Pub Date : 2023-01-01DOI: 10.3389/fviro.2023.1106634
Gregory W Kirschen, Irina Burd
In addition to facilitating nutrient, oxygen, and waste transfer between developing fetus and mother, the placenta provides important immune barrier function against infection. Elucidation of the complexity of placental barrier function at the maternal-fetal interface has been greatly aided through experimental model organism systems. In this review, we focus on models of vertical transmission of cytomegalovirus (CMV), a ubiquitous double-stranded DNA viruses whose vertical transmission during pregnancy can lead to devastating neurological and obstetric sequelae. We review the current evidence related to guinea pig and murine models of congenital CMV infection, discuss the possible translatability of a non-human primate model, and conclude with recently developed technology using human placental organoids.
{"title":"Modeling of vertical transmission and pathogenesis of cytomegalovirus in pregnancy: Opportunities and challenges.","authors":"Gregory W Kirschen, Irina Burd","doi":"10.3389/fviro.2023.1106634","DOIUrl":"https://doi.org/10.3389/fviro.2023.1106634","url":null,"abstract":"<p><p>In addition to facilitating nutrient, oxygen, and waste transfer between developing fetus and mother, the placenta provides important immune barrier function against infection. Elucidation of the complexity of placental barrier function at the maternal-fetal interface has been greatly aided through experimental model organism systems. In this review, we focus on models of vertical transmission of cytomegalovirus (CMV), a ubiquitous double-stranded DNA viruses whose vertical transmission during pregnancy can lead to devastating neurological and obstetric sequelae. We review the current evidence related to guinea pig and murine models of congenital CMV infection, discuss the possible translatability of a non-human primate model, and conclude with recently developed technology using human placental organoids.</p>","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9108228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-22DOI: 10.3389/fviro.2022.1044652
Krishna Bhattarai, M. Holcik
Understanding the host-virus interactions helps to decipher the viral replication strategies and pathogenesis. Viruses have limited genetic content and rely significantly on their host cell to establish a successful infection. Viruses depend on the host for a broad spectrum of cellular RNA-binding proteins (RBPs) throughout their life cycle. One of the major RBP families is the heterogeneous nuclear ribonucleoproteins (hnRNPs) family. hnRNPs are typically localized in the nucleus, where they are forming complexes with pre-mRNAs and contribute to many aspects of nucleic acid metabolism. hnRNPs contain RNA binding motifs and frequently function as RNA chaperones involved in pre-mRNA processing, RNA splicing, and export. Many hnRNPs shuttle between the nucleus and the cytoplasm and influence cytoplasmic processes such as mRNA stability, localization, and translation. The interactions between the hnRNPs and viral components are well-known. They are critical for processing viral nucleic acids and proteins and, therefore, impact the success of the viral infection. This review discusses the molecular mechanisms by which hnRNPs interact with and regulate each stage of the viral life cycle, such as replication, splicing, translation, and assembly of virus progeny. In addition, we expand on the role of hnRNPs in the antiviral response and as potential targets for antiviral drug research and development.
{"title":"Diverse roles of heterogeneous nuclear ribonucleoproteins in viral life cycle","authors":"Krishna Bhattarai, M. Holcik","doi":"10.3389/fviro.2022.1044652","DOIUrl":"https://doi.org/10.3389/fviro.2022.1044652","url":null,"abstract":"Understanding the host-virus interactions helps to decipher the viral replication strategies and pathogenesis. Viruses have limited genetic content and rely significantly on their host cell to establish a successful infection. Viruses depend on the host for a broad spectrum of cellular RNA-binding proteins (RBPs) throughout their life cycle. One of the major RBP families is the heterogeneous nuclear ribonucleoproteins (hnRNPs) family. hnRNPs are typically localized in the nucleus, where they are forming complexes with pre-mRNAs and contribute to many aspects of nucleic acid metabolism. hnRNPs contain RNA binding motifs and frequently function as RNA chaperones involved in pre-mRNA processing, RNA splicing, and export. Many hnRNPs shuttle between the nucleus and the cytoplasm and influence cytoplasmic processes such as mRNA stability, localization, and translation. The interactions between the hnRNPs and viral components are well-known. They are critical for processing viral nucleic acids and proteins and, therefore, impact the success of the viral infection. This review discusses the molecular mechanisms by which hnRNPs interact with and regulate each stage of the viral life cycle, such as replication, splicing, translation, and assembly of virus progeny. In addition, we expand on the role of hnRNPs in the antiviral response and as potential targets for antiviral drug research and development.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47610739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-14DOI: 10.3389/fviro.2022.1078454
Li Wang, M. Guzman, I. Sola, L. Enjuanes, S. Zúñiga
RNA metabolism in the eukaryotic cell includes the formation of ribonucleoprotein complexes (RNPs) that, depending on their protein components, have a different function. Cytoplasmic RNPs, such as stress granules (SGs) or P-bodies (PBs) are quite relevant during infections modulating viral and cellular RNA expression and as key players in the host cell antiviral response. RNA helicases are abundant components of RNPs and could have a significant effect on viral infection. This review focuses in the role that RNPs and RNA helicases have during coronavirus (CoVs) infection. CoVs are emerging highly pathogenic viruses with a large single-stranded RNA genome. During CoV infection, a complex network of RNA-protein interactions in different RNP structures is established. In general, RNA helicases and RNPs have an antiviral function, but there is limited knowledge on whether the viral protein interactions with cell components are mediators of this antiviral effect or are part of the CoV antiviral counteraction mechanism. Additional data is needed to elucidate the role of these RNA-protein interactions during CoV infection and their potential contribution to viral replication or pathogenesis.
{"title":"Cytoplasmic ribonucleoprotein complexes, RNA helicases and coronavirus infection","authors":"Li Wang, M. Guzman, I. Sola, L. Enjuanes, S. Zúñiga","doi":"10.3389/fviro.2022.1078454","DOIUrl":"https://doi.org/10.3389/fviro.2022.1078454","url":null,"abstract":"RNA metabolism in the eukaryotic cell includes the formation of ribonucleoprotein complexes (RNPs) that, depending on their protein components, have a different function. Cytoplasmic RNPs, such as stress granules (SGs) or P-bodies (PBs) are quite relevant during infections modulating viral and cellular RNA expression and as key players in the host cell antiviral response. RNA helicases are abundant components of RNPs and could have a significant effect on viral infection. This review focuses in the role that RNPs and RNA helicases have during coronavirus (CoVs) infection. CoVs are emerging highly pathogenic viruses with a large single-stranded RNA genome. During CoV infection, a complex network of RNA-protein interactions in different RNP structures is established. In general, RNA helicases and RNPs have an antiviral function, but there is limited knowledge on whether the viral protein interactions with cell components are mediators of this antiviral effect or are part of the CoV antiviral counteraction mechanism. Additional data is needed to elucidate the role of these RNA-protein interactions during CoV infection and their potential contribution to viral replication or pathogenesis.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47348842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-06DOI: 10.3389/fviro.2022.1073619
Marc Tallo-Parra, Elena Muscolino, J. Díez
Viruses completely depend on the host translation machineries to express the viral proteins. Recent data reveal an unprecedented interaction of positive strand RNA ((+)RNA) viruses with the host tRNA epitranscriptome to favor viral protein expression via a specific reprogramming of codon optimality that ultimately favors decoding of the viral codons. We propose that this feature is shared by multiple RNA viruses and that the involved tRNA modifying enzymes represent promising novel targets for the development of broad-spectrum antivirals.
{"title":"The host tRNA epitranscriptome: A new player in RNA virus infections","authors":"Marc Tallo-Parra, Elena Muscolino, J. Díez","doi":"10.3389/fviro.2022.1073619","DOIUrl":"https://doi.org/10.3389/fviro.2022.1073619","url":null,"abstract":"Viruses completely depend on the host translation machineries to express the viral proteins. Recent data reveal an unprecedented interaction of positive strand RNA ((+)RNA) viruses with the host tRNA epitranscriptome to favor viral protein expression via a specific reprogramming of codon optimality that ultimately favors decoding of the viral codons. We propose that this feature is shared by multiple RNA viruses and that the involved tRNA modifying enzymes represent promising novel targets for the development of broad-spectrum antivirals.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43595087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.3389/fviro.2022.1028335
John J Orgera, James J. Kelley, Omri Bar, Sathyanarayanan Vaidhyanathan, A. Grigoriev
SARSNTdb offers a curated, nucleotide-centric database for users of varying levels of SARS-CoV-2 knowledge. Its user-friendly interface enables querying coding regions and coordinate intervals to find out the various functional and selective constraints that act upon the corresponding nucleotides and amino acids. Users can easily obtain information about viral genes and proteins, functional domains, repeats, secondary structure formation, intragenomic interactions, and mutation prevalence. Currently, many databases are focused on the phylogeny and amino acid substitutions, mainly in the spike protein. We took a novel, more nucleotide-focused approach as RNA does more than just code for proteins and many insights can be gleaned from its study. For example, RNA-targeted drug therapies for SARS-CoV-2 are currently being developed and it is essential to understand the features only visible at that level. This database enables the user to identify regions that are more prone to forming secondary structures that drugs can target. SARSNTdb also provides illustrative mutation data from a subset of ~25,000 patient samples with a reliable read coverage across the whole genome (from different locations and time points in the pandemic. Finally, the database allows for comparing SARS-CoV-2 and SARS-CoV domains and sequences. SARSNTdb can serve the research community by being a curated repository for information that gives a jump start to analyze a mutation’s effect far beyond just determining synonymous/non-synonymous substitutions in protein sequences.
{"title":"SARSNTdb database: Factors affecting SARS-CoV-2 sequence conservation","authors":"John J Orgera, James J. Kelley, Omri Bar, Sathyanarayanan Vaidhyanathan, A. Grigoriev","doi":"10.3389/fviro.2022.1028335","DOIUrl":"https://doi.org/10.3389/fviro.2022.1028335","url":null,"abstract":"SARSNTdb offers a curated, nucleotide-centric database for users of varying levels of SARS-CoV-2 knowledge. Its user-friendly interface enables querying coding regions and coordinate intervals to find out the various functional and selective constraints that act upon the corresponding nucleotides and amino acids. Users can easily obtain information about viral genes and proteins, functional domains, repeats, secondary structure formation, intragenomic interactions, and mutation prevalence. Currently, many databases are focused on the phylogeny and amino acid substitutions, mainly in the spike protein. We took a novel, more nucleotide-focused approach as RNA does more than just code for proteins and many insights can be gleaned from its study. For example, RNA-targeted drug therapies for SARS-CoV-2 are currently being developed and it is essential to understand the features only visible at that level. This database enables the user to identify regions that are more prone to forming secondary structures that drugs can target. SARSNTdb also provides illustrative mutation data from a subset of ~25,000 patient samples with a reliable read coverage across the whole genome (from different locations and time points in the pandemic. Finally, the database allows for comparing SARS-CoV-2 and SARS-CoV domains and sequences. SARSNTdb can serve the research community by being a curated repository for information that gives a jump start to analyze a mutation’s effect far beyond just determining synonymous/non-synonymous substitutions in protein sequences.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43196008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-28DOI: 10.3389/fviro.2022.1026452
Bailey S. Mosher, T. Kowalik, A. Yurochko
Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in the immunocompromised and developing fetuses. Infection has also been linked to chronic inflammatory diseases, cardiovascular disease, and the development of certain cancers. The wide range of pathologies associated with HCMV infection is attributable to the broad cellular tropism of the virus where infection affects every organ system. Like other viruses, HCMV must tailor host cells to support productive infection. In particular, HCMV dedicates many resources and various strategies to manipulate host intracellular trafficking networks to facilitate various aspects of infection across all infected cell types. The dysregulation of host intracellular trafficking networks allows the virus to translocate to the host cell nucleus for genome replication, facilitate nuclear import/export of viral proteins and immature virions, subvert the host immune response, form new organelles for progeny virion assembly, maturation and egress, and promote cellular migration and viral spread. However, due to their complex nature, many aspects of these processes are not well-studied. New research and omics-based technologies have recently begun to elucidate the extent to which HCMV dysregulates host cell trafficking machinery. Here we review the variety of strategies HCMV utilizes to dysregulate intracellular trafficking networks to promote productive infection.
{"title":"Overview of how HCMV manipulation of host cell intracellular trafficking networks can promote productive infection","authors":"Bailey S. Mosher, T. Kowalik, A. Yurochko","doi":"10.3389/fviro.2022.1026452","DOIUrl":"https://doi.org/10.3389/fviro.2022.1026452","url":null,"abstract":"Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in the immunocompromised and developing fetuses. Infection has also been linked to chronic inflammatory diseases, cardiovascular disease, and the development of certain cancers. The wide range of pathologies associated with HCMV infection is attributable to the broad cellular tropism of the virus where infection affects every organ system. Like other viruses, HCMV must tailor host cells to support productive infection. In particular, HCMV dedicates many resources and various strategies to manipulate host intracellular trafficking networks to facilitate various aspects of infection across all infected cell types. The dysregulation of host intracellular trafficking networks allows the virus to translocate to the host cell nucleus for genome replication, facilitate nuclear import/export of viral proteins and immature virions, subvert the host immune response, form new organelles for progeny virion assembly, maturation and egress, and promote cellular migration and viral spread. However, due to their complex nature, many aspects of these processes are not well-studied. New research and omics-based technologies have recently begun to elucidate the extent to which HCMV dysregulates host cell trafficking machinery. Here we review the variety of strategies HCMV utilizes to dysregulate intracellular trafficking networks to promote productive infection.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45776117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-17DOI: 10.3389/fviro.2022.1050880
Idrissa Dieng, S. Sagne, Mignane Ndiaye, M. A. Barry, C. Talla, Moufid Mhamadi, Diamilatou Balde, Cheikh Talibouya Touré, B. Diop, A. Sall, G. Fall, C. Loucoubar, O. Faye, O. Faye
Dengue virus 2 (DENV-2) was detected in a febrile patient living in Saré Yoba in the Kolda region of southern Senegal. Phylogenetic analysis based on the full coding region revealed that the virus belongs to the DENV-2 sylvatic genotype and is closely related to a strain (JF260983/99.66% identity) detected in Spain in a tourist who traveled to Guinea-Bissau (which borders the Kolda region) in 2009. This highlights a potential recent under-reported circulation of sylvatic dengue in the southern part of Senegal and calls for reinforced integrated surveillance among humans, non-human primates, and arboreal mosquitoes through a one-health approach.
{"title":"Detection of human case of dengue virus 2 belonging to sylvatic genotype during routine surveillance of fever in Senegal, Kolda 2021","authors":"Idrissa Dieng, S. Sagne, Mignane Ndiaye, M. A. Barry, C. Talla, Moufid Mhamadi, Diamilatou Balde, Cheikh Talibouya Touré, B. Diop, A. Sall, G. Fall, C. Loucoubar, O. Faye, O. Faye","doi":"10.3389/fviro.2022.1050880","DOIUrl":"https://doi.org/10.3389/fviro.2022.1050880","url":null,"abstract":"Dengue virus 2 (DENV-2) was detected in a febrile patient living in Saré Yoba in the Kolda region of southern Senegal. Phylogenetic analysis based on the full coding region revealed that the virus belongs to the DENV-2 sylvatic genotype and is closely related to a strain (JF260983/99.66% identity) detected in Spain in a tourist who traveled to Guinea-Bissau (which borders the Kolda region) in 2009. This highlights a potential recent under-reported circulation of sylvatic dengue in the southern part of Senegal and calls for reinforced integrated surveillance among humans, non-human primates, and arboreal mosquitoes through a one-health approach.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45224418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-10DOI: 10.3389/fviro.2022.968338
Hyeree Choi, S. Kudchodkar, Ziyang Xu, Michelle Ho, Peng Xiao, S. Ramos, Laurent Humeau, D. Weiner, K. Muthumani
Nipah virus (NiV) is a re-emerging pathogen that causes severe disease in animals and humans. Current treatment measures for NiV infection are insufficient, and there is no approved vaccine against NiV for either humans or animals. Nipah virus is listed as a high-priority pathogen for vaccine and therapeutic research by the World Health Organization (WHO). In the present study, we employed synthetic enhanced DNA technologies developed to design and produce novel consensus NiV Fusion (NiV-F) and Glycoprotein (NiV-G) antigen sequences for inclusion in synthetic DNA vaccines for NiV. The expression of each vaccine antigen was confirmed in vitro using immune-binding assays. Electroporation-enhanced intramuscular injection of each NiV-F and NiV-G into mice induced potent cellular immune responses to multiple epitopes of NiV-G and NiV-F that included antigen-specific CD8+ T cells. Both vaccines elicited high antibody titers in mice, with a single immunization sufficient to seroconvert 100% of immunized animals. Additionally, the NiV-F vaccine also induced antibodies to neutralize NiV-F-pseudotyped virus particles. These data support further study of these novel synthetic enhanced NiV nucleic acid-based antigens as potential components of an effective vaccine against the Nipah virus.
{"title":"Elicitation of immune responses against Nipah virus by an engineered synthetic DNA vaccine","authors":"Hyeree Choi, S. Kudchodkar, Ziyang Xu, Michelle Ho, Peng Xiao, S. Ramos, Laurent Humeau, D. Weiner, K. Muthumani","doi":"10.3389/fviro.2022.968338","DOIUrl":"https://doi.org/10.3389/fviro.2022.968338","url":null,"abstract":"Nipah virus (NiV) is a re-emerging pathogen that causes severe disease in animals and humans. Current treatment measures for NiV infection are insufficient, and there is no approved vaccine against NiV for either humans or animals. Nipah virus is listed as a high-priority pathogen for vaccine and therapeutic research by the World Health Organization (WHO). In the present study, we employed synthetic enhanced DNA technologies developed to design and produce novel consensus NiV Fusion (NiV-F) and Glycoprotein (NiV-G) antigen sequences for inclusion in synthetic DNA vaccines for NiV. The expression of each vaccine antigen was confirmed in vitro using immune-binding assays. Electroporation-enhanced intramuscular injection of each NiV-F and NiV-G into mice induced potent cellular immune responses to multiple epitopes of NiV-G and NiV-F that included antigen-specific CD8+ T cells. Both vaccines elicited high antibody titers in mice, with a single immunization sufficient to seroconvert 100% of immunized animals. Additionally, the NiV-F vaccine also induced antibodies to neutralize NiV-F-pseudotyped virus particles. These data support further study of these novel synthetic enhanced NiV nucleic acid-based antigens as potential components of an effective vaccine against the Nipah virus.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48855561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-02DOI: 10.3389/fviro.2022.1049134
A. Beukenhorst, J. Frallicciardi, Clarissa M. Koch, Angela M. Phillips, Michael M. Desai, K. Wichapong, G. Nicolaes, W. Koudstaal, G. Alter, J. Goudsmit
Human monoclonal antibodies (hmAbs) that protect against all influenza A and B strains are considered the road to universal influenza vaccines. Based on publicly-available data, we analyze the mechanistic and structural basis of pan-influenza protection by CR9114, a hemagglutinin (HA) stem-reactive antibody that protects against influenza subtypes from groups A1, A2, and B. The mechanistic basis of CR9114’s universal protection is not limited to in vitro neutralization, as CR9114 also protects in vivo from strains that escape its neutralizing activity: some H2 strains and influenza B. Fusion inhibition, viral egress inhibition, and activation of Fc-mediated effector functions are key contributors to CR9114’s universal protection. A comparative analysis of paratopes – between CR9114 (pan-influenza protection) and structurally similar VH1-69 hmAb CR6261 (influenza A1 protection) – pinpoints the structural basis of pan-influenza protection. CR9114’s heterosubtypic binding is conferred by its ability to bind HA with multiple domains: three HCDR loops and FR3. In contrast to other VH1-69 hmAbs, CR9114 uses a long and polar side chain of tyrosine (Y) residues on its HCDR3 for crucial H-bonds with H3, H5, and B HA. The recognition of a highly conserved epitope by CR9114 results in a high genetic barrier for escape by influenza strains. The nested, hierarchical structure of the mutations between the germline ancestor and CR9114 demonstrates that it is the result of a narrow evolutionary pathway within the B cell population. This rare evolutionary pathway indicates an immuno-recessive epitope and limited opportunity for vaccines to induce a polyclonal CR9114-like response.
{"title":"The influenza hemagglutinin stem antibody CR9114: Evidence for a narrow evolutionary path towards universal protection","authors":"A. Beukenhorst, J. Frallicciardi, Clarissa M. Koch, Angela M. Phillips, Michael M. Desai, K. Wichapong, G. Nicolaes, W. Koudstaal, G. Alter, J. Goudsmit","doi":"10.3389/fviro.2022.1049134","DOIUrl":"https://doi.org/10.3389/fviro.2022.1049134","url":null,"abstract":"Human monoclonal antibodies (hmAbs) that protect against all influenza A and B strains are considered the road to universal influenza vaccines. Based on publicly-available data, we analyze the mechanistic and structural basis of pan-influenza protection by CR9114, a hemagglutinin (HA) stem-reactive antibody that protects against influenza subtypes from groups A1, A2, and B. The mechanistic basis of CR9114’s universal protection is not limited to in vitro neutralization, as CR9114 also protects in vivo from strains that escape its neutralizing activity: some H2 strains and influenza B. Fusion inhibition, viral egress inhibition, and activation of Fc-mediated effector functions are key contributors to CR9114’s universal protection. A comparative analysis of paratopes – between CR9114 (pan-influenza protection) and structurally similar VH1-69 hmAb CR6261 (influenza A1 protection) – pinpoints the structural basis of pan-influenza protection. CR9114’s heterosubtypic binding is conferred by its ability to bind HA with multiple domains: three HCDR loops and FR3. In contrast to other VH1-69 hmAbs, CR9114 uses a long and polar side chain of tyrosine (Y) residues on its HCDR3 for crucial H-bonds with H3, H5, and B HA. The recognition of a highly conserved epitope by CR9114 results in a high genetic barrier for escape by influenza strains. The nested, hierarchical structure of the mutations between the germline ancestor and CR9114 demonstrates that it is the result of a narrow evolutionary pathway within the B cell population. This rare evolutionary pathway indicates an immuno-recessive epitope and limited opportunity for vaccines to induce a polyclonal CR9114-like response.","PeriodicalId":73114,"journal":{"name":"Frontiers in virology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47635012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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