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2.
BMC Infect Dis ; 22(1): 820, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344911

RESUMO

BACKGROUND: Influenza is responsible for more than 5 million severe cases and 290,000 to 650,000 deaths every year worldwide. Developing countries account for 99% of influenza deaths in children under 5 years of age. This paper aimed to determine the dynamics of influenza viruses in African transmission areas to identify regional seasonality for appropriate decision-making and the development of regional preparedness and response strategies. METHODS: We used data from the WHO FluMart website collected by National Influenza Centers for seven transmission periods (2013-2019). We calculated weekly proportions of positive influenza cases and determined transmission trends in African countries to determine the seasonality. RESULTS: From 2013 to 2019, influenza A(H1N1)pdm2009, A(H3N2), and A(H5N1) viruses, as well as influenza B Victoria and Yamagata lineages, circulated in African regions. Influenza A(H1N1)pdm2009 and A(H3N2) highly circulated in northern and southern Africa regions. Influenza activity followed annual and regional variations. In the tropical zone, from eastern to western via the middle regions, influenza activities were marked by the predominance of influenza A subtypes despite the circulation of B lineages. One season was identified for both the southern and northern regions of Africa. In the eastern zone, four influenza seasons were differentiated, and three were differentiated in the western zone. CONCLUSION: Circulation dynamics determined five intense influenza activity zones in Africa. In the tropics, influenza virus circulation waves move from the east to the west, while alternative seasons have been identified in northern and southern temperate zones. Health authorities from countries with the same transmission zone, even in the absence of local data based on an established surveillance system, should implement concerted preparedness and control activities, such as vaccination.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza B , Influenza Humana , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Vírus da Influenza B/genética , Vírus da Influenza B/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/transmissão , Influenza Humana/virologia , Estações do Ano , África/epidemiologia
3.
Curr Opin Immunol ; 78: 102252, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36215931

RESUMO

The outbreak of the COVID-19 pandemic one year after the centennial of the 1918 influenza pandemic reaffirms the catastrophic impact respiratory viruses can have on global health and economy. A key feature of SARS-CoV-2 and influenza A viruses (IAV) is their remarkable ability to suppress or dysregulate human immune responses. Here, we summarize the growing knowledge about the interplay of SARS-CoV-2 and antiviral innate immunity, with an emphasis on the regulation of type-I or -III interferon responses that are critically implicated in COVID-19 pathogenesis. Furthermore, we draw parallels to IAV infection and discuss shared innate immune sensing mechanisms and the respective viral countermeasures.


Assuntos
COVID-19 , Influenza Humana , Interferons , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Imunidade Inata , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Influenza Humana/metabolismo , Influenza Humana/virologia , Interferons/imunologia , Pandemias , SARS-CoV-2/imunologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-36154657

RESUMO

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 2,393 human influenza positive samples between 1 January 2020 and 31 December 2021 (2020: n = 2,021 samples; 2021: n = 372 samples). Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hen's eggs for potential use in seasonal influenza virus vaccines. During 2020-2021, influenza A viruses (A(H1N1)pdm09 in 2020 and A(H3N2) in 2021) predominated over influenza B viruses. In 2020, the majority of A(H1N1)pdm09, A(H3N2) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the southern hemisphere in 2020. In 2021, the majority of A(H1N1)pdm09 and A(H3N2) viruses were found to be antigenically distinct relative to the WHO recommended vaccine strains for the southern hemisphere in 2021. Of the influenza B viruses analysed at the Centre, 46.7% were found to be antigenically distinct to the respective WHO recommended vaccine strains. Of 1,538 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir (in 2020, n = 1,374; in 2021, n = 164), two A(H1N1)pdm09 viruses showed highly reduced inhibition against oseltamivir, and one A(H1N1)pdm09 virus showed highly reduced inhibition against zanamivir. All of these samples were received in 2020.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Influenza Humana , Antivirais/farmacologia , Austrália/epidemiologia , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza B/genética , Vacinas contra Influenza , Influenza Humana/epidemiologia , Influenza Humana/virologia , Neuraminidase , Oseltamivir/farmacologia , Organização Mundial da Saúde , Zanamivir/farmacologia
5.
Sheng Wu Gong Cheng Xue Bao ; 38(9): 3390-3405, 2022 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-36151808

RESUMO

Influenza B virus (IBV) is more likely to cause complications than influenza A virus (IAV) and even causes higher disease burden than IAV in a certain season, but IBV has received less attention. In order to analyze the genetic evolution characteristics of the clinical strain IBV (B/Guangxi-Jiangzhou/1352/2018), we constructed genetic evolution trees and analyzed the homology and different amino acids of hemagglutinin and neuraminidase referring to the vaccine strains recommended by World Health Organization (WHO). We found that strain B/Guangxi-Jiangzhou/1352/2018 was free of interlineage reassortment and poorly matched with the vaccine strain B/Colorado/06/2017 of the same year. We also determined the median lethal dose (LD50) and the pathogenicity of strain B/Guangxi-Jiangzhou/1352/2018 in mice. The results showed that the LD50 was 105.9 TCID50 (median tissue culture infective dose), the IBV titer in the lungs reached peak 1 d post infection and the mRNA level of the most of inflammatory cytokines in the lungs reached peak 12 h post infection. The alveoli in the lungs were severely damaged and a large number of inflammatory cells were infiltrated post infection. The study demonstrated that the clinical strain IBV (B/Guangxi-Jiangzhou/1352/2018) could infect mice and induce typical lung inflammation. This will facilitate the research on the pathogenesis and transmission mechanism of IBV, and provide an ideal animal model for evaluation of new vaccines, antiviral and anti-inflammatory drug.


Assuntos
Vírus da Influenza B , Influenza Humana , Aminoácidos/genética , Animais , Antivirais/farmacologia , China , Citocinas/metabolismo , Hemaglutininas/metabolismo , Humanos , Vírus da Influenza B/genética , Vírus da Influenza B/patogenicidade , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Neuraminidase/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Filogenia , RNA Mensageiro/metabolismo , Virulência/genética
6.
PLoS One ; 17(9): e0271321, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36149889

RESUMO

Recent reports of haemagglutinin antigen (HA) mismatch between vaccine composition strains and circulating strains, have led to renewed interest in influenza B viruses. Additionally, there are concerns about resistance to neuraminidase inhibitors in new influenza B isolates. To assess the potential impact in Ghana, we characterized the lineages of influenza B viruses that circulated in Ghana between 2016 and 2017 from different regions of the country: Southern, Northern and Central Ghana. Eight representative specimens from the three regions that were positive for influenza B virus by real-time RT-PCR were sequenced and compared to reference genomes from each lineage. A total of eleven amino acids substitutions were detected in the B/Victoria lineage and six in the B/Yamagata lineage. The strains of influenza B viruses were closely related to influenza B/Brisbane/60/2008 and influenza B/Phuket/3073/2013 for the Victoria and Yamagata lineages, respectively. Three main amino acid substitutions (P31S, I117V and R151K) were found in B/Victoria lineages circulating between 2016 and 2017, while one strain of B/Victoria possessed a unique glycosylation site at amino acid position 51 in the HA2 subunit. Two main substitutions (L172Q and M251V) were detected in the HA gene of the B/Yamagata lineage. The U.S. CDC recently reported a deletion sub-group in influenza B virus, but this was not identified among the Ghanaian specimens. Close monitoring of the patterns of influenza B evolution is necessary for the efficient selection of representative viruses for the design and formulation of effective influenza vaccines.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza B , Influenza Humana , Aminoácidos/genética , Gana/epidemiologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza B/genética , Influenza Humana/virologia , Neuraminidase/genética , Filogenia
7.
FASEB J ; 36(10): e22537, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36070077

RESUMO

Influenza A viruses (IAVs) rely on viral ribonucleoprotein (vRNP) complexes to control transcription and replication. Each vRNP consists of one viral genomic RNA segment associated with multiple nucleoproteins (NP) and a trimeric IAV RNA polymerase complex. Previous studies showed that post-translational modifications of vRNP components, such as NP, by host factors would in turn affect the IAV life cycle or modulate host anti-viral response. In this study, we found host E3 ubiquitin ligase Pirh2 interacted with NP and mediated short-chain ubiquitination of NP at lysine 351, which suppressed NP-PB2 interaction and vRNP formation. In addition, we showed that knockdown of Pirh2 promoted IAV replication, whereas overexpression of Pirh2 inhibited IAV replication. However, Pirh2-ΔRING lacking E3 ligase activity failed to inhibit IAV infection. Moreover, we showed that Pirh2 had no effect on the replication of a rescued virus, WSN-K351R, carrying lysine-to-arginine substitution at residue 351. Interestingly, by analyzing human and avian IAVs from 2011 to 2020 in influenza research databases, we found that 99.18% of 26 977 human IAVs encode lysine, but 95.3% of 9956 avian IAVs encode arginine at residue 351 of NP protein. Consistently, knockdown of Pirh2 failed to promote propagation of two avian-like influenza viruses, H9N2-W1 and H9N2-C1, which naturally encode arginine at residue 351 of NP. Taken together, we demonstrated that Pirh2 is a host factor restricting IAV infection by modulating short-chain ubiquitination of NP. Meanwhile, it is noteworthy that residue 351 of NP targeted by Pirh2 may associate with the evasion of human anti-viral response against avian-like influenza viruses.


Assuntos
Vírus da Influenza A Subtipo H9N2 , Ribonucleoproteínas , Ubiquitina-Proteína Ligases , Replicação Viral , Arginina/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/fisiologia , Influenza Humana/virologia , Lisina/metabolismo , RNA Viral/metabolismo , Ribonucleoproteínas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
8.
J Virol ; 96(16): e0097122, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35916512

RESUMO

The continuous antigenic variation of influenza A viruses remains a major hurdle for vaccine selection; however, the molecular determinants and mechanisms of antigenic change remain largely unknown. In this study, two escape mutants were generated by serial passages of the Eurasian avian-like H1N1 swine influenza virus (EA H1N1 SIV) A/swine/Henan/11/2005 (HeN11) in the presence of two neutralizing monoclonal antibodies (mAbs) against the hemagglutinin (HA) protein, which were designated HeN11-2B6-P5 and HeN11-4C7-P8, respectively. The HeN11-2B6-P5 mutant simultaneously harbored the N190D and I230M substitutions in HA, whereas HeN11-4C7-P8 harbored the M269R substitution in HA (H3 numbering). The effects of each of these substitutions on viral antigenicity were determined by measuring the neutralization and hemagglutination inhibition (HI) titers with mAbs and polyclonal sera raised against the representative viruses. The results indicate that residues 190 and 269 are key determinants of viral antigenic variation. In particular, the N190D mutation had the greatest antigenic impact, as determined by the HI assay. Further studies showed that both HeN11-2B6-P5 and HeN11-4C7-P8 maintained the receptor-binding specificity of the parent virus, although the single mutation N190D decreased the binding affinity for the human-type receptor. The replicative ability in vitro of HeN11-2B6-P5 was increased, whereas that of HeN11-4C7-P8 was decreased. These findings extend our understanding of the antigenic evolution of influenza viruses under immune pressure and provide insights into the functional effects of amino acid substitutions near the receptor-binding site and the interplay among receptor binding, viral replication, and antigenic drift. IMPORTANCE The antigenic changes that occur continually in the evolution of influenza A viruses remain a great challenge for the effective control of disease outbreaks. Here, we identified three amino acid substitutions (at positions 190, 230, and 269) in the HA of EA H1N1 SIVs that determine viral antigenicity and result in escape from neutralizing monoclonal antibodies. All three of these substitutions have emerged in nature. Of note, residues 190 and 230 have synergistic effects on receptor binding and antigenicity. Our findings provide a better understanding of the functional effects of amino acid substitutions in HA and their consequences for the antigenic drift of influenza viruses.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Evasão da Resposta Imune , Vírus da Influenza A Subtipo H1N1 , Animais , Anticorpos Monoclonais , Anticorpos Neutralizantes/genética , Anticorpos Antivirais , Deriva e Deslocamento Antigênicos , Antígenos Virais/genética , Hemaglutininas , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Mutação , Suínos
9.
J Virol ; 96(16): e0089622, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35916534

RESUMO

Among circulating influenza viruses in humans, H3N2 viruses typically evolve faster than other subtypes and have caused disease in millions of people since emerging in 1968. Computationally optimized broadly reactive antigen (COBRA) technology is one strategy to broaden vaccine-elicited antibody responses among influenza subtypes. In this study, we determined the structural integrity of an H3N2 COBRA hemagglutinin (HA), TJ5, and we probed the antigenic profile of several H3N2 COBRA HAs by assessing recognition of these immunogens by human B cells from seasonally vaccinated human subjects. Of three recently described COBRA H3 HA antigens (TJ5, NG2, and J4), we determined that TJ5 and J4 HA proteins recognize pre-existing B cells more effectively than NG2 HA and a wild-type Hong Kong/4801/2014 protein. We also isolated a panel of 12 H3 HA-specific human monoclonal antibodies (MAbs) and identified that most MAbs recognize both wild-type and COBRA HA proteins and have functional activity against a broad panel of H3N2 viruses. Most MAbs target the receptor-binding site, and one MAb targets the HA stem. MAb TJ5-5 recognizes TJ5 and J4 COBRA HA proteins but has poor recognition of NG2 HA, similar to the global B-cell analysis. We determined a 3.4 Å structure via cryo-electron microscopy of Fab TJ5-5 complexed with the H3 COBRA TJ5, which revealed residues important to the differential binding. Overall, these studies determined that COBRA H3 HA proteins have correct antigenic and structural features, and the proteins are recognized by B cells and MAbs isolated from seasonally vaccinated humans. IMPORTANCE Vaccine development for circulating influenza viruses, particularly for the H3N2 subtype, remains challenging due to consistent antigenic drift. Computationally optimized broadly reactive antigen (COBRA) technology has proven effective for broadening influenza hemagglutinin (HA)-elicited antibody responses compared to wild-type immunogens. Here, we determined the structural features and antigenic profiles of H3 COBRA HA proteins. Two H3 COBRA HA proteins, TJ5 and J4, are better recognized by pre-existing B cells and monoclonal antibodies from the 2017 to 2018 vaccine season compared to COBRA NG2 and a wild-type A/Hong Kong/2014 HA protein. We determined a cryo-electron microscopy (cryo-EM) structure of one MAb that poorly recognizes NG2, MAb TJ5-5, in complex with the TJ5 COBRA HA protein and identified residues critical to MAb recognition. As NG2 is more effective than TJ5 for the recent Hong Kong/2019 virus, these data provide insights into the diminished effectiveness of influenza vaccines across vaccine seasons.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Vacinas contra Influenza , Influenza Humana , Anticorpos Monoclonais , Microscopia Crioeletrônica , Hemaglutininas , Humanos , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/química , Influenza Humana/imunologia , Influenza Humana/virologia
10.
Virus Genes ; 58(5): 392-402, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35900664

RESUMO

The evolution of seasonal influenza viruses, which can cause virus antigenic drift to escape human herd immunity, is a significant public health problem. Here, we obtained hemagglutinin (HA), neuraminidase (NA), and polymerase acidic protein (PA) the gene sequences of 84 influenza virus isolates collected in Guangdong Province during the 2019-2020 influenza season. Phylogenetic analyses revealed all these isolates were genetically similar to the viruses of clade 3C2a A1b, specifically those within subclades of A1b 137F (59 cases), A1b 186D (19 cases), and A1b 94 N (6 cases). The influenza virus isolates were distinct from the World Health Organization recommended influenza A vaccine virus for the 2019-2020 Northern Hemisphere season (A/Kansas/14/2017; H3N2). Phylogenies inferred from the individual gene segment sequences revealed that one reassortment event occurred among these clades. The genetic variation involved mutations within viral antigenic epitopes and two N-glycosylation site alterations. The novel mutation sites of G202D and D206N in the HA gene, E344K in the NA gene, and K626R in the PA gene which may affect the spread of the virus were observed. We investigated the evolution of these genes and found that the HA and NA genes were under greater pressure than PA gene. Mutations associated with conferring resistance to NA inhibitors or baloxavir acid were not found. Our results suggest that a rapid evolution of the H3N2 influenza virus occurred, thus continuous monitoring is critical for establishing appropriate vaccine formulations or drug delivery for targeting influenza.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana , Neuraminidase/genética , China , Epitopos , Evolução Molecular , Humanos , Influenza Humana/epidemiologia , Influenza Humana/virologia , Filogenia , RNA Viral/genética
11.
J Virol ; 96(15): e0076522, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35862681

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) represent two highly transmissible airborne pathogens with pandemic capabilities. Although these viruses belong to separate virus families-SARS-CoV-2 is a member of the family Coronaviridae, while IAV is a member of the family Orthomyxoviridae-both have shown zoonotic potential, with significant animal reservoirs in species in close contact with humans. The two viruses are similar in their capacity to infect human airways, and coinfections resulting in significant morbidity and mortality have been documented. Here, we investigate the interaction between SARS-CoV-2 USA-WA1/2020 and influenza H1N1 A/California/04/2009 virus during coinfection. Competition assays in vitro were performed in susceptible cells that were either interferon type I/III (IFN-I/-III) nonresponsive or IFN-I/-III responsive, in addition to an in vivo golden hamster model. We find that SARS-CoV-2 infection does not interfere with IAV biology in vivo, regardless of timing between the infections. In contrast, we observe a significant loss of SARS-CoV-2 replication following IAV infection. The latter phenotype correlates with increased levels of IFN-I/-III and immune priming that interferes with the kinetics of SARS-CoV-2 replication. Together, these data suggest that cocirculation of SARS-CoV-2 and IAV is unlikely to result in increased severity of disease. IMPORTANCE The human population now has two circulating respiratory RNA viruses with high pandemic potential, namely, SARS-CoV-2 and influenza A virus. As both viruses infect the airways and can result in significant morbidity and mortality, it is imperative that we also understand the consequences of getting coinfected. Here, we demonstrate that the host response to influenza A virus uniquely interferes with SARS-CoV-2 biology although the inverse relationship is not evident. Overall, we find that the host response to both viruses is comparable to that to SARS-CoV-2 infection alone.


Assuntos
COVID-19 , Coinfecção , Apresentação Cruzada , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , SARS-CoV-2 , Replicação Viral , Animais , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Coinfecção/imunologia , Coinfecção/virologia , Apresentação Cruzada/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Interferons/imunologia , Mesocricetus/imunologia , Mesocricetus/virologia , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/imunologia , Replicação Viral/imunologia
12.
J Virol ; 96(15): e0041622, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35862707

RESUMO

Avian or human influenza A viruses bind preferentially to avian- or human-type sialic acid receptors, respectively, indicating that receptor tropism is an important factor for determining the viral host range. However, there are currently no reliable methods for analyzing receptor tropism biologically under physiological conditions. In this study, we established a novel system using MDCK cells with avian- or human-type sialic acid receptors and with both sialic acid receptors knocked out (KO). When we examined the replication of human and avian influenza viruses in these KO cells, we observed unique viral receptor tropism that could not be detected using a conventional solid-phase sialylglycan binding assay, which directly assesses physical binding between the virus and sialic acids. Furthermore, we serially passaged an engineered avian-derived H4N5 influenza virus, whose PB2 gene was deleted, in avian-type receptor KO cells stably expressing PB2 to select a mutant with enhanced replication in KO cells; however, its binding to human-type sialylglycan was undetectable using the solid-phase binding assay. These data indicate that a panel of sialic acid receptor KO cells could be a useful tool for determining the biological receptor tropism of influenza A viruses. Moreover, the PB2KO virus experimental system could help to safely and efficiently identify the mutations required for avian influenza viruses to adapt to human cells that could trigger a new influenza pandemic. IMPORTANCE The acquisition of mutations that allow avian influenza A virus hemagglutinins to recognize human-type receptors is mandatory for the transmission of avian viruses to humans, which could lead to a pandemic. In this study, we established a novel system using a set of genetically engineered MDCK cells with knocked out sialic acid receptors to biologically evaluate the receptor tropism for influenza A viruses. Using this system, we observed unique receptor tropism in several virus strains that was undetectable using conventional solid-phase binding assays that measure physical binding between the virus and artificially synthesized sialylglycans. This study contributes to elucidation of the relationship between the physical binding of virus and receptor and viral infectivity. Furthermore, the system using sialic acid knockout cells could provide a useful tool to explore the sialic acid-independent entry mechanism. In addition, our system could be safely used to identify mutations that could acquire human-type receptor tropism.


Assuntos
Vírus da Influenza A , Ácido N-Acetilneuramínico , Receptores de Superfície Celular , Receptores Virais , Tropismo Viral , Internalização do Vírus , Animais , Aves/virologia , Cães , Técnicas de Inativação de Genes , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/metabolismo , Influenza Aviária/virologia , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Ácido N-Acetilneuramínico/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/metabolismo
13.
J Virol ; 96(15): e0091822, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35867563

RESUMO

Oseltamivir-resistant influenza viruses arise due to amino acid mutations in key residues of the viral neuraminidase (NA). These changes often come at a fitness cost; however, it is known that permissive mutations in the viral NA can overcome this cost. This result was observed in former seasonal A(H1N1) viruses in 2007 which expressed the H275Y substitution (N1 numbering) with no apparent fitness cost and lead to widespread oseltamivir resistance. Therefore, this study aims to predict permissive mutations that may similarly enable fit H275Y variants to arise in currently circulating A(H1N1)pdm09 viruses. The first approach in this study utilized in silico analyses to predict potentially permissive mutations. The second approach involved the generation of a virus library which encompassed all possible NA mutations while keeping H275Y fixed. Fit variants were then selected by serially passaging the virus library either through ferrets by transmission or passaging once in vitro. The fitness impact of selected substitutions was further evaluated experimentally. The computational approach predicted three candidate permissive NA mutations which, in combination with each other, restored the replicative fitness of an H275Y variant. The second approach identified a stringent bottleneck during transmission between ferrets; however, three further substitutions were identified which may improve transmissibility. A comparison of fit H275Y variants in vitro and in experimentally infected animals showed a statistically significant correlation in the variants that were positively selected. Overall, this study provides valuable tools and insights into potential permissive mutations that may facilitate the emergence of a fit H275Y A(H1N1)pdm09 variant. IMPORTANCE Oseltamivir (Tamiflu) is the most widely used antiviral for the treatment of influenza infections. Therefore, resistance to oseltamivir is a public health concern. This study is important as it explores the different evolutionary pathways available to current circulating influenza viruses that may lead to widespread oseltamivir resistance. Specifically, this study develops valuable experimental and computational tools to evaluate the fitness landscape of circulating A(H1N1)pmd09 influenza viruses bearing the H275Y mutation. The H275Y substitution is most commonly reported to confer oseltamivir resistance but also leads to loss of virus replication and transmission fitness, which limits its spread. However, it is known from previous influenza seasons that influenza viruses can evolve to overcome this loss of fitness. Therefore, this study aims to prospectively predict how contemporary A(H1N1)pmd09 influenza viruses may evolve to overcome the fitness cost of bearing the H275Y NA substitution, which could result in widespread oseltamivir resistance.


Assuntos
Substituição de Aminoácidos , Farmacorresistência Viral , Aptidão Genética , Vírus da Influenza A Subtipo H1N1 , Mutação , Neuraminidase , Proteínas Virais , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Simulação por Computador , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Furões/virologia , Aptidão Genética/genética , Humanos , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/transmissão , Influenza Humana/virologia , Neuraminidase/genética , Neuraminidase/metabolismo , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Proteínas Virais/genética , Proteínas Virais/metabolismo
14.
PLoS One ; 17(7): e0270814, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35793318

RESUMO

INTRODUCTION: Influenza A virus infection is a contagious acute respiratory infection which mostly evolves in an epidemic form, less frequently as pandemic outbreaks. It can take a severe clinical form that needs to be managed in intensive care unit (ICU). The aim of this study was to describe the epidemiological and clinical aspects of influenza A, then to determine independent predictive factors of ICU mortality in Abderrahmen Mami hospital, Ariana, Tunisia. METHODS: It was a single-center study, including all hospitalized patients in intensive care, between November 1st, 2009 and October 31st, 2019, with influenza A virus infection. We recorded demographic, clinical and biological data, evolving features; then multivariate analysis of the predictive factors of ICU mortality was realized. RESULTS: During the study period (10 consecutive seasons), 120 patients having severe Influenza A were admitted (Proportion = 2.5%) from all hospitalized patients, with a median age of 48 years and a gender-ratio of 1.14. Among women, 14 were pregnant. Only 7 patients (5.8%) have had seasonal flu vaccine during the year before ICU admission. The median values of the Simplified Acute Physiology Score II, Acute Physiologic and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment were respectively 26, 10 and 3. Virus strains identified with polymerase chain reaction were H1N1 pdm09 (84.2%) and H3N2 (15.8%). Antiviral therapy was prescribed in 88 (73.3%) patients. A co-infection was recorded in 19 cases: bacterial (n = 17) and aspergillaire (n = 2). An acute respiratory distress syndrome (ARDS) was diagnosed in 82 patients. Non-invasive ventilation (NIV) was conducted for 72 (60%) patients with success in 34 cases. Endotracheal intubation was performed in 59 patients with median duration of invasive mechanical ventilation 8 [3.25-13] days. The most frequent complications were acute kidney injury (n = 50, 41.7%), shock (n = 48, 40%), hospital-acquired infections (n = 46, 38.8%) and thromboembolic events (n = 19, 15.8%). The overall ICU mortality rate was of 31.7% (deceased n = 38). Independent predictive factors of ICU mortality identified were: age above 56 years (OR = 7.417; IC95% [1.474-37.317]; p = 0.015), PaO2/FiO2 ≤ 95 mmHg (OR = 9.078; IC95% [1.636-50.363]; p = 0.012) and lymphocytes count ≤ 1.325 109/L (OR = 10.199; IC95% [1.550-67.101]; p = 0.016). CONCLUSION: Influenza A in ICU is not uncommon, even in A(H1N1) dominant seasons; its management is highly demanding. It is responsible for considerable morbi-mortality especially in elderly patients.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Influenza Humana , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Influenza Humana/epidemiologia , Influenza Humana/mortalidade , Influenza Humana/terapia , Influenza Humana/virologia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva , Gravidade do Paciente , Gravidez , Fatores de Risco , Tunísia/epidemiologia
15.
PLoS Pathog ; 18(6): e1010228, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35675358

RESUMO

Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis.


Assuntos
Fator 9 de Crescimento de Fibroblastos , Vírus da Influenza A , Influenza Humana , Interferon Tipo I , Infecções por Orthomyxoviridae , Animais , Citocinas/metabolismo , Células Epiteliais/metabolismo , Fator 9 de Crescimento de Fibroblastos/biossíntese , Humanos , Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Influenza Humana/virologia , Interferon Tipo I/metabolismo , Camundongos , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia
16.
Int J Infect Dis ; 121: 195-202, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35584743

RESUMO

OBJECTIVES: Because of the spread of the Omicron variant, many countries have experienced COVID-19 case numbers unseen since the start of the pandemic. We aimed to compare the epidemiological characteristics of Omicron with previous variants and different strains of influenza to provide context for public health responses. METHODS: We developed transmission models for SARS-CoV-2 variants and influenza, in which transmission, death, and vaccination rates were taken to be time-varying. We fit our model based on publicly available data in South Africa, the United States, and Canada. We used this model to evaluate the relative transmissibility and mortality of Omicron compared with previous variants and influenza. RESULTS: We found that Omicron is more transmissible and less fatal than both seasonal and 2009 H1N1 influenza and the Delta variant; these characteristics make Omicron epidemiologically more similar to influenza than it is to Delta. We estimate that as of February 7, 2022, booster doses have prevented 4.29×107 and 1.14×106 Omicron infections in the United States and Canada, respectively. CONCLUSION: Our findings indicate that the high infectivity of Omicron will keep COVID-19 endemic, similar to influenza. However, because of Omicron's lower fatality rate, our work suggests that human populations living with SARS-CoV-2 are most likely.


Assuntos
COVID-19 , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Mutação , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/prevenção & controle , Influenza Humana/virologia , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Estados Unidos/epidemiologia
17.
J Virol ; 96(11): e0220021, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35588275

RESUMO

An H1N1 influenza virus caused a pandemic in 2009, and descendants of this virus continue to circulate seasonally in humans. Upon infection with the 2009 H1N1 pandemic strain (pH1N1), many humans produced antibodies against epitopes in the hemagglutinin (HA) stalk. HA stalk-focused antibody responses were common among pH1N1-infected individuals because HA stalk epitopes were conserved between the pH1N1 strain and previously circulating H1N1 strains. Here, we completed a series of experiments to determine if the pH1N1 HA stalk has acquired substitutions since 2009 that prevent the binding of human antibodies. We identified several amino acid substitutions that accrued in the pH1N1 HA stalk from 2009 to 2019. We completed enzyme-linked immunosorbent assays, absorption-based binding assays, and surface plasmon resonance experiments to determine if these substitutions affect antibody binding. Using sera collected from 230 humans (aged 21 to 80 years), we found that pH1N1 HA stalk substitutions that have emerged since 2009 do not affect antibody binding. Our data suggest that the HA stalk domain of pH1N1 viruses remained antigenically stable after circulating in humans for a decade. IMPORTANCE In 2009, a new pandemic H1N1 (pH1N1) virus began circulating in humans. Many individuals mounted hemagglutinin (HA) stalk-focused antibody responses upon infection with the 2009 pH1N1 strain, since the HA stalk of this virus was relatively conserved with other seasonal H1N1 strains. Here, we completed a series of studies to determine if the 2009 pH1N1 strain has undergone antigenic drift in the HA stalk domain over the past decade. We found that serum antibodies from 230 humans could not antigenically distinguish the 2009 and 2019 HA stalk. These data suggest that the HA stalk of pH1N1 has remained antigenically stable, despite the presence of high levels of HA stalk antibodies within the human population.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Epitopos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/virologia , Pessoa de Meia-Idade , Adulto Jovem
18.
Viruses ; 14(5)2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35632832

RESUMO

During 2016-2017, the H7N2 feline influenza virus infected more than 500 cats in animal shelters in New York, USA. A veterinarian who had treated the cats became infected with this feline virus and showed mild respiratory symptoms. This suggests that the H7N2 feline influenza virus may evolve into a novel pandemic virus with a high pathogenicity and transmissibility as a result of mutations in humans. In this study, to gain insight into the molecular basis of the transmission of the feline virus to humans, we selected mutant viruses with enhanced growth in human respiratory A549 cells via successive passages of the virus and found almost all mutations to be in the envelope glycoproteins, such as hemagglutinin (HA) and neuraminidase (NA). The reverse genetics approach revealed that the HA mutations, HA1-H16Q, HA2-I47T, or HA2-Y119H, in the stalk region can lead to a high growth of mutant viruses in A549 cells, possibly by changing the pH threshold for membrane fusion. Furthermore, NA mutation, I28S/L, or three-amino-acid deletion in the transmembrane region can enhance viral growth in A549 cells, possibly by changing the HA-NA functional balance. These findings suggest that the H7N2 feline influenza virus has the potential to become a human pathogen by adapting to human respiratory cells, owing to the synergistic biological effect of the mutations in its envelope glycoproteins.


Assuntos
Evolução Molecular , Vírus da Influenza A Subtipo H7N2 , Influenza Humana , Animais , Gatos , Técnicas de Cultura de Células , Glicoproteínas , Hemaglutininas/genética , Humanos , Vírus da Influenza A Subtipo H7N2/genética , Influenza Humana/virologia , Neuraminidase/genética , Neuraminidase/metabolismo
19.
Cell Mol Immunol ; 19(6): 715-725, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35459853

RESUMO

Host immune responses, such as those initiated by pattern recognition receptor (PRR) activation, are important for viral clearance and pathogenesis. However, little is known about the interactions of viral proteins with surface PRRs or, more importantly, the association of innate immune activation with viral pathogenesis. In this study, we showed that internal influenza virus proteins were released from infected cells. Among these proteins, nucleoprotein (NP) played a critical role in viral pathogenesis by stimulating neighboring cells through toll-like receptor (TLR)2, TLR4, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Through the activation of these PRRs, NP induced the production of interleukin (IL)-1ß and IL-6, which subsequently led to the induction of trypsin. Trypsin induced by NP increased the infectivity of influenza virus, leading to increases in viral replication and pathology upon subsequent viral infection. These results reveal the role of released NP in influenza pathogenesis and highlight the importance of the interactions of internal viral proteins with PRRs in the extracellular compartment during viral pathogenesis.


Assuntos
Influenza Humana , Orthomyxoviridae , Receptor 4 Toll-Like , Humanos , Inflamassomos/metabolismo , Influenza Humana/metabolismo , Influenza Humana/virologia , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleoproteínas , Orthomyxoviridae/metabolismo , Receptor 4 Toll-Like/metabolismo , Tripsina/metabolismo
20.
J Virol ; 96(9): e0033222, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35446141

RESUMO

Influenza virus neuraminidase (NA)-targeting antibodies are an independent correlate of protection against influenza. Antibodies against the NA act by blocking enzymatic activity, preventing virus release and transmission. As we advance the development of improved influenza virus vaccines that incorporate standard amounts of NA antigen, it is important to identify the antigenic targets of human monoclonal antibodies (mAbs). Here, we describe escape mutants generated by serial passage of A/Netherlands/602/2009 (H1N1)pdm09 in the presence of human anti-N1 mAbs. We observed escape mutations on the head domain of the N1 protein around the enzymatic site (S364N, N369T, and R430Q) and also detected escape mutations located on the sides and bottom of the NA (N88D, N270D, and Q313K/R). This work increases our understanding of how human antibody responses target the N1 protein. IMPORTANCE As improved influenza virus vaccines are being developed, the influenza virus neuraminidase (NA) is becoming an important new target for immune responses. By identifying novel epitopes of anti-NA antibodies, we can improve vaccine design. Additionally, characterizing escape mutations in these epitopes aids in identifying NA antigenic drift in circulating viruses.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Anticorpos Monoclonais , Anticorpos Antivirais/metabolismo , Epitopos/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza A Subtipo H1N1/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Mutação , Neuraminidase/química , Neuraminidase/genética , Neuraminidase/imunologia
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