A , Abad N , Ahmed N , Albarracin D , Altieri E , Anoko JN , Arcos R , Azlan AA , Bayer J , Bechmann A , Bezbaruah S , Briand SC , Brooks I , Bucci LM , Burzo S , Czerniak C , De Domenico M , Dunn AG , Ecker UKH , Espinosa L , Francois C , Gradon K , Gruzd A , Gülgün BS , Haydarov R , Hurley C , Astuti SI , Ishizumi A , Johnson N , Johnson Restrepo D , Kajimoto M , Koyuncu A , Kulkarni S , Lamichhane J , Lewis R , Mahajan A , Mandil A , McAweeney E , Messer M , Moy W , Ndumbi Ngamala P , Nguyen T , Nunn M , Omer SB , Pagliari C , Patel P , Phuong L , Prybylski D , Rashidian A , Rempel E , Rubinelli S , Sacco P , Schneider A , Shu K , Smith M , Sufehmi H , Tangcharoensathien V , Terry R , Thacker N , Trewinnard T , Turner S , Tworek H , Uakkas S , Vraga E , Wardle C , Wasserman H , Wilhelm E , Würz A , Yau B , Zhou L , Purnat TD . JMIR Infodemiology 2021 1 (1) e30979 BACKGROUND: An infodemic is an overflow of information of varying quality that surges across digital and physical environments during an acute public health event. It leads to confusion, risk-taking, and behaviors that can harm health and lead to erosion of trust in health authorities and public health responses. Owing to the global scale and high stakes of the health emergency, responding to the infodemic related to the pandemic is particularly urgent. Building on diverse research disciplines and expanding the discipline of infodemiology, more evidence-based interventions are needed to design infodemic management interventions and tools and implement them by health emergency responders. OBJECTIVE: The World Health Organization organized the first global infodemiology conference, entirely online, during June and July 2020, with a follow-up process from August to October 2020, to review current multidisciplinary evidence, interventions, and practices that can be applied to the COVID-19 infodemic response. This resulted in the creation of a public health research agenda for managing infodemics. METHODS: As part of the conference, a structured expert judgment synthesis method was used to formulate a public health research agenda. A total of 110 participants represented diverse scientific disciplines from over 35 countries and global public health implementing partners. The conference used a laddered discussion sprint methodology by rotating participant teams, and a managed follow-up process was used to assemble a research agenda based on the discussion and structured expert feedback. This resulted in a five-workstream frame of the research agenda for infodemic management and 166 suggested research questions. The participants then ranked the questions for feasibility and expected public health impact. The expert consensus was summarized in a public health research agenda that included a list of priority research questions. RESULTS: The public health research agenda for infodemic management has five workstreams: (1) measuring and continuously monitoring the impact of infodemics during health emergencies; (2) detecting signals and understanding the spread and risk of infodemics; (3) responding and deploying interventions that mitigate and protect against infodemics and their harmful effects; (4) evaluating infodemic interventions and strengthening the resilience of individuals and communities to infodemics; and (5) promoting the development, adaptation, and application of interventions and toolkits for infodemic management. Each workstream identifies research questions and highlights 49 high priority research questions. CONCLUSIONS: Public health authorities need to develop, validate, implement, and adapt tools and interventions for managing infodemics in acute public health events in ways that are appropriate for their countries and contexts. Infodemiology provides a scientific foundation to make this possible. This research agenda proposes a structured framework for targeted investment for the scientific community, policy makers, implementing organizations, and other stakeholders to consider. |
HMG-CoA Reductase Inhibitors as Drug Leads against Naegleria fowleri .
Hahn HJ , Abagyan R , Podust LM , Roy S , Ali IKM , Debnath A . ACS Chem Neurosci 2020 11 (19) 3089-3096 Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Treatment of PAM relies on amphotericin B in combination with other drugs, but few patients have survived with the existing drug treatment regimens. Therefore, development of effective drugs is a critical unmet need to avert deaths from PAM. Since ergosterol is one of the major sterols in the membrane of N. fowleri, disruption of isoprenoid and sterol biosynthesis by small-molecule inhibitors may be an effective intervention strategy against N. fowleri. The genome of N. fowleri contains a gene encoding HMG-CoA reductase (HMGR); the catalytic domains of human and N. fowleri HMGR share <60% sequence identity with only two amino acid substitutions in the active site of the enzyme. Considering the similarity of human and N. fowleri HMGR, we tested well-tolerated and widely used HMGR inhibitors, known as cholesterol-lowering statins, against N. fowleri. We identified blood-brain-barrier-permeable pitavastatin as a potent amebicidal agent against the U.S., Australian, and European strains of N. fowleri. Pitavastatin was equipotent to amphotericin B against the European strain of N. fowleri; it killed about 80% of trophozoites within 16 h of drug exposure. Pretreatment of trophozoites with mevalonate, the product of HMGR, rescued N. fowleri from inhibitory effects of statins, demonstrating that HMGR of N. fowleri is the target of statins. Because of the good safety profile and availability for both adult and pediatric uses, consideration should be given to repurposing the fast-acting pitavastatin for the treatment of PAM. |
Cross-protection by inactivated H5 pre-pandemic vaccine seed strains against diverse Goose/Guangdong lineage H5N1 highly pathogenic avian influenza viruses.
Criado MF , Sá ESilva M , Lee DH , de Lima Salge CA , Spackman E , Donis R , Wan XF , Swayne DE . J Virol 2020 94 (24) The highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 lineage (Gs/GD) is endemic in poultry across several countries in the world, and has caused lethal, sporadic infections in humans. Vaccines are important in HPAI control for both poultry and in pre-pandemic preparedness in humans. This study assessed inactivated pre-pandemic vaccine strains in a One Health framework, focusing on the genetic and antigenic diversity of field H5N1 Gs/GD viruses from the agricultural sector and assessing cross protection in a chicken challenge model. Nearly half (47.92%) of the forty-eight combinations of vaccine/challenge viruses examined had bird protection of 80% or above. Most vaccinated groups had prolonged mean death time (MDT) and the virus shedding titers were significantly lower compared to the sham group (p≤ 0.05). The antibody titers in the pre-challenge sera were not predictive of protection. Although vaccinated birds had higher titers of hemagglutination inhibiting (HI) antibodies against homologous vaccine antigen, most of them also had lower or no antibody titer against the challenge antigen. The comparison of all parameters, homologous or closely related vaccine and challenge viruses, gave the best prediction protection. Through additional analysis, we identified a pattern of epitopes substitutions in the hemagglutinin (HA) of each challenge virus that impacted protection, regardless of the vaccine used. These changes were situated in the antigenic sites and/or reported epitopes associated with virus escape from antibody neutralization. As a result, this study highlights virus diversity, immune response complexity, and the importance of strain selection for vaccine development to control H5N1 HPAIV in the agricultural sector and for human pre-pandemic preparedness. We suggest that the engineering of specific antigenic sites can improve the immunogenicity of H5 vaccines.ImportanceThe sustained circulation of highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 lineage (Gs/GD) in the agricultural sector and some wild birds has led to the evolution and selection of distinct viral lineages involved in the escape from vaccine protection. Our results using inactivated vaccine candidates from the human pandemic preparedness program in a chicken challenge model identified critical antigenic conformational epitopes on the H5 hemagglutinin (HA) from different clades that were associated with antibody recognition and escape. Even though other investigators have reported epitope mapping in the H5 HA, much of this information pertains to epitopes reactive towards mouse antibodies. Our findings validate changes in antigenic epitopes of HA associated with virus escape from antibody neutralization in chickens, which has direct relevance to field protection and virus evolution. Therefore, the knowledge of these immunodominant regions is essential to proactively develop diagnostic tests, improve surveillance platforms to monitor AIV outbreaks, and design more efficient and broad-spectrum agricultural and human prepandemic vaccines. |
Understanding the Emergence of Multidrug-Resistant Candida : Using Whole-Genome Sequencing to Describe the Population Structure of Candida haemulonii Species Complex.
Gade L , Munoz JF , Sheth M , Wagner D , Berkow EL , Forsberg K , Jackson BR , Ramos-Castro R , Escandon P , Dolande M , Ben-Ami R , Espinosa-Bode A , Caceres DH , Lockhart SR , Cuomo CA , Litvintseva AP . Front Genet 2020 11 554 The recent emergence of a multidrug-resistant yeast, Candida auris, has drawn attention to the closely related species from the Candida haemulonii complex that include C. haemulonii, Candida duobushaemulonii, Candida pseudohaemulonii, and the recently identified Candida vulturna. Here, we used antifungal susceptibility testing and whole-genome sequencing (WGS) to investigate drug resistance and genetic diversity among isolates of C. haemulonii complex from different geographic areas in order to assess population structure and the extent of clonality among strains. Although most isolates of all four species were genetically distinct, we detected evidence of the in-hospital transmission of C. haemulonii and C. duobushaemulonii in one hospital in Panama, indicating that these species are also capable of causing outbreaks in healthcare settings. We also detected evidence of the rising azole resistance among isolates of C. haemulonii and C. duobushaemulonii in Colombia, Panama, and Venezuela linked to substitutions in ERG11 gene as well as amplification of this gene in C. haemulonii in isolates in Colombia suggesting the presence of evolutionary pressure for developing azole resistance in this region. Our results demonstrate that these species need to be monitored as possible causes of outbreaks of invasive infection. |
Mutations in the Neuraminidase-Like Protein of Bat Influenza H18N11 Virus Enhance Virus Replication in Mammalian Cells, Mice, and Ferrets.
Zhong G , Fan S , Hatta M , Nakatsu S , Walters KB , Lopes TJS , Wang JI , Ozawa M , Karasin A , Li Y , Tong S , Donis RO , Neumann G , Kawaoka Y . J Virol 2019 94 (5) To characterize bat influenza H18N11 virus, we propagated a reverse genetics-generated H18N11 virus in MDCK II cells and detected two adapting mutations in the neuraminidase (NA)-like protein (NA-F144C and NA-T342A, N2 numbering) that increased virus titers in three mammalian cell lines (i.e., Madin-Darby canine kidney, Madin-Darby canine kidney II, and human lung adenocarcinoma Calu-3 cells). In mice, wild-type H18N11 virus replicated only in the lungs of the infected animals, whereas the NA-T342A and NA-F144C/T342A mutant viruses were detected in the nasal turbinates in addition to the lungs. Bat influenza viruses have not been tested for their virulence and organ tropism in ferrets. We detected wild-type and single mutant viruses each possessing NA-F144C or NA-T342A in the nasal turbinates of one or several infected ferret(s), respectively. A mutant virus possessing both NA-F144C and T342A was isolated from both the lung and trachea, suggesting broader organ tropism compared with wild-type virus. However, none of the H18N11 viruses caused symptoms in mice or ferrets. The NA-F144C/T342A double mutation did not substantially affect virion morphology or the release of virions from cells. Collectively, our data demonstrate that propagation of bat influenza H18N11 virus in mammalian cells can result in mammalian-adapting mutations that could increase virus replicative ability and/or organ tropism; overall, however, these viruses did not replicate to high titers throughout the respiratory tract of mice and ferrets.IMPORTANCE Bats are reservoirs for several severe zoonotic pathogens. The genomes of influenza A viruses of the H17N10 and H18N11 subtypes were identified in bats, but no live virus has been isolated. The characterization of artificially generated bat influenza H18N11 virus in mammalian cell lines and animal models revealed that this virus can acquire mammalian-adapting mutations that could increase its zoonotic potential; however, the wild-type and mutant viruses did not replicate in the lungs of all infected animals. |
Building children's preparedness capacity at the Centers for Disease Control and Prevention one event at a time, 2009-2018
Leeb RT , Franks JL , Dziuban EJ , Ruben W , Bartenfeld M , Hinton CF , Chatham-Stephens K , Peacock G . Am J Public Health 2019 109 S260-s262 This issue of AJPH highlights the importance of community preparedness for public health emergencies. An essential component of community preparedness is the capacity to address the needs of children, who comprise nearly one quarter of the US population and are particularly vulnerable to disaster-related morbidity and mortality (Figure 1).1 However, communities may not be well equipped to address children’s needs. |
Avian influenza surveillance in domestic waterfowl and environment of live bird markets in Bangladesh, 2007-2012.
Khan SU , Gurley ES , Gerloff N , Rahman MZ , Simpson N , Rahman M , Haider N , Chowdhury S , Balish A , Zaman RU , Nasreen S , Chandra Das B , Azziz-Baumgartner E , Sturm-Ramirez K , Davis CT , Donis RO , Luby SP . Sci Rep 2018 8 (1) 9396 Avian influenza viruses, including highly pathogenic strains, pose severe economic, animal and public health concerns. We implemented live bird market surveillance in Bangladesh to identify the subtypes of avian influenza A viruses in domestic waterfowl and market environments. We collected waterfowl samples monthly from 4 rural sites from 2007 to 2012 and environmental samples from 4 rural and 16 urban sites from 2009 to 2012. Samples were tested through real-time RT-PCR, virus culture, and sequencing to detect and characterize avian influenza A viruses. Among 4,308 waterfowl tested, 191 (4.4%) were positive for avian influenza A virus, including 74 (1.9%) avian influenza A/H5 subtype. The majority (99%, n = 73) of the influenza A/H5-positive samples were from healthy appearing waterfowl. Multiple subtypes, including H1N1, H1N3, H3N2, H3N6, H3N8, H4N1, H4N2, H4N6, H5N1 (clades 2.2.2, 2.3.2.1a, 2.3.4.2), H5N2, H6N1, H7N9, H9N2, H11N2 and H11N3, H11N6 were detected in waterfowl and environmental samples. Environmental samples tested positive for influenza A viruses throughout the year. Avian influenza viruses, including H5N1 and H9N2 subtypes were also identified in backyard and small-scale raised poultry. Live bird markets could be high-risk sites for harboring the viruses and have the potential to infect naive birds and humans exposed to them. |
Improving the selection and development of influenza vaccine viruses - Report of a WHO informal consultation on improving influenza vaccine virus selection, Hong Kong SAR, China, 18-20 November 2015.
Hampson A , Barr I , Cox N , Donis RO , Hirve S , Jernigan D , Katz J , McCauley J , Motta F , Odagiri T , Tami JS , Waddell A , Webby R , Ziegler T , Zhang W . Vaccine 2017 35 (8) 1104-1109 Since 2010 the WHO has held a series of informal consultations to explore ways of improving the currently highly complex and time-pressured influenza vaccine virus selection and development process. In November 2015 experts from around the world met to review the current status of efforts in this field. Discussion topics included strengthening influenza surveillance activities to increase the availability of candidate vaccine viruses and improve the extent, timeliness and quality of surveillance data. Consideration was also given to the development and potential application of newer laboratory assays to better characterize candidate vaccine viruses, the potential importance of antibodies directed against influenza virus neuraminidase, and the role of vaccine effectiveness studies. Advances in next generation sequencing and whole genome sequencing of influenza viruses were also discussed, along with associated developments in synthetic genomics technologies, evolutionary analysis and predictive mathematical modelling. Discussions were also held on the late emergence of an antigenic variant influenza A(H3N2) virus in mid-2014 that could not be incorporated in time into the 2014-15 northern hemisphere vaccine. There was broad recognition that given the current highly constrained influenza vaccine development and production timeline it would remain impossible to incorporate any variant virus which emerged significantly long after the relevant WHO biannual influenza vaccine composition meetings. Discussions were also held on the development of pandemic and broadly protective vaccines, and on associated regulatory and manufacturing requirements and constraints. With increasing awareness of the health and economic burdens caused by seasonal influenza, the ever-present threat posed by zoonotic influenza viruses, and the significant impact of the 2014-15 northern hemisphere seasonal influenza vaccine mismatch, this consultation provided a very timely opportunity to share developments and exchange views. In all areas, a renewed and strengthened emphasis was placed on developing concrete and measurable actions and identifying the key stakeholders responsible for their implementation. |
A Phylogeny-Based Global Nomenclature System and Automated Annotation Tool for H1 Hemagglutinin Genes from Swine Influenza A Viruses.
Anderson TK , Macken CA , Lewis NS , Scheuermann RH , Van Reeth K , Brown IH , Swenson SL , Simon G , Saito T , Berhane Y , Ciacci-Zanella J , Pereda A , Davis CT , Donis RO , Webby RJ , Vincent AL . mSphere 2016 1 (6) The H1 subtype of influenza A viruses (IAVs) has been circulating in swine since the 1918 human influenza pandemic. Over time, and aided by further introductions from nonswine hosts, swine H1 viruses have diversified into three genetic lineages. Due to limited global data, these H1 lineages were named based on colloquial context, leading to a proliferation of inconsistent regional naming conventions. In this study, we propose rigorous phylogenetic criteria to establish a globally consistent nomenclature of swine H1 virus hemagglutinin (HA) evolution. These criteria applied to a data set of 7,070 H1 HA sequences led to 28 distinct clades as the basis for the nomenclature. We developed and implemented a web-accessible annotation tool that can assign these biologically informative categories to new sequence data. The annotation tool assigned the combined data set of 7,070 H1 sequences to the correct clade more than 99% of the time. Our analyses indicated that 87% of the swine H1 viruses from 2010 to the present had HAs that belonged to 7 contemporary cocirculating clades. Our nomenclature and web-accessible classification tool provide an accurate method for researchers, diagnosticians, and health officials to assign clade designations to HA sequences. The tool can be updated readily to track evolving nomenclature as new clades emerge, ensuring continued relevance. A common global nomenclature facilitates comparisons of IAVs infecting humans and pigs, within and between regions, and can provide insight into the diversity of swine H1 influenza virus and its impact on vaccine strain selection, diagnostic reagents, and test performance, thereby simplifying communication of such data. IMPORTANCE A fundamental goal in the biological sciences is the definition of groups of organisms based on evolutionary history and the naming of those groups. For influenza A viruses (IAVs) in swine, understanding the hemagglutinin (HA) genetic lineage of a circulating strain aids in vaccine antigen selection and allows for inferences about vaccine efficacy. Previous reporting of H1 virus HA in swine relied on colloquial names, frequently with incriminating and stigmatizing geographic toponyms, making comparisons between studies challenging. To overcome this, we developed an adaptable nomenclature using measurable criteria for historical and contemporary evolutionary patterns of H1 global swine IAVs. We also developed a web-accessible tool that classifies viruses according to this nomenclature. This classification system will aid agricultural production and pandemic preparedness through the identification of important changes in swine IAVs and provides terminology enabling discussion of swine IAVs in a common context among animal and human health initiatives. |
Genetically Diverse Low Pathogenicity Avian Influenza A Virus Subtypes Co-Circulate among Poultry in Bangladesh.
Gerloff NA , Khan SU , Zanders N , Balish A , Haider N , Islam A , Chowdhury S , Rahman MZ , Haque A , Hosseini P , Gurley ES , Luby SP , Wentworth DE , Donis RO , Sturm-Ramirez K , Davis CT . PLoS One 2016 11 (3) e0152131 Influenza virus surveillance, poultry outbreak investigations and genomic sequencing were assessed to understand the ecology and evolution of low pathogenicity avian influenza (LPAI) A viruses in Bangladesh from 2007 to 2013. We analyzed 506 avian specimens collected from poultry in live bird markets and backyard flocks to identify influenza A viruses. Virus isolation-positive specimens (n = 50) were subtyped and their coding-complete genomes were sequenced. The most frequently identified subtypes among LPAI isolates were H9N2, H11N3, H4N6, and H1N1. Less frequently detected subtypes included H1N3, H2N4, H3N2, H3N6, H3N8, H4N2, H5N2, H6N1, H6N7, and H7N9. Gene sequences were compared to publicly available sequences using phylogenetic inference approaches. Among the 14 subtypes identified, the majority of viral gene segments were most closely related to poultry or wild bird viruses commonly found in Southeast Asia, Europe, and/or northern Africa. LPAI subtypes were distributed over several geographic locations in Bangladesh, and surface and internal protein gene segments clustered phylogenetically with a diverse number of viral subtypes suggesting extensive reassortment among these LPAI viruses. H9N2 subtype viruses differed from other LPAI subtypes because genes from these viruses consistently clustered together, indicating this subtype is enzootic in Bangladesh. The H9N2 strains identified in Bangladesh were phylogenetically and antigenically related to previous human-derived H9N2 viruses detected in Bangladesh representing a potential source for human infection. In contrast, the circulating LPAI H5N2 and H7N9 viruses were both phylogenetically and antigenically unrelated to H5 viruses identified previously in humans in Bangladesh and H7N9 strains isolated from humans in China. In Bangladesh, domestic poultry sold in live bird markets carried a wide range of LPAI virus subtypes and a high diversity of genotypes. These findings, combined with the seven year timeframe of sampling, indicate a continuous circulation of these viruses in the country. |
Optimizing intradermal administration of cryopreserved Plasmodium falciparum sporozoites in controlled human malaria infection
Lyke KE , Laurens MB , Strauss K , Adams M , Billingsley PF , James E , Manoj A , Chakravarty S , Plowe CV , Li ML , Ruben A , Edelman R , Green M , Dube TJ , Sim BK , Hoffman SL . Am J Trop Med Hyg 2015 93 (6) 1274-1284 Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was shown to induce P. falciparum malaria; however, 100% infection rates were not achieved by ID injection. To optimize ID PfSPZ dosing so as to achieve 100% infection, 30 adults aged 18-45 years were randomized to one of six groups composed of five volunteers each. The parameters of dose (1 x 104 versus 5 x 104 PfSPZ total dose per volunteer), number of injections (two versus eight), and aliquot volume per ID injection (10 muL versus 50 muL) were studied. Three groups attained 100% infection: 1 x 104 PfSPZ in 50 muL/2 doses, 1 x 104 PfSPZ in 10 muL/2 doses, and 5 x 104 PfSPZ in 10 muL/8 doses. The group that received 5 x 104 PfSPZ total dose in eight 10-muL injections had a 100% infection rate and the shortest prepatent period (mean of 12.7 days), approaching the prepatent period for the current CHMI standard of five infected mosquitoes. |
Clinical inquiries received by CDC regarding suspected Ebola virus disease in children - United States, July 9, 2014-January 4, 2015
Goodman AB , Meites E , Anstey EH , Fullerton KE , Jayatilleke A , Ruben W , Koumans E , Oster AM , Karwowski MP , Dziuban E , Kirkcaldy RD , Glover M , Lowe L , Peacock G , Mahon B , Griese SE . MMWR Morb Mortal Wkly Rep 2015 64 (36) 1006-10 The 2014-2015 Ebola virus disease (Ebola) epidemic is the largest in history and represents the first time Ebola has been diagnosed in the United States. On July 9, 2014, CDC activated its Emergency Operations Center and established an Ebola clinical consultation service to assist U.S. state and local public health officials and health care providers with the evaluation of suspected cases. CDC reviewed all 89 inquiries received by the consultation service during July 9, 2014- January 4, 2015, about children (persons aged </=18 years). Most (56 [63%]) children had no identifiable epidemiologic risk factors for Ebola; among the 33 (37%) who did have an epidemiologic risk factor, in every case this was travel from an Ebola-affected country. Thirty-two of these children met criteria for a person under investigation (PUI) because of clinical signs or symptoms. Fifteen PUIs had blood samples tested for Ebola virus RNA by reverse transcription-polymerase chain reaction; all tested negative. Febrile children who have recently traveled from an Ebola-affected country can be expected to have other common diagnoses, such as malaria and influenza, and in the absence of epidemiologic risk factors for Ebola, the likelihood of Ebola is extremely low. Delaying evaluation and treatment for these other more common illnesses might lead to poorer clinical outcomes. Additionally, many health care providers expressed concerns about whether and how parents should be allowed in the isolation room. While maintaining an appropriate level of vigilance for Ebola, public health officials and health care providers should ensure that pediatric PUIs receive timely triage, diagnosis, and treatment of other more common illnesses, and care reflecting best practices in supporting children's psychosocial needs. |
Identification of Influenza A/PR/8/34 Donor Viruses Imparting High Hemagglutinin Yields to Candidate Vaccine Viruses in Eggs.
Johnson A , Chen LM , Winne E , Santana W , Metcalfe MG , Mateu-Petit G , Ridenour C , Hossain MJ , Villanueva J , Zaki SR , Williams TL , Cox NJ , Barr JR , Donis RO . PLoS One 2015 10 (6) e0128982 One of the important lessons learned from the 2009 H1N1 pandemic is that a high yield influenza vaccine virus is essential for efficient and timely production of pandemic vaccines in eggs. The current seasonal and pre-pandemic vaccine viruses are generated either by classical reassortment or reverse genetics. Both approaches utilize a high growth virus, generally A/Puerto Rico/8/1934 (PR8), as the donor of all or most of the internal genes, and the wild type virus recommended for inclusion in the vaccine to contribute the hemagglutinin (HA) and neuraminidase (NA) genes encoding the surface glycoproteins. As a result of extensive adaptation through sequential egg passaging, PR8 viruses with different gene sequences and high growth properties have been selected at different laboratories in past decades. The effect of these related but distinct internal PR8 genes on the growth of vaccine viruses in eggs has not been examined previously. Here, we use reverse genetics to analyze systematically the growth and HA antigen yield of reassortant viruses with 3 different PR8 backbones. A panel of 9 different HA/NA gene pairs in combination with each of the 3 different lineages of PR8 internal genes (27 reassortant viruses) was generated to evaluate their performance. Virus and HA yield assays showed that the PR8 internal genes influence HA yields in most subtypes. Although no single PR8 internal gene set outperformed the others in all candidate vaccine viruses, a combination of specific PR8 backbone with individual HA/NA pairs demonstrated improved HA yield and consequently the speed of vaccine production. These findings may be important both for production of seasonal vaccines and for a rapid global vaccine response during a pandemic. |
Nomenclature updates resulting from the evolution of avian influenza A(H5) virus clades 2.1.3.2a, 2.2.1, and 2.3.4 during 2013-2014.
Donis RO , Smith GJ . Influenza Other Respir Viruses 2015 9 (5) 271-6 The divergence of the A(H5) hemagglutinin (HA) gene of highly pathogenic avian influenza (HPAI) viruses (A/goose/Guangdong/96 lineage) was analyzed by phylogenetic and average pairwise distance methods to identify new clades that merit nomenclature changes. Three new clade designations were recommended based on division of clade 2.1.3.2a (Indonesia), 2.2.1 (Egypt) and 2.3.4 (widespread detection in Asia, Europe and North America) that includes newly emergent HPAI virus subtypes H5N2, H5N3, H5N5, H5N6 and H5N8. |
Emergence of Highly Pathogenic Avian Influenza A(H5N1) Virus PB1-F2 Variants and Their Virulence in BALB/c Mice.
Kamal RP , Kumar A , Davis CT , Tzeng WP , Nguyen T , Donis RO , Katz JM , York IA . J Virol 2015 89 (11) 5835-46 Influenza A viruses (IAV) express the PB1-F2 protein from an alternate reading frame within the PB1 gene segment. The roles of PB1-F2 are not well understood, but appear to involve modulation of host cell responses. As shown in previous studies, we find that PB1-F2 of mammalian IAV frequently have premature stop codons that are expected to cause truncations of the protein, whereas avian IAV usually express a full-length 90 amino acid PB1-F2. However, in contrast to other avian IAV, recent isolates of highly pathogenic H5N1 influenza viruses had a high proportion of PB1-F2 truncations (15% since 2010; 61% of isolates in 2013) due to several independent mutations that have persisted and expanded in circulating viruses. One natural H5N1 IAV containing a mutated PB1-F2 start codon (i.e., lacking ATG) was 1000-fold more virulent for BALB/c mice than a closely-related H5N1 containing intact PB1-F2. In vitro, we detected expression of an in-frame protein (C-terminal PB1-F2) from downstream ATGs in PB1-F2 plasmids lacking the well-conserved ATG start codon. Transient expression of full-length, truncated (25 amino acids), and PB1-F2 lacking the initiating ATG in mammalian and avian cells had no effect on cell apoptosis or interferon expression in human lung epithelial cells. Full length and C-terminal PB1-F2 mutants co-localized with mitochondria in A549 cells. Close monitoring of alterations of PB1-F2 and their frequency in contemporary avian H5N1 viruses should continue, as such changes may be markers for mammalian virulence. IMPORTANCE: Although most avian influenza viruses are harmless for humans, some (such as highly pathogenic H5N1 avian influenza viruses) are capable of infecting humans and causing severe disease with a high mortality rate. A number of risk factors potentially associated with adaptation to mammalian infection have been noted. Here we demonstrate that the protein PB1-F2 is frequently truncated in recent isolates of highly pathogenic H5N1 viruses. Truncation of PB1-F2 has been proposed to act as an adaptation to mammalian infection. We show that some forms of truncation of PB1-F2 may be associated with increased virulence in mammals. Our data support the assessment of PB1-F2 truncations for genomic surveillance of influenza viruses. |
Use of highly pathogenic avian influenza A(H5N1) gain-of-function studies for molecular-based surveillance and pandemic preparedness.
Davis CT , Chen LM , Pappas C , Stevens J , Tumpey TM , Gubareva LV , Katz JM , Villanueva JM , Donis RO , Cox NJ . mBio 2014 5 (6) Zoonotic influenza viruses circulating in poultry and swine pose an ever present threat to human health. In particular, the rapid geographical expansion of highly pathogenic avian influenza (HPAI) A(H5N1) throughout Asia and then into Europe, the Middle East, and Africa during the 2000s galvanized the global community in an attempt to control this rapidly growing threat. Despite successful control efforts in some countries, the virus remains endemic in poultry in at least six countries and continues to cause human illness and deaths as well as countless outbreaks in birds. During the past decade, 668 cases and 393 deaths were detected and reported to the World Health Organization (WHO) (1). During the 17 years since human infections with HPAI A(H5N1) were first identified in Hong Kong, Special Administrative Region, People’s Republic of China, in 1997, these viruses have evolved substantially through mutation and reassortment, resulting in multiple divergent genotypes and clades (2). | Ongoing H5N1 circulation has appropriately resulted in a focus on sequencing viral genomes to understand the evolution of these viruses and the significance of observed genetic changes. Expanded laboratory capacity for high-throughput Sanger sequencing and recent technological advances, such as next-generation sequencing and parallel computing, have revolutionized the quantity, quality, and availability of gene sequences and our ability to quickly and accurately analyze these data (3). Consequently, the number of animal and human influenza virus sequences available in publically accessible databases has dramatically increased over the years, as have the bioinformatics tools required for efficient investigation (4, 5). These advances in laboratory and analytical methods provide strong incentives to utilize molecular data for pandemic risk assessment of zoonotic influenza viruses at the animal-human interface (6). |
Improving pandemic influenza risk assessment.
Russell CA , Kasson PM , Donis RO , Riley S , Dunbar J , Rambaut A , Asher J , Burke S , Davis CT , Garten RJ , Gnanakaran S , Hay SI , Herfst S , Lewis NS , Lloyd-Smith JO , Macken CA , Maurer-Stroh S , Neuhaus E , Parrish CR , Pepin KM , Shepard SS , Smith DL , Suarez DL , Trock SC , Widdowson MA , George DB , Lipsitch M , Bloom JD . Elife 2014 3 e03883 Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response. |
Identification of molecular markers associated with alteration of receptor-binding specificity in a novel genotype of highly pathogenic avian influenza A(H5N1) viruses detected in Cambodia in 2013.
Rith S , Davis CT , Duong V , Sar B , Horm SV , Chin S , Ly S , Laurent D , Richner B , Oboho I , Jang Y , Davis W , Thor S , Balish A , Iuliano AD , Sorn S , Holl D , Sok T , Seng H , Tarantola A , Tsuyuoka R , Parry A , Chea N , Allal L , Kitsutani P , Warren D , Prouty M , Horwood P , Widdowson MA , Lindstrom S , Villanueva J , Donis R , Cox N , Buchy P . J Virol 2014 88 (23) 13897-909 Human infections with influenza A(H5N1) virus in Cambodia increased sharply during 2013. Molecular characterization of viruses detected in clinical specimens from human cases revealed the presence of mutations associated with alteration of receptor-binding specificity (K189R, Q222L) and respiratory droplet transmission in ferrets (N220K with Q222L). Discovery of quasispecies at position 222 (Q/L), in addition to absence of the mutations in poultry/environmental samples, suggested the mutations occurred during human infection and did not transmit further. |
Diversity of the murine antibody response targeting influenza A(H1N1pdm09) hemagglutinin.
Wilson JR , Tzeng WP , Spesock A , Music N , Guo Z , Barrington R , Stevens J , Donis RO , Katz JM , York IA . Virology 2014 458-459 (1) 114-124 We infected mice with the 2009 influenza A pandemic virus (H1N1pdm09), boosted with an inactivated vaccine, and cloned immunoglobulins (Igs) from HA-specific B cells. Based on the redundancy in germline gene utilization, we inferred that between 72-130 unique IgH VDJ and 35 different IgL VJ combinations comprised the anti-HA recall response. The IgH VH1 and IgL VK14 variable gene families were employed most frequently. A representative panel of antibodies were cloned and expressed to confirm reactivity with H1N1pdm09 HA. The majority of the recombinant antibodies were of high avidity and capable of inhibiting H1N1pdm09 hemagglutination. Three of these antibodies were subtype-specific cross-reactive, binding to the HA of A/South Carolina/1/1918(H1N1), and one further reacted with A/swine/Iowa/15/1930(H1N1). These results help to define the genetic diversity of the influenza anti-HA antibody repertoire profile induced following infection and vaccination, which may facilitate the development of influenza vaccines that are more protective and broadly neutralizing. Importance: Protection against influenza viruses is mediated mainly by antibodies, and in most cases this antibody response is narrow, only providing protection against closely related viruses. In spite of this limited range of protection, recent findings indicate that individuals immune to one influenza virus may contain antibodies (generally a minority of the overall response) that are more broadly reactive. These findings have raised the possibility that influenza vaccines could induce a more broadly protective response, reducing the need for frequent vaccine strain changes. However, interpretation of these observations is hampered by the lack of quantitative characterization of the antibody repertoire. In this study, we used single-cell cloning of influenza HA-specific B cells to assess the diversity and nature of the antibody response to influenza hemagglutinin in mice. Our findings help to put bounds on the diversity of the anti-hemagglutinin antibody response, as well as characterizing the cross-reactivity, affinity, and molecular nature of the antibody response. |
Genetic characterization of clade 2.3.2.1 avian influenza A(H5N1) viruses, Indonesia, 2012.
Dharmayanti NL , Hartawan R , Wibawa H , Balish A , Donis R , Davis CT , Samaan G . Emerg Infect Dis 2014 20 (4) 677-80 After reports of unusually high mortality rates among ducks on farms in Java Island, Indonesia, in September 2012, influenza A(H5N1) viruses were detected and characterized. Sequence analyses revealed all genes clustered with contemporary clade 2.3.2.1 viruses, rather than enzootic clade 2.1.3 viruses, indicating the introduction of an exotic H5N1 clade into Indonesia. |
Characterization of reverse genetics-derived cold-adapted master donor virus A/Leningrad/134/17/57 (H2N2) and reassortants with H5N1 surface genes in a mouse model.
Isakova-Sivak I , Chen LM , Bourgeois M , Matsuoka Y , Voeten JT , Heldens JG , van den Bosch H , Klimov A , Rudenko L , Cox NJ , Donis RO . Clin Vaccine Immunol 2014 21 (5) 722-31 Live attenuated influenza vaccines offer significant advantages over subunit or split inactivated vaccines to mitigate an eventual influenza pandemic, including simpler manufacturing process and more cross-protective immune responses. Using an established reverse genetics (rg) system for wild type A/Leningrad/134/1957 and cold-adapted (ca) A/Leningrad/134/17/1957 (Len17) master donor virus (MDV) we produced and characterized three rg H5N1 reassortant viruses carrying modified HA and intact NA genes from either A/Vietnam/1203/2004 (H5N1, VN1203, clade 1) or A/Egypt/321/2007 (H5N1, EG321, clade 2) viruses. A mouse model of infection was used to determine the infectivity and tissue tropism of the parent wt viruses as compared to the ca master donor viruses as well as the H5N1 resassortants. All ca viruses showed reduced replication in lungs and enhanced replication in nasal epithelium. In addition, the H5N1 HA and NA enhanced replication in lungs unless it was restricted by the internal genes of the ca MDV. Mice inoculated twice four weeks apart with the H5N1 reassortant LAIV candidate viruses developed serum HI and IgA antibody titers to the homologous and heterologous viruses consistent with protective immunity. These animals remained healthy after challenge inoculation with a lethal dose with homologous or heterologous wt H5N1 HPAI. The profiles of viral replication in respiratory tissues, immunogenicity and protective efficacy characteristics of the two ca H5N1 candidate LAIV warrant further development into a vaccine for human use. |
LABEL: fast and accurate lineage assignment with assessment of H5N1 and H9N2 influenza A hemagglutinins.
Shepard SS , Davis CT , Bahl J , Rivailler P , York IA , Donis RO . PLoS One 2014 9 (1) e86921 The evolutionary classification of influenza genes into lineages is a first step in understanding their molecular epidemiology and can inform the subsequent implementation of control measures. We introduce a novel approach called Lineage Assignment By Extended Learning (LABEL) to rapidly determine cladistic information for any number of genes without the need for time-consuming sequence alignment, phylogenetic tree construction, or manual annotation. Instead, LABEL relies on hidden Markov model profiles and support vector machine training to hierarchically classify gene sequences by their similarity to pre-defined lineages. We assessed LABEL by analyzing the annotated hemagglutinin genes of highly pathogenic (H5N1) and low pathogenicity (H9N2) avian influenza A viruses. Using the WHO/FAO/OIE H5N1 evolution working group nomenclature, the LABEL pipeline quickly and accurately identified the H5 lineages of uncharacterized sequences. Moreover, we developed an updated clade nomenclature for the H9 hemagglutinin gene and show a similarly fast and reliable phylogenetic assessment with LABEL. While this study was focused on hemagglutinin sequences, LABEL could be applied to the analysis of any gene and shows great potential to guide molecular epidemiology activities, accelerate database annotation, and provide a data sorting tool for other large-scale bioinformatic studies. |
Multiple reassortment events among highly pathogenic avian influenza A(H5N1) viruses detected in Bangladesh.
Gerloff NA , Khan SU , Balish A , Shanta IS , Simpson N , Berman L , Haider N , Poh MK , Islam A , Gurley E , Hasnat MA , Dey T , Shu B , Emery S , Lindstrom S , Haque A , Klimov A , Villanueva J , Rahman M , Azziz-Baumgartner E , Ziaur Rahman M , Luby SP , Zeidner N , Donis RO , Sturm-Ramirez K , Davis CT . Virology 2014 450-451 297-307 In Bangladesh, little is known about the genomic composition and antigenicity of highly pathogenic avian influenza A(H5N1) viruses, their geographic distribution, temporal patterns, or gene flow within the avian host population. Forty highly pathogenic avian influenza A(H5N1) viruses isolated from humans and poultry in Bangladesh between 2008 and 2012 were analyzed by full genome sequencing and antigenic characterization. The analysis included viruses collected from avian hosts and environmental sampling in live bird markets, backyard poultry flocks, outbreak investigations in wild birds or poultry and from three human cases. Phylogenetic analysis indicated that the ancestors of these viruses reassorted (1) with other gene lineages of the same clade, (2) between different clades and (3) with low pathogenicity avian influenza A virus subtypes. Bayesian estimates of the time of most recent common ancestry, combined with geographic information, provided evidence of probable routes and timelines of virus spread into and out of Bangladesh. |
Race/ethnicity disparities in dysglycemia among U.S. women of childbearing age found mainly in the nonoverweight/nonobese
Marcinkevage JA , Alverson CJ , Narayan KM , Kahn HS , Ruben J , Correa A . Diabetes Care 2013 36 (10) 3033-9 OBJECTIVE: To describe the burden of dysglycemia-abnormal glucose metabolism indicative of diabetes or high risk for diabetes-among U.S. women of childbearing age, focusing on differences by race/ethnicity. RESEARCH DESIGN AND METHODS: Using U.S. National Health and Nutrition Examination Survey data (1999-2008), we calculated the burden of dysglycemia (i.e., prediabetes or diabetes from measures of fasting glucose, A1C, and self-report) in nonpregnant women of childbearing age (15-49 years) by race/ethnicity status. We estimated prevalence risk ratios (PRRs) for dysglycemia in subpopulations stratified by BMI (measured as kilograms divided by the square of height in meters), using predicted marginal estimates and adjusting for age, waist circumference, C-reactive protein, and socioeconomic factors. RESULTS: Based on data from 7,162 nonpregnant women, representing >59,000,000 women nationwide, 19% (95% CI 17.2-20.9) had some level of dysglycemia, with higher crude prevalence among non-Hispanic blacks and Mexican Americans vs. non-Hispanic whites (26.3% [95% CI 22.3-30.8] and 23.8% [19.5-28.7] vs. 16.8% [14.4-19.6], respectively). In women with BMI <25 kg/m2, dysglycemia prevalence was roughly twice as high in both non-Hispanic blacks and Mexican Americans vs. non-Hispanic whites. This relative increase persisted in adjusted models (PRRadj 1.86 [1.16-2.98] and 2.23 [1.38-3.60] for non-Hispanic blacks and Mexican Americans, respectively). For women with BMI 25-29.99 kg/m2, only non-Hispanic blacks showed increased prevalence vs. non-Hispanic whites (PRRadj 1.55 [1.03-2.34] and 1.28 [0.73-2.26] for non-Hispanic blacks and Mexican Americans, respectively). In women with BMI >30 kg/m2, there was no significant increase in prevalence of dysglycemia by race/ethnicity category. CONCLUSIONS: Our findings show that dysglycemia affects a significant portion of U.S. women of childbearing age and that disparities by race/ethnicity are most prominent in the nonoverweight/nonobese. |
Autism training in pediatric residency: evaluation of a case-based curriculum
Major NE , Peacock G , Ruben W , Thomas J , Weitzman CC . J Autism Dev Disord 2013 43 (5) 1171-7 Despite recent studies indicating the high prevalence of autism spectrum disorders (ASDs), there has been little focus on improving ASD education during pediatric residency training. The objective of this study was to evaluate a new curriculum developed in partnership with the Centers for Disease Control and Prevention and the Maternal and Child Health Bureau about ASDs. "Autism Case Training (ACT): A Developmental-Behavioral Pediatrics Curriculum" consists of 7 case-based teaching modules. Modules were facilitated by faculty at 26 pediatric residency programs and data were obtained on 114 residents. Pre- and post-test data revealed significant short-term improvements in residents' knowledge and self-assessed competence regarding ASDs. Findings suggest that the ACT curriculum is effective in enhancing training about ASDs in pediatric residency programs. |
Evolution of highly pathogenic avian influenza (H5N1) virus populations in Vietnam between 2007 and 2010.
Nguyen T , Rivailler P , Davis CT , Thi Hoa D , Balish A , Hoang Dang N , Jones J , Thi Vui D , Simpson N , Thu Huong N , Shu B , Loughlin R , Ferdinand K , Lindstrom SE , York IA , Klimov A , Donis RO . Virology 2012 432 (2) 405-16 We report on the genetic analysis of 213 highly pathogenic avian influenza (HPAI) H5N1 viruses isolated from poultry in Vietnam between 2007 and 2010. Phylogenetic analyses of the viral genomes revealed 38 distinct viral genotypes, 29 were novel and 9 were reported in Vietnam or neighboring countries in recent years. Viruses from only six genotypes persisted beyond one season or year. Thus, most reassortant viruses were transient, suggesting that such genotypes lacked significant fitness advantages. Viruses with clade 2.3.2.1 HA were re-introduced into Vietnam in 2009 and their prevalence rose steeply towards the end of 2010. Clade 2.3.4-like viruses (genotype V) were predominant in northern Vietnam and caused the majority of zoonotic infections, whereas clade 1.1 (genotype Z) viruses were only detected in the Mekong delta region, in southern Vietnam. Antigenic analysis of representative viruses from the four clades indicated substantial drift. |
Evolutionary history and phylodynamics of influenza A and B neuraminidase (NA) genes inferred from large-scale sequence analyses.
Xu J , Davis CT , Christman MC , Rivailler P , Zhong H , Donis RO , Lu G . PLoS One 2012 7 (7) e38665 BACKGROUND: Influenza neuraminidase (NA) is an important surface glycoprotein and plays a vital role in viral replication and drug development. The NA is found in influenza A and B viruses, with nine subtypes classified in influenza A. The complete knowledge of influenza NA evolutionary history and phylodynamics, although critical for the prevention and control of influenza epidemics and pandemics, remains lacking. METHODOLOGY/PRINCIPAL FINDINGS: Evolutionary and phylogenetic analyses of influenza NA sequences using Maximum Likelihood and Bayesian MCMC methods demonstrated that the divergence of influenza viruses into types A and B occurred earlier than the divergence of influenza A NA subtypes. Twenty-three lineages were identified within influenza A, two lineages were classified within influenza B, and most lineages were specific to host, subtype or geographical location. Interestingly, evolutionary rates vary not only among lineages but also among branches within lineages. The estimated tMRCAs of influenza lineages suggest that the viruses of different lineages emerge several months or even years before their initial detection. The d(N)/d(S) ratios ranged from 0.062 to 0.313 for influenza A lineages, and 0.257 to 0.259 for influenza B lineages. Structural analyses revealed that all positively selected sites are at the surface of the NA protein, with a number of sites found to be important for host antibody and drug binding. CONCLUSIONS/SIGNIFICANCE: The divergence into influenza type A and B from a putative ancestral NA was followed by the divergence of type A into nine NA subtypes, of which 23 lineages subsequently diverged. This study provides a better understanding of influenza NA lineages and their evolutionary dynamics, which may facilitate early detection of newly emerging influenza viruses and thus improve influenza surveillance. |
Increased immunogenicity of avian influenza DNA vaccine delivered to the skin using a microneedle patch.
Kim YC , Song JM , Lipatov AS , Choi SO , Lee JW , Donis RO , Compans RW , Kang SM , Prausnitz MR . Eur J Pharm Biopharm 2012 81 (2) 239-47 Effective public health responses to an influenza pandemic require an effective vaccine that can be manufactured and administered to large populations in the shortest possible time. In this study, we evaluated a method for vaccination against avian influenza virus that uses a DNA vaccine for rapid manufacturing and delivered by a microneedle skin patch for simplified administration and increased immunogenicity. We prepared patches containing 700-mcm long microneedles coated with an avian H5 influenza hemagglutinin DNA vaccine from A/Viet Nam/1203/04 influenza virus. The coating DNA dose increased with DNA concentration in the coating solution and the number of dip-coating cycles. Coated DNA was released into the skin tissue by dissolution within minutes. Vaccination of mice using microneedles induced higher levels of antibody responses and hemagglutination inhibition titers, and improved protection against lethal infection with avian influenza as compared to conventional intramuscular delivery of the same dose of the DNA vaccine. Additional analysis showed that the microneedle coating solution containing carboxymethylcellulose and a surfactant may have negatively affected the immunogenicity of the DNA vaccine. Overall, this study shows that DNA vaccine delivery by microneedles can be a promising approach for improved vaccination to mitigate an influenza pandemic. |
The 3' untranslated regions of influenza genomic sequences are 5'PPP-independent ligands for RIG-I.
Davis WG , Bowzard JB , Sharma SD , Wiens ME , Ranjan P , Gangappa S , Stuchlik O , Pohl J , Donis RO , Katz JM , Cameron CE , Fujita T , Sambhara S . PLoS One 2012 7 (3) e32661 Retinoic acid inducible gene-I (RIG-I) is a key regulator of antiviral immunity. RIG-I is generally thought to be activated by ssRNA species containing a 5'-triphosphate (PPP) group or by unphosphorylated dsRNA up to approximately 300 bp in length. However, it is not yet clear how changes in the length, nucleotide sequence, secondary structure, and 5' end modification affect the abilities of these ligands to bind and activate RIG-I. To further investigate these parameters in the context of naturally occurring ligands, we examined RNA sequences derived from the 5' and 3' untranslated regions (UTR) of the influenza virus NS1 gene segment. As expected, RIG-I-dependent interferon-beta (IFN-beta) induction by sequences from the 5' UTR of the influenza cRNA or its complement (26 nt in length) required the presence of a 5'PPP group. In contrast, activation of RIG-I by the 3' UTR cRNA sequence or its complement (172 nt) exhibited only a partial 5'PPP-dependence, as capping the 5' end or treatment with CIP showed a modest reduction in RIG-I activation. Furthermore, induction of IFN-beta by a smaller, U/A-rich region within the 3' UTR was completely 5'PPP-independent. Our findings demonstrated that RNA sequence, length, and secondary structure all contributed to whether or not the 5'PPP moiety is needed for interferon induction by RIG-I. |
A distinct lineage of influenza A virus from bats.
Tong S , Li Y , Rivailler P , Conrardy C , Castillo DA , Chen LM , Recuenco S , Ellison JA , Davis CT , York IA , Turmelle AS , Moran D , Rogers S , Shi M , Tao Y , Weil MR , Tang K , Rowe LA , Sammons S , Xu X , Frace M , Lindblade KA , Cox NJ , Anderson LJ , Rupprecht CE , Donis RO . Proc Natl Acad Sci U S A 2012 109 (11) 4269-74 Influenza A virus reservoirs in animals have provided novel genetic elements leading to the emergence of global pandemics in humans. Most influenza A viruses circulate in waterfowl, but those that infect mammalian hosts are thought to pose the greatest risk for zoonotic spread to humans and the generation of pandemic or panzootic viruses. We have identified an influenza A virus from little yellow-shouldered bats captured at two locations in Guatemala. It is significantly divergent from known influenza A viruses. The HA of the bat virus was estimated to have diverged at roughly the same time as the known subtypes of HA and was designated as H17. The neuraminidase (NA) gene is highly divergent from all known influenza NAs, and the internal genes from the bat virus diverged from those of known influenza A viruses before the estimated divergence of the known influenza A internal gene lineages. Attempts to propagate this virus in cell cultures and chicken embryos were unsuccessful, suggesting distinct requirements compared with known influenza viruses. Despite its divergence from known influenza A viruses, the bat virus is compatible for genetic exchange with human influenza viruses in human cells, suggesting the potential capability for reassortment and contributions to new pandemic or panzootic influenza A viruses. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Apr 29, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure