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Viruses Jun 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA genome-containing virus which has infected millions of people all... (Comparative Study)
Comparative Study
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA genome-containing virus which has infected millions of people all over the world. The virus has been mutating rapidly enough, resulting in the emergence of new variants and sub-variants which have reportedly been spread from Wuhan city in China, the epicenter of the virus, to the rest of China and all over the world. The occurrence of mutations in the viral genome, especially in the viral spike protein region, has resulted in the evolution of multiple variants and sub-variants which gives the virus the benefit of host immune evasion and thus renders modern-day vaccines and therapeutics ineffective. Therefore, there is a continuous need to study the genetic characteristics and evolutionary dynamics of the SARS-CoV-2 variants. Hence, in this study, a total of 832 complete genomes of SARS-CoV-2 variants from the cities of Taiyuan and Wuhan in China was genetically characterized and their phylogenetic and evolutionary dynamics studied using phylogenetics, genetic similarity, and phylogenetic network analyses. This study shows that the four most prevalent lineages in Taiyuan and Wuhan are as follows: the Omicron lineages EG.5.1.1, followed by HK.3, FY.3, and XBB.1.16 (Pangolin classification), and clades 23F (EG.5.1), followed by 23H (HK.3), 22F (XBB), and 23D (XBB.1.9) (Nextclade classification), and lineage B followed by the Omicron FY.3, lineage A, and Omicron FL.2.3 (Pangolin classification), and the clades 19A, followed by 22F (XBB), 23F (EG.5.1), and 23H (HK.3) (Nextclade classification), respectively. Furthermore, our genetic similarity analysis show that the SARS-CoV-2 clade 19A-B.4 from Wuhan (name starting with 412981) has the least genetic similarity of about 95.5% in the spike region of the genome as compared to the query sequence of Omicron XBB.2.3.2 from Taiyuan (name starting with 18495234), followed by the Omicron FR.1.4 from Taiyuan (name starting with 18495199) with ~97.2% similarity and Omicron DY.3 (name starting with 17485740) with ~97.9% similarity. The rest of the variants showed ≥98% similarity with the query sequence of Omicron XBB.2.3.2 from Taiyuan (name starting with 18495234). In addition, our recombination analysis results show that the SARS-CoV-2 variants have three statistically significant recombinant events which could have possibly resulted in the emergence of Omicron XBB.1.16 (recombination event 3), FY.3 (recombination event 5), and FL.2.4 (recombination event 7), suggesting some very important information regarding viral evolution. Also, our phylogenetic tree and network analyses show that there are a total of 14 clusters and more than 10,000 mutations which may have probably resulted in the emergence of cluster-I, followed by 47 mutations resulting in the emergence of cluster-II and so on. The clustering of the viral variants of both cities reveals significant information regarding the phylodynamics of the virus among them. The results of our temporal phylogenetic analysis suggest that the variants of Taiyuan have likely emerged as independent variants separate from the variants of Wuhan. This study, to the best of our knowledge, is the first ever genetic comparative study between Taiyuan and Wuhan cities in China. This study will help us better understand the virus and cope with the emergence and spread of new variants at a local as well as an international level, and keep the public health authorities informed for them to make better decisions in designing new viral vaccines and therapeutics. It will also help the outbreak investigators to better examine any future outbreak.
Topics: SARS-CoV-2; China; Phylogeny; Humans; COVID-19; Genome, Viral; Evolution, Molecular; Mutation; Spike Glycoprotein, Coronavirus; Cities; Betacoronavirus
PubMed: 38932199
DOI: 10.3390/v16060907 -
Viruses Jun 2024Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The... (Review)
Review
Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about the possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories of broadly neutralizing antibodies (bnAbs) that retain prominent effectiveness against emerging variants including Omicron sub-lineages. The molecular characteristics, epitope conservation, and resistance mechanisms of these antibodies are further detailed, aiming to offer suggestion or direction for the development of therapeutic antibodies, and facilitate the design of vaccines with broad-spectrum potential.
Topics: SARS-CoV-2; Humans; Antibodies, Viral; COVID-19; Broadly Neutralizing Antibodies; Epitopes; Spike Glycoprotein, Coronavirus; Antibodies, Neutralizing; Immune Evasion; COVID-19 Vaccines
PubMed: 38932192
DOI: 10.3390/v16060900 -
Viruses Jun 2024Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and generally causes mild respiratory symptoms. HCoV-229E infection can cause...
Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and generally causes mild respiratory symptoms. HCoV-229E infection can cause cell death, but the molecular pathways that lead to virus-induced cell death as well as the interplay between viral proteins and cellular cell death effectors remain poorly characterized for HCoV-229E. Studying how HCoV-229E and other common cold coronaviruses interact with and affect cell death pathways may help to understand its pathogenesis and compare it to that of highly pathogenic coronaviruses. Here, we report that the main protease (Mpro) of HCoV-229E can cleave gasdermin D (GSDMD) at two different sites (Q29 and Q193) within its active N-terminal domain to generate fragments that are now unable to cause pyroptosis, a form of lytic cell death normally executed by this protein. Despite GSDMD cleavage by HCoV-229E Mpro, we show that HCoV-229E infection still leads to lytic cell death. We demonstrate that during virus infection caspase-3 cleaves and activates gasdermin E (GSDME), another key executioner of pyroptosis. Accordingly, GSDME knockout cells show a significant decrease in lytic cell death upon virus infection. Finally, we show that HCoV-229E infection leads to increased lytic cell death levels in cells expressing a GSDMD mutant uncleavable by Mpro (GSDMD Q29A+Q193A). We conclude that GSDMD is inactivated by Mpro during HCoV-229E infection, preventing GSDMD-mediated cell death, and point to the caspase-3/GSDME axis as an important player in the execution of virus-induced cell death. In the context of similar reported findings for highly pathogenic coronaviruses, our results suggest that these mechanisms do not contribute to differences in pathogenicity among coronaviruses. Nonetheless, understanding the interactions of common cold-associated coronaviruses and their proteins with the programmed cell death machineries may lead to new clues for coronavirus control strategies.
Topics: Humans; Phosphate-Binding Proteins; Pyroptosis; Intracellular Signaling Peptides and Proteins; Coronavirus 229E, Human; Cell Death; Coronavirus Infections; Neoplasm Proteins; Viral Proteins; Cell Line; Host-Pathogen Interactions; HEK293 Cells; Gasdermins
PubMed: 38932190
DOI: 10.3390/v16060898 -
Viruses May 2024Proteins of the Bcl-2 family regulate cellular fate via multiple mechanisms including apoptosis, autophagy, senescence, metabolism, inflammation, redox homeostasis, and... (Review)
Review
Proteins of the Bcl-2 family regulate cellular fate via multiple mechanisms including apoptosis, autophagy, senescence, metabolism, inflammation, redox homeostasis, and calcium flux. There are several regulated cell death (RCD) pathways, including apoptosis and autophagy, that use distinct molecular mechanisms to elicit the death response. However, the same proteins/genes may be deployed in multiple biochemical pathways. In apoptosis, Bcl-2 proteins control the integrity of the mitochondrial outer membrane (MOM) by regulating the formation of pores in the MOM and apoptotic cell death. A number of prosurvival genes populate the genomes of viruses including those of the pro-survival Bcl-2 family. Viral Bcl-2 proteins are sequence and structural homologs of their cellular counterparts and interact with cellular proteins in apoptotic and autophagic pathways, potentially allowing them to modulate these pathways and determine cellular fate.
Topics: Humans; Proto-Oncogene Proteins c-bcl-2; DNA Viruses; Autophagy; Apoptosis; Viral Proteins; Animals; Mitochondrial Membranes
PubMed: 38932171
DOI: 10.3390/v16060879 -
Viruses May 2024Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral...
cGAS-STING-TBK1 Signaling Promotes Valproic Acid-Responsive Human Cytomegalovirus Immediate-Early Transcription during Infection of Incompletely Differentiated Myeloid Cells.
Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral IE transcription and protein accumulation can be elevated during latency by treatment with histone deacetylase inhibitors such as valproic acid (VPA), rendering infected cells visible to adaptive immune responses. However, the latency-associated viral protein UL138 inhibits the ability of VPA to enhance IE gene expression during infection of incompletely differentiated myeloid cells that support latency. UL138 also limits the accumulation of IFNβ transcripts by inhibiting the cGAS-STING-TBK1 DNA-sensing pathway. Here, we show that, in the absence of UL138, the cGAS-STING-TBK1 pathway promotes both IFNβ accumulation and VPA-responsive IE gene expression in incompletely differentiated myeloid cells. Inactivation of this pathway by either genetic or pharmacological inhibition phenocopied UL138 expression and reduced VPA-responsive IE transcript and protein accumulation. This work reveals a link between cytoplasmic pathogen sensing and epigenetic control of viral lytic phase transcription and suggests that manipulation of pattern recognition receptor signaling pathways could aid in the refinement of MIEP regulatory strategies to target latent viral reservoirs.
Topics: Humans; Valproic Acid; Myeloid Cells; Signal Transduction; Membrane Proteins; Cytomegalovirus; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Cytomegalovirus Infections; Virus Latency; Transcription, Genetic; Cell Differentiation; Gene Expression Regulation, Viral; Genes, Immediate-Early; Interferon-beta
PubMed: 38932169
DOI: 10.3390/v16060877 -
Viruses May 2024Human cytomegalovirus is a ubiquitous herpesvirus that, while latent in most individuals, poses a great risk to immunocompromised patients. In contrast to directly...
Human cytomegalovirus is a ubiquitous herpesvirus that, while latent in most individuals, poses a great risk to immunocompromised patients. In contrast to directly acting traditional antiviral drugs, such as ganciclovir, we aim to emulate a physiological infection control using T cells. For this, we constructed several bispecific T-cell engager (BiTE) constructs targeting different viral glycoproteins of the murine cytomegalovirus and evaluated them in vitro for their efficacy. To isolate the target specific effect without viral immune evasion, we established stable reporter cell lines expressing the viral target glycoprotein B, and the glycoprotein complexes gN-gM and gH-gL, as well as nano-luciferase (nLuc). First, we evaluated binding capacities using flow cytometry and established killing assays, measuring nLuc-release upon cell lysis. All BiTE constructs proved to be functional mediators for T-cell recruitment and will allow a proof of concept for this treatment option. This might pave the way for strikingly safer immunosuppression in vulnerable patient groups.
Topics: Animals; T-Lymphocytes; Mice; Muromegalovirus; Humans; Antibodies, Bispecific; Cell Line; Herpesviridae Infections; Viral Envelope Proteins
PubMed: 38932161
DOI: 10.3390/v16060869 -
Viruses May 2024As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In...
As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In SOT recipients previously vaccinated with at least three doses of BNT162b2, we investigated humoral responses to BNT162b2 booster doses. Anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) was measured using an in-house ELISA. Linear mixed models were fitted to investigate the change in the geometric mean concentration (GMC) of anti-SARS-CoV-2 RBD IgG after vaccination in participants with intervals of more or less than six months between the last two doses of vaccine. We included 107 SOT recipients vaccinated with a BNT162b2 vaccine. In participants with an interval of more than six months between the last two vaccine doses, we found a 1.34-fold change in GMC per month (95% CI 1.25-1.44), while we found a 1.09-fold change in GMC per month (95% CI 0.89-1.34) in participants with an interval of less than six months between the last two vaccine doses, resulting in a rate ratio of 0.82 (95% CI 0.66 to 1.01, = 0.063). In conclusion, the administration of identical COVID-19 mRNA vaccine boosters within six months to SOT recipients may result in limited humoral immunogenicity of the last dose.
Topics: Humans; BNT162 Vaccine; COVID-19; Male; Female; Antibodies, Viral; Middle Aged; Immunity, Humoral; Transplant Recipients; SARS-CoV-2; Immunization, Secondary; Immunoglobulin G; Aged; Organ Transplantation; Adult; COVID-19 Vaccines; Vaccination; Spike Glycoprotein, Coronavirus
PubMed: 38932153
DOI: 10.3390/v16060860 -
Viruses May 2024The human hepatitis delta virus (HDV) is a satellite RNA virus that depends on hepatitis B virus (HBV) surface proteins (HBsAg) to assemble into infectious virions...
The human hepatitis delta virus (HDV) is a satellite RNA virus that depends on hepatitis B virus (HBV) surface proteins (HBsAg) to assemble into infectious virions targeting the same organ (liver) as HBV. Until recently, the evolutionary origin of HDV remained largely unknown. The application of bioinformatics on whole sequence databases lead to discoveries of HDV-like agents (DLA) and shed light on HDV's evolution, expanding our understanding of HDV biology. DLA were identified in heterogeneous groups of vertebrates and invertebrates, highlighting that the evolution of HDV, represented by eight distinct genotypes, is broader and more complex than previously foreseen. In this study, we focused on the characterization of three mammalian DLA discovered in woodchuck (), white-tailed deer (), and lesser dog-like bat () in terms of replication, cell-type permissiveness, and spreading pathways. We generated replication-competent constructs expressing 1.1-fold over-length antigenomic RNA of each DLA. Replication was initiated by transfecting the cDNAs into human (HuH7, HeLa, HEK293T, A549) and non-human (Vero E6, CHO, PaKi, LMH) cell lines. Upon transfection and replication establishment, none of the DLA expressed a large delta antigen. A cell division-mediated viral amplification assay demonstrated the capability of non-human DLA to replicate and propagate in hepatic and non-hepatic tissues, without the requirement of envelope proteins from a helper virus. Remarkably L-HDAg but not S-HDAg from HDV can artificially mediate envelopment of WoDV and DeDV ribonucleoproteins (RNPs) by HBsAg to form infectious particles, as demonstrated by co-transfection of HuH7 cells with the respective DLA expression constructs and a plasmid encoding HBV envelope proteins. These chimeric viruses are sensitive to HDV entry inhibitors and allow synchronized infections for comparative replication studies. Our results provide a more detailed understanding of the molecular biology, evolution, and virus-host interaction of this unique group of animal viroid-like agents in relation to HDV.
Topics: Virus Replication; Animals; Hepatitis Delta Virus; Humans; Hepatitis B virus; Marmota; Cell Division; Chiroptera; Viral Envelope Proteins; Cell Line; Hepatitis B; Hepatitis B Surface Antigens; Genotype; HEK293 Cells; Hepatitis D; RNA, Viral
PubMed: 38932152
DOI: 10.3390/v16060859 -
Viruses May 2024The devastating effects of COVID-19 have highlighted the importance of prophylactic and therapeutic strategies to combat respiratory diseases. Stimulator of interferon...
The devastating effects of COVID-19 have highlighted the importance of prophylactic and therapeutic strategies to combat respiratory diseases. Stimulator of interferon gene (STING) is an essential component of the host defense mechanisms against respiratory viral infections. Although the role of the cGAS/STING signaling axis in the innate immune response to DNA viruses has been thoroughly characterized, mounting evidence shows that it also plays a key role in the prevention of RNA virus infections. In this study, we investigated the role of STING activation during Influenza virus (IFV) infection. In both mouse bone marrow-derived macrophages and monocytic cell line THP-1 differentiated with PMA, we found that dimeric amidobenzimidazole (diABZI), a STING agonist, had substantial anti-IFV activity against multiple strains of IFV, including A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. On the other hand, a pharmacological antagonist of STING (H-151) or the loss of STING in human macrophages leads to enhanced viral replication but suppressed IFN expression. Furthermore, diABZI was antiviral against IFV in primary air-liquid interface cultures of nasal epithelial cells. Our data suggest that STING agonists may serve as promising therapeutic antiviral agents to combat IFV.
Topics: Animals; Humans; Immunity, Innate; Mice; Antiviral Agents; Macrophages; Membrane Proteins; THP-1 Cells; Virus Replication; Influenza, Human; Dogs; Mice, Inbred C57BL; Orthomyxoviridae Infections; Orthomyxoviridae; Benzimidazoles; Signal Transduction
PubMed: 38932148
DOI: 10.3390/v16060855 -
Viruses May 2024Mucosal immunity may contribute to clearing SARS-CoV-2 infection prior to systemic infection, thereby allowing hosts to remain seronegative. We describe the meaningful...
Mucosal immunity may contribute to clearing SARS-CoV-2 infection prior to systemic infection, thereby allowing hosts to remain seronegative. We describe the meaningful detection of SARS-CoV-2-specific nasal mucosal antibodies in a group of exposed-household individuals that evaded systemic infection. Between June 2020 and February 2023, nasopharyngeal swab (NPS) and acute and convalescent blood were collected from individuals exposed to a SARS-CoV-2-confirmed household member. Nasal secretory IgA (SIgA) antibodies targeting the SARS-CoV-2 spike protein were measured using a modified ELISA. Of the 36 exposed individuals without SARS-CoV-2 detected by the RT-PCR of NPS specimens and seronegative for SARS-CoV-2-specific IgG at enrollment and convalescence, 13 (36.1%) had positive SARS-CoV-2-specific SIgA levels detected in the nasal mucosa at enrollment. These individuals had significantly higher nasal SIgA (median 0.52 AU/mL) compared with never-exposed, never-infected controls (0.001 AU/mL) and infected-family participants (0.0002 AU/mL) during the acute visit, respectively (both < 0.001). The nasal SARS-CoV-2-specific SIgA decreased rapidly over two weeks in the exposed seronegative individuals compared to a rise in SIgA in infected-family members. The nasal SARS-CoV-2-specific SIgA may have a protective role in preventing systemic infection.
Topics: Humans; SARS-CoV-2; COVID-19; Immunoglobulin A, Secretory; Male; Female; Adult; Antibodies, Viral; Middle Aged; Antibodies, Neutralizing; Nasal Mucosa; Spike Glycoprotein, Coronavirus; Young Adult; Immunity, Mucosal; Aged; Immunoglobulin G
PubMed: 38932145
DOI: 10.3390/v16060852