RESUMO
SARS-CoV-2 spike mRNA vaccines1-3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4-6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinação , Vacinas Sintéticas/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Vacina BNT162 , Linfócitos T CD4-Positivos/imunologia , COVID-19/virologia , Células Cultivadas , Epitopos de Linfócito T/imunologia , Humanos , Imunização Secundária , Memória Imunológica/imunologia , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , Vacinas de mRNARESUMO
The viral hemagglutinins of conventional influenza A viruses (IAVs) bind to sialylated glycans on host cell surfaces for attachment and subsequent infection. In contrast, hemagglutinins of bat-derived IAVs target major histocompatibility complex class II (MHC-II) for cell entry. MHC-II proteins from various vertebrate species can facilitate infection with the bat IAV H18N11. Yet, it has been difficult to biochemically determine the H18:MHC-II binding. Here, we followed a different approach and generated MHC-II chimeras from the human leukocyte antigen DR (HLA-DR), which supports H18-mediated entry, and the nonclassical MHC-II molecule HLA-DM, which does not. In this context, viral entry was supported only by a chimera containing the HLA-DR α1, α2, and ß1 domains. Subsequent modeling of the H18:HLA-DR interaction identified the α2 domain as central for this interaction. Further mutational analyses revealed highly conserved amino acids within loop 4 (N149) and ß-sheet 6 (V190) of the α2 domain as critical for virus entry. This suggests that conserved residues in the α1, α2, and ß1 domains of MHC-II mediate H18-binding and virus propagation. The conservation of MHC-II amino acids, which are critical for H18N11 binding, may explain the broad species specificity of this virus.
Assuntos
Quirópteros , Vírus da Influenza A , Animais , Humanos , Aminoácidos , Antígenos de Histocompatibilidade Classe II , Antígenos HLA-DR/metabolismo , Antígenos HLARESUMO
The coordinated packaging of the segmented genome of the influenza A virus (IAV) into virions is an essential step of the viral life cycle. This process is controlled by the interaction of packaging signals present in all eight viral RNA (vRNA) segments and the viral nucleoprotein (NP), which binds vRNA via a positively charged binding groove. However, mechanistic models of how the packaging signals and NP work together to coordinate genome packaging are missing. Here, we studied genome packaging in influenza A/SC35M virus mutants that carry mutated packaging signals as well as specific amino acid substitutions at the highly conserved lysine (K) residues 184 and 229 in the RNA-binding groove of NP. Because these lysines are acetylated and thus neutrally charged in infected host cells, we replaced them with glutamine to mimic the acetylated, neutrally charged state or arginine to mimic the non-acetylated, positively charged state. Our analysis shows that the coordinated packaging of eight vRNAs is influenced by (i) the charge state of the replacing amino acid and (ii) its location within the RNA-binding groove. Accordingly, we propose that lysine acetylation induces different charge states within the RNA-binding groove of NP, thereby supporting the activity of specific packaging signals during coordinated genome packaging. IMPORTANCE: Influenza A viruses (IAVs) have a segmented viral RNA (vRNA) genome encapsidated by multiple copies of the viral nucleoprotein (NP) and organized into eight distinct viral ribonucleoprotein complexes. Although genome segmentation contributes significantly to viral evolution and adaptation, it requires a highly sophisticated genome-packaging mechanism. How eight distinct genome complexes are incorporated into the virion is poorly understood, but previous research suggests an essential role for both vRNA packaging signals and highly conserved NP amino acids. By demonstrating that the packaging process is controlled by charge-dependent interactions of highly conserved lysine residues in NP and vRNA packaging signals, our study provides new insights into the sophisticated packaging mechanism of IAVs.
Assuntos
Vírus da Influenza A , Proteínas do Nucleocapsídeo , Empacotamento do Genoma Viral , Animais , Cães , Humanos , Substituição de Aminoácidos , Linhagem Celular , Genoma Viral , Vírus da Influenza A/química , Vírus da Influenza A/genética , Vírus da Influenza A/metabolismo , Lisina/genética , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , RNA Viral/metabolismo , Empacotamento do Genoma Viral/genética , Vírion/química , Vírion/genética , Vírion/metabolismo , Mutação , Eletricidade EstáticaRESUMO
Zoonotic influenza A viruses of avian origin can cause severe disease in individuals, or even global pandemics, and thus pose a threat to human populations. Waterfowl and shorebirds are believed to be the reservoir for all influenza A viruses, but this has recently been challenged by the identification of novel influenza A viruses in bats1,2. The major bat influenza A virus envelope glycoprotein, haemagglutinin, does not bind the canonical influenza A virus receptor, sialic acid or any other glycan1,3,4, despite its high sequence and structural homology with conventional haemagglutinins. This functionally uncharacterized plasticity of the bat influenza A virus haemagglutinin means the tropism and zoonotic potential of these viruses has not been fully determined. Here we show, using transcriptomic profiling of susceptible versus non-susceptible cells in combination with genome-wide CRISPR-Cas9 screening, that the major histocompatibility complex class II (MHC-II) human leukocyte antigen DR isotype (HLA-DR) is an essential entry determinant for bat influenza A viruses. Genetic ablation of the HLA-DR α-chain rendered cells resistant to infection by bat influenza A virus, whereas ectopic expression of the HLA-DR complex in non-susceptible cells conferred susceptibility. Expression of MHC-II from different bat species, pigs, mice or chickens also conferred susceptibility to infection. Notably, the infection of mice with bat influenza A virus resulted in robust virus replication in the upper respiratory tract, whereas mice deficient for MHC-II were resistant. Collectively, our data identify MHC-II as a crucial entry mediator for bat influenza A viruses in multiple species, which permits a broad vertebrate tropism.
Assuntos
Quirópteros/virologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Especificidade de Hospedeiro , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Zoonoses/imunologia , Zoonoses/virologia , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Galinhas/genética , Galinhas/imunologia , Quirópteros/genética , Quirópteros/imunologia , Quirópteros/metabolismo , Feminino , Perfilação da Expressão Gênica , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Especificidade de Hospedeiro/genética , Especificidade de Hospedeiro/imunologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Sistema Respiratório/virologia , Suínos/genética , Suínos/imunologia , Tropismo Viral/genética , Tropismo Viral/imunologia , Replicação Viral , Zoonoses/genética , Zoonoses/metabolismoRESUMO
Small RNA viruses only have a very limited coding capacity, thus most viral proteins have evolved to fulfill multiple functions. The highly conserved matrix protein 1 (M1) of influenza A viruses is a prime example for such a multifunctional protein, as it acts as a master regulator of virus replication whose different functions have to be tightly regulated. The underlying mechanisms, however, are still incompletely understood. Increasing evidence points towards an involvement of posttranslational modifications in the spatio-temporal regulation of M1 functions. Here, we analyzed the role of M1 tyrosine phosphorylation in genuine infection by using recombinant viruses expressing M1 phosphomutants. Presence of M1 Y132A led to significantly decreased viral replication compared to wildtype and M1 Y10F. Characterization of phosphorylation dynamics by mass spectrometry revealed the presence of Y132 phosphorylation in M1 incorporated into virions that is most likely mediated by membrane-associated Janus kinases late upon infection. Molecular dynamics simulations unraveled a potential phosphorylation-induced exposure of the positively charged linker domain between helices 4 and 5, supposably acting as interaction platform during viral assembly. Consistently, M1 Y132A showed a defect in lipid raft localization due to reduced interaction with viral HA protein resulting in a diminished structural stability of viral progeny and the formation of filamentous particles. Importantly, reduced M1-RNA binding affinity resulted in an inefficient viral genome incorporation and the production of non-infectious virions that interferes with virus pathogenicity in mice. This study advances our understanding of the importance of dynamic phosphorylation as a so far underestimated level of regulation of multifunctional viral proteins and emphasizes the potential feasibility of targeting posttranslational modifications of M1 as a novel antiviral intervention.
Assuntos
Vírus da Influenza A/metabolismo , Mutação de Sentido Incorreto , Proteínas da Matriz Viral/metabolismo , Células A549 , Substituição de Aminoácidos , Animais , Cães , Feminino , Células HEK293 , Humanos , Vírus da Influenza A/genética , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Proteínas da Matriz Viral/genéticaRESUMO
In 2012 and 2013, influenza virus genome sequences of two new influenza A virus (IAV) subtypes were discovered in bat specimens, but further characterization was largely impeded by the lack of infectious virus. With the identification of highly susceptible cell lines, reconstitution of infectious bat IAV by reverse genetics recently succeeded and allowed a first insight into the life cycle of these viruses. Although there is a certain degree of functional compatibility between bat and conventional influenza A virus proteins, there are striking differences, including receptor usage, polarity of infection and reassortment potential.
Assuntos
Quirópteros/virologia , Vírus da Influenza A/genética , Infecções por Orthomyxoviridae/veterinária , Animais , Infecções por Orthomyxoviridae/virologiaAssuntos
Adaptação Biológica , Quirópteros/virologia , Reservatórios de Doenças/virologia , Evolução Molecular , Vírus da Influenza A/patogenicidade , Influenza Humana/epidemiologia , Infecções por Orthomyxoviridae/veterinária , Animais , Humanos , Influenza Humana/virologia , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/virologia , Seleção Genética , Proteínas Virais/metabolismoRESUMO
New World fruit bats were recently found to harbor two distinct and previously unknown influenza A viruses (IAVs) of the subtypes H17N10 and H18N11. Although viral genome sequences were detected in the liver, intestine, lung, and kidney of infected bats and the complete genome sequences have been isolated from their rectal swab samples, all attempts to isolate an infectious virus from bats in nature have failed. The lack of an infectious bat IAV isolate was overcome by reverse genetic approaches that led to the generation of an infectious virus in vitro. Using such synthetic bat IAVs enabled the identification of their unconventional cell entry via major histocompatibility complex II (MCH-II) molecules and their ability to replicate in mice, ferrets, and bats. Importantly, we also showed that these synthetic recombinant bat IAVs are not able to reassort with conventional IAVs, preventing the acquisition of enhanced transmission properties in non-bat species by reassortment with conventional IAVs. As authentic viruses are key for understanding the molecular biology of bat IAVs, in this chapter, we describe our recently established reverse genetics protocol for generating H17N10 and H18N11 in vitro. This step-by-step protocol starts with cloning of cDNA copies of the viral RNA segments into reverse genetics plasmids, followed by the generation of a highly concentrated stock and finally a method to determine viral titers.
Assuntos
Quirópteros , Vírus da Influenza A , Infecções por Orthomyxoviridae , Animais , Camundongos , Vírus da Influenza A/genética , Genética Reversa , Furões/genéticaRESUMO
Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.
RESUMO
Influenza A viruses (IAVs) of subtype H9N2 have reached an endemic stage in poultry farms in the Middle East and Asia. As a result, human infections with avian H9N2 viruses have been increasingly reported. In 2017, an H9N2 virus was isolated for the first time from Egyptian fruit bats (Rousettus aegyptiacus). Phylogenetic analyses revealed that bat H9N2 is descended from a common ancestor dating back centuries ago. However, the H9 and N2 sequences appear to be genetically similar to current avian IAVs, suggesting recent reassortment events. These observations raise the question of the zoonotic potential of the mammal-adapted bat H9N2. Here, we investigate the infection and transmission potential of bat H9N2 in vitro and in vivo, the ability to overcome the antiviral activity of the human MxA protein, and the presence of N2-specific cross-reactive antibodies in human sera. We show that bat H9N2 has high replication and transmission potential in ferrets, efficiently infects human lung explant cultures, and is able to evade antiviral inhibition by MxA in transgenic B6 mice. Together with its low antigenic similarity to the N2 of seasonal human strains, bat H9N2 fulfils key criteria for pre-pandemic IAVs.
Assuntos
Quirópteros , Furões , Vírus da Influenza A Subtipo H9N2 , Infecções por Orthomyxoviridae , Replicação Viral , Animais , Furões/virologia , Vírus da Influenza A Subtipo H9N2/genética , Vírus da Influenza A Subtipo H9N2/fisiologia , Vírus da Influenza A Subtipo H9N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/isolamento & purificação , Quirópteros/virologia , Humanos , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/imunologia , Camundongos , Filogenia , Influenza Humana/transmissão , Influenza Humana/virologia , Pulmão/virologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangueRESUMO
Jamaican fruit bats (Artibeus jamaicensis) naturally harbor a wide range of viruses of human relevance. These infections are typically mild in bats, suggesting unique features of their immune system. To better understand the immune response to viral infections in bats, we infected male Jamaican fruit bats with the bat-derived influenza A virus (IAV) H18N11. Using comparative single-cell RNA sequencing, we generated single-cell atlases of the Jamaican fruit bat intestine and mesentery. Gene expression profiling showed that H18N11 infection resulted in a moderate induction of interferon-stimulated genes and transcriptional activation of immune cells. H18N11 infection was predominant in various leukocytes, including macrophages, B cells, and NK/T cells. Confirming these findings, human leukocytes, particularly macrophages, were also susceptible to H18N11, highlighting the zoonotic potential of this bat-derived IAV. Our study provides insight into a natural virus-host relationship and thus serves as a fundamental resource for future in-depth characterization of bat immunology.
Assuntos
Quirópteros , Infecções por Orthomyxoviridae , Análise de Célula Única , Animais , Quirópteros/virologia , Quirópteros/imunologia , Quirópteros/genética , Masculino , Humanos , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/veterinária , Macrófagos/imunologia , Macrófagos/virologia , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Perfilação da Expressão GênicaRESUMO
A specialized and fine-tuned immune response of bats upon infection with viruses is believed to provide the basis for a "friendly" coexistence with these pathogens, which are often lethal for humans and other mammals. First insights into the immunity of bats suggest that bats have evolved to possess their own strategies to cope with viral infections. Yet, the molecular details for this innocuous coexistence remain poorly described and bat infection models are the key to unveiling these secrets. In Jamaican fruit bats (Artibeus jamaicensis), a New World bat species, infection experiments with its (putative) natural viral pathogens Tacaribe virus (TCRV), rabies virus (RABV), and the bat influenza A virus (IAV) H18N11, have contributed to an accurate, though still incomplete, representation of the bat-imposed immunity. Surprisingly, though many aspects of their innate and adaptive immune responses differ from that of the human immune response, such as a contraction of the IFN locus and reduction in the number of immunoglobulin subclasses, variations could also be observed between Jamaican fruit bats and other bat species.
Assuntos
Quirópteros/imunologia , Quirópteros/virologia , Viroma , Viroses/veterinária , Imunidade Adaptativa , Animais , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/veterinária , Infecções por Arenaviridae/virologia , Arenavirus do Novo Mundo/isolamento & purificação , Imunidade Inata , Vírus da Influenza A/isolamento & purificação , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/veterinária , Raiva/imunologia , Raiva/veterinária , Raiva/virologia , Vírus da Raiva/isolamento & purificação , Viroses/imunologiaRESUMO
Recurring epizootic influenza A virus (IAV) infections in domestic livestock such as swine and poultry are associated with a substantial economic burden and pose a constant threat to human health. Therefore, universally applicable and safe animal vaccines are urgently needed. We recently demonstrated that a reassortment-incompatible chimeric bat H17N10 virus harboring the A/swan/Germany/R65/2006 (H5N1) surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) can be efficiently used as a modified live influenza vaccine (MLIV). To ensure vaccine safety and, thus, improve the applicability of this novel MLIV for mammalian usage, we performed consecutive passaging in eggs and chickens. Following passaging, we identified mutations in the viral polymerase subunits PB2 (I382S), PB1 (Q694H and I695K), and PA (E141K). Strikingly, recombinant chimeric viruses encoding these mutations showed no growth deficiencies in avian cells but displayed impaired growth in human cells and mice. Homologous prime-boost immunization of mice with one of these avian-adapted chimeric viruses, designated rR65mono/H17N10EP18, elicited a strong neutralizing antibody response and conferred full protection against lethal highly pathogenic avian influenza virus (HPAIV) H5N1 challenge infection. Importantly, the insertion of the avian-adaptive mutations into the conventional avian-like A/SC35M/1980 (H7N7) and prototypic human A/PR/8/34 (H1N1) viruses led to attenuated viral growth in human cells and mice. Collectively, our data show that the polymerase mutations identified here can be utilized to further improve the safety of our novel H17N10-based MLIV candidates for future mammalian applications. IMPORTANCE Recurring influenza A virus outbreaks in livestock, particularly in swine and chickens, pose a constant threat to humans. Live attenuated influenza vaccines (LAIVs) might be a potent tool to prevent epizootic outbreaks and the resulting human IAV infections; however, LAIVs have several disadvantages, especially in terms of reassortment with circulating IAVs. Notably, the newly identified bat influenza A viruses H17N10 and H18N11 cannot reassort with conventional IAVs. Chimeric bat influenza A viruses encoding surface glycoproteins of conventional IAV subtypes might thus function as safe and applicable modified live influenza vaccines (MLIVs).
Assuntos
Quirópteros , Vírus da Influenza A , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Animais , Camundongos , Anticorpos Antivirais , Galinhas , Quirópteros/virologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Infecções por Orthomyxoviridae/prevenção & controleRESUMO
A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease. We identify two independent ligands mediating extreme FcγRIIIA/CD16A activation. Soluble circulating IgG immune complexes (sICs) are detected in about 80% of patients with severe and critical COVID-19 at levels comparable to active systemic lupus erythematosus (SLE) disease. FcγRIIIA/CD16A activation is further enhanced by afucosylation of SARS-CoV-2 specific IgG. Utilizing cell-based reporter systems we provide evidence that sICs can be formed prior to a specific humoral response against SARS-CoV-2. Our data suggest a cycle of immunopathology driven by an early formation of sICs in predisposed patients. These findings suggest a reason for the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. The involvement of circulating sICs in the promotion of immunopathology in predisposed patients opens new possibilities for intervention strategies to mitigate critical COVID-19 progression.
Assuntos
COVID-19 , Anticorpos Antivirais , Complexo Antígeno-Anticorpo , Antivirais , Humanos , Imunoglobulina G , SARS-CoV-2RESUMO
Immunization with two mRNA vaccine doses elicits robust spike-specific CD8+ T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains unclear. Here we show that spike-specific CD8+ T cells are activated and expanded in all analyzed individuals receiving the 3rd and 4th mRNA vaccine shots. This CD8+ T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8+ T memory stem cell pool is not affected by the 3rd vaccination. Both 4th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8+ T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8+ T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.
Assuntos
Linfócitos T CD8-Positivos , COVID-19 , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , RNA Mensageiro , Vacinas Sintéticas , Vacinas de mRNARESUMO
Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.
Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Epitopos de Linfócito T/genética , Humanos , RNA Mensageiro/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Influenza A viruses (IAVs) originating from aquatic waterfowl recurrently cross interspecies barriers, which is greatly facilitated by utilizing cell surface-exposed monosaccharide sialic acids located on vertebrate cells as a universal host cell receptor. These glycan structures are first bound by the viral hemagglutinin (HA) for cell entry and then cleaved by the viral neuraminidase (NA) for particle release. In contrast, viruses of the recently identified bat-borne IAV subtypes H17N10 and H18N11 encode HA and NA homologs unable to interact with sialic acid residues despite a high degree of structural homology with their conventional counterparts. However, the most recent findings show that bat IAV HAs make use of the major histocompatibility complex class II proteins of different vertebrate species to gain entry into host cells, potentially permitting a broader host tropism. This review recapitulates current progress in the field of bat IAV research including the first assessment of the spillover potential of these bat viruses into other mammals.
Assuntos
Quirópteros/virologia , Vírus da Influenza A/metabolismo , Replicação Viral , Animais , Humanos , Tropismo Viral , Zoonoses ViraisRESUMO
Zoonotic infections of humans with influenza A viruses (IAVs) from animal reservoirs can result in severe disease in individuals and, in rare cases, lead to pandemic outbreaks; this is exemplified by numerous cases of human infection with avian IAVs (AIVs) and the 2009 swine influenza pandemic. In fact, zoonotic transmissions are strongly facilitated by manmade reservoirs that were created through the intensification and industrialization of livestock farming. This can be witnessed by the repeated introduction of IAVs from natural reservoirs of aquatic wild bird metapopulations into swine and poultry, and the accompanied emergence of partially- or fully-adapted human pathogenic viruses. On the other side, human adapted IAV have been (and still are) introduced into livestock by reverse zoonotic transmission. This link to manmade reservoirs was also observed before the 20th century, when horses seemed to have been an important reservoir for IAVs but lost relevance when the populations declined due to increasing industrialization. Therefore, to reduce zoonotic events, it is important to control the spread of IAV within these animal reservoirs, for example with efficient vaccination strategies, but also to critically surveil the different manmade reservoirs to evaluate the emergence of new IAV strains with pandemic potential.
Assuntos
Reservatórios de Doenças/virologia , Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/transmissão , Zoonoses Virais/transmissão , Agricultura , Animais , Aves/virologia , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Mamíferos/virologia , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Pandemias/prevenção & controle , Zoonoses Virais/epidemiologia , Zoonoses Virais/prevenção & controle , Zoonoses Virais/virologiaRESUMO
Previous influenza A virus (IAV) pandemics have invariably been caused by the introduction of an emergent IAV strain from an animal host into a human population with no or only little pre-existing immunity to the novel strain. Although zoonotic spillover of IAVs into humans can be associated with severe disease and a high fatality rate, these strains are typically poorly adapted to humans and are unable to establish sustained transmission between humans. Given the presumably very high degree of exposure to animal populations with endemic IAV, the number of pandemics remains surprisingly low. In this review, we provide an updated perspective on the molecular mechanisms underlying the adaptation of zoonotic IAV to human hosts, and discuss the implications for future pandemics.
Assuntos
Interações Hospedeiro-Patógeno , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Animais , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/epidemiologia , Influenza Humana/transmissão , Pandemias , Zoonoses ViraisRESUMO
Importance: School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. Objective: To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. Design, Setting, and Participants: This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. Exposures: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. Results: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). Conclusions and Relevance: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.