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The outbreak of 2022 monkeypox virus (MPXV) infection in nonendemic regions is a global public health concern. A highly effective and safe MPXV vaccine that is available to the general public is urgently needed to control the mpox pandemic. Here, we developed a multivalent mRNA vaccine candidate, MPXV-1103, which expresses the full-length B6, A35, A29 and M1 proteins with three flexible linkers (G4S1)3 in a single sequence. Compared with the monovalent MPXV mRNA vaccine candidates or the quadrivalent mRNA vaccine from mixtures of the four monovalent MPXV mRNA vaccines, MPXV-1103 elicits a robust humoral response and an MPXV-specific T-cell response and protects mice from lethal vaccinia virus (VACV) challenge, with no live virus detected in the nasal or lungs even at dosages as low as 1 µg. Furthermore, analysis of complete blood counts and photomicrographs of tissue from the main organs of mice vaccinated with MPXV-1103 at doses of 5 µg and 20 µg revealed that two doses of MPXV-1103 did not cause any observable pathological changes in the mice. Collectively, our results suggest that MPXV-1103, with features of high efficacy, safety and a simplified manufacturing process, is a promising vaccine candidate for defending against MPXV infection.
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Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia's severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.
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COVID-19 , Carioferinas , Ribonuclease III , SARS-CoV-2 , Fatores de Processamento de Serina-Arginina , Animais , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Humanos , Ribonuclease III/metabolismo , Ribonuclease III/genética , SARS-CoV-2/genética , COVID-19/metabolismo , COVID-19/virologia , COVID-19/genética , Camundongos , Carioferinas/metabolismo , Carioferinas/genética , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Regulação para Baixo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Splicing de RNA , Autofagia/genética , Dano ao DNA , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-BRESUMO
Hyperactivation of pro-inflammatory type 1 cytokines (e.g., tumor necrosis factor alpha [TNF-α] and interferon gamma [IFN-γ]) mirrors the inflammation of coronavirus disease 2019. Helminths could alleviate excessive immune responses. Here, helminth Trichinella spiralis (Ts) infection was shown to protect against TNF-α- and IFN-γ-induced shock. Mechanistically, Ts-induced protection was interleukin-9 (IL-9) dependent but not IL-4Rα. Recombinant IL-9 treatment not only improved the survival of wild-type mice with TNF-α- and IFN-γ-induced shock but also that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected K18-human angiotensin-converting enzyme 2 (hACE2) mice, emphasizing the significance of IL-9 in alleviating cytokine storm syndromes during SARS-CoV-2 infection. Interestingly, Ts excretory/secretory (TsES)-induced protection was also observed in SARS-CoV-2 infection, indicating that identifying anti-inflammatory molecules from TsES could be a novel way to mitigate adverse pathological inflammation during pathogen infection.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is linked to cytokine storm triggered by type 1 pro-inflammatory immune responses. TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19. Helminths (e.g., Trichinella spiralis, Ts) can potently activate anti-inflammatory type 2 immune response. Here, we found that helminth Ts-induced protection against TNF-α and IFN-γ shock was IL-9 dependent. Treatment with recombinant IL-9 could protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in K18-hACE2 mice. Helminth Ts excretory/secretory (TsES) products also ameliorated SARS-CoV-2 infection-related cytokine storm. In conclusion, our study emphasizes the significance of IL-9 in protecting from cytokine storm syndromes associated with SARS-CoV-2 infection. Anti-inflammatory molecules from TsES could be a new source to mitigate adverse pathological inflammation associated with infections, including COVID-19.
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COVID-19 , Síndrome da Liberação de Citocina , Interleucina-9 , SARS-CoV-2 , Trichinella spiralis , Animais , COVID-19/imunologia , Camundongos , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Trichinella spiralis/imunologia , SARS-CoV-2/imunologia , Humanos , Interleucina-9/metabolismo , Interleucina-9/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Citocinas/metabolismo , Citocinas/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Modelos Animais de Doenças , Triquinelose/imunologia , Feminino , Camundongos Endogâmicos C57BL , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genéticaRESUMO
The 2022 mpox outbreak led the World Health Organization (WHO) to declare it a public health emergency of international concern (PHEIC). There is a need to develop more effective and safer mpox virus (MPXV)-specific vaccines in response to the mpox epidemic. The mRNA vaccine is a promising platform to protect against MPXV infection. In this study, we construct two bivalent MPXV mRNA vaccines, designated LBA (B6R-A29L) and LAM (A35R-M1R), and a quadrivalent mRNA vaccine, LBAAM (B6R-A35R-A29L-M1R). The immunogenicity and protective efficacy of these vaccines alone or in combination were evaluated in a lethal mouse model. All mRNA vaccine candidates could elicit potential antigen-specific humoral and cellular immune responses and provide protection against vaccinia virus (VACV) infection. The protective effect of the combination of two bivalent mRNA vaccines and the quadrivalent vaccine was superior to that of the individual bivalent mRNA vaccine. Our study provides valuable insights for the development of more efficient and safer mRNA vaccines against mpox.
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Vaccinia virus , Vacinas de mRNA , Animais , Vaccinia virus/imunologia , Vaccinia virus/genética , Camundongos , Feminino , Vacinas de mRNA/imunologia , Humanos , Camundongos Endogâmicos BALB C , Mpox/prevenção & controle , Mpox/imunologia , Vacínia/imunologia , Vacínia/prevenção & controle , Anticorpos Antivirais/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Imunidade HumoralRESUMO
The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop ß1S2-ß1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Microscopia Crioeletrônica , Infecções por Henipavirus , Proteínas Virais de Fusão , Animais , Anticorpos Neutralizantes/imunologia , Feminino , Anticorpos Antivirais/imunologia , Infecções por Henipavirus/virologia , Infecções por Henipavirus/imunologia , Proteínas Virais de Fusão/imunologia , Proteínas Virais de Fusão/química , Humanos , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/química , Vírus Nipah/imunologia , Internalização do Vírus/efeitos dos fármacos , Henipavirus/imunologia , Cricetinae , Reações Cruzadas/imunologia , Vírus Hendra/imunologia , Macaca , Mesocricetus , Cristalografia por Raios XRESUMO
BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).
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Anticorpos Neutralizantes , Sprays Nasais , Animais , Cricetinae , Humanos , China , Traqueia , Voluntários SaudáveisRESUMO
Since the outbreak of monkeypox (mpox) in 2022, widespread concern has been placed on imposing an urgent demand for specific vaccines that offer safer and more effective protection. Using an efficient and scalable circular RNA (circRNA) platform, we constructed four circRNA vaccines that could induce robust neutralizing antibodies as well as T cell responses by expressing different surface proteins of mpox virus (MPXV), resulting in potent protection against vaccinia virus (VACV) in mice. Strikingly, the combination of the four circular RNA vaccines demonstrated the best protection against VACV challenge among all the tested vaccines. Our study provides a favorable approach for developing MPXV-specific vaccines by using a circular mRNA platform and opens up novel avenues for future vaccine research.
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Anticorpos Neutralizantes , Monkeypox virus , RNA Circular , Vaccinia virus , Animais , Camundongos , Vaccinia virus/genética , Vaccinia virus/imunologia , RNA Circular/genética , Anticorpos Neutralizantes/imunologia , Monkeypox virus/imunologia , Monkeypox virus/genética , Anticorpos Antivirais/imunologia , Vacínia/prevenção & controle , Vacínia/imunologia , Mpox/prevenção & controle , Mpox/imunologia , Vacinas Virais/imunologia , Vacinas Virais/genética , Humanos , Modelos Animais de Doenças , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.
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Infecções por Henipavirus , Vírus Nipah , Humanos , Anticorpos Neutralizantes/metabolismo , Vírus Nipah/metabolismo , Anticorpos AntiviraisRESUMO
As the world continues to confront severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV) is also causing severe respiratory illness in millions of infants, elderly individuals, and immunocompromised people globally. Exacerbating the situation is the fact that co-infection with multiple viruses is occurring, something which has greatly increased the clinical severity of the infections. Thus, our team developed a bivalent vaccine that delivered mRNAs encoding SARS-CoV-2 Omicron spike (S) and RSV fusion (F) proteins simultaneously, SF-LNP, which induced S and F protein-specific binding antibodies and cellular immune responses in BALB/c mice. Moreover, SF-LNP immunization effectively protected BALB/c mice from RSV infection and hamsters from SARS-CoV-2 Omicron infection. Notably, our study pointed out the antigenic competition problem of bivalent vaccines and provided a solution. Overall, our results demonstrated the potential of preventing two infectious diseases with a single vaccine and provided a paradigm for the subsequent design of multivalent vaccines.
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COVID-19 , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Humanos , Camundongos , Lactente , Cricetinae , Animais , Idoso , Vacinas de mRNA , Vacinas Combinadas , Anticorpos Antivirais , Vacinas contra Vírus Sincicial Respiratório/genética , Proteínas Virais de Fusão/genética , COVID-19/prevenção & controle , SARS-CoV-2/genética , Vírus Sincicial Respiratório Humano/genética , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Anticorpos NeutralizantesRESUMO
OBJECTIVES: Sternotomy pain is common after cardiac surgery. The deep parasternal intercostal plane (DPIP) block is a novel technique that provides analgesia to the anterior chest wall. The aim of this study was to investigate the analgesic effect of bilateral DPIP blocks on intraoperative pain control in cardiac surgery. DESIGN: This is a double-blinded, prospective randomized controlled trial (Oct 2020-Dec 2022). SETTINGS: This study was conducted in a single institution, which is an academic university hospital. PARTICIPANTS: Eighty-six elective cardiac surgical patients with median sternotomy were recruited. INTERVENTIONS: Patients were randomly divided into DPIP or control group. Either 20ml 0.25% levobupivacaine or 0.9% normal saline was injected for the DPIP under ultrasound guidance after induction of general anaesthesia. MEASUREMENTS AND MAIN RESULTS: The primary outcome was intraoperative opioids consumption and hemodynamic changes at sternotomy. Secondary outcomes included postoperative morphine consumption, postoperative pain and time to tracheal extubation. Intraoperative opioids requirement was reduced from a median (IQR) intravenous morphine equivalence of 21.4mg (13.8-24.3mg) in control group to 9.5mg (7.3-11.2mg) in the DPIP group (P<0.001). Hemodynamic parameters were more stable in DPIP group at sternotomy, as evidenced by lower percentage increase in systolic, diastolic and mean arterial blood pressure from baseline. No difference was observed in time to tracheal extubation, postoperative morphine consumption, postoperative pain score and spirometry. CONCLUSIONS: Bilateral DPIP block provides effective intraoperative analgesia and opioid-sparing. It may be included as part of the multimodal analgesia for enhanced recovery in cardiac surgery.
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Procedimentos Cirúrgicos Cardíacos , Ácido Iopanoico/análogos & derivados , Bloqueio Nervoso , Humanos , Esternotomia/efeitos adversos , Estudos Prospectivos , Bloqueio Nervoso/métodos , Procedimentos Cirúrgicos Cardíacos/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Analgésicos Opioides , MorfinaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron and its subvariants (such as BQ.1, XBB and the latest variants, including XBB.1.16, EG.5, and BA.2.86), as the dominant variants, currently account for almost all new infections in the world due to their high transmissibility and immune escape ability. Omicron-specific mRNA vaccines showed great potential to protect against Omicron infections. However, whether the vaccine could provide long-term protection is unknown. Toward this goal, we evaluated the immunogenicity of a preclinical Omicron (BA.1)-specific mRNA vaccine (SOmicron-6P) in different animal models. SOmicron-6P induced the highest levels of antibody titers at 1-2 weeks in different animals after the second dose. Even 9 months after the immunization, we observed modest neutralizing activity against Omicron subvariants in macaques. In addition, immunological memory cells can be rapidly reactivated upon stimulation. SOmicron-6P at concentrations higher than 10 µg effectively protected hamsters from BA.1 challenge 253 days after the first immunization, which could be attributed to the reactivation of immune systems. In addition, the toxicity tests conducted in rats revealed a highly favorable biosafety profile for SOmicron-6P, even at high dosages. Our data suggest that the Omicron-specific mRNA vaccine is highly effective and safe in animal models and provides long-term immunologic protection against SARS-CoV-2 Omicron infections.
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Nipah virus (NiV), a bat-borne paramyxovirus, results in neurological and respiratory diseases with high mortality in humans and animals. Developing vaccines is crucial for fighting these diseases. Previously, only a few studies focused on the fusion (F) protein alone as the immunogen. Numerous NiV strains have been identified, including 2 representative strains from Malaysia (NiV-M) and Bangladesh (NiV-B), which differ significantly from each other. In this study, an F protein sequence with the potential to prevent different NiV strain infections was designed by bioinformatics analysis after an in-depth study of NiV sequences in GenBank. Then, a chimpanzee adenoviral vector vaccine and a DNA vaccine were developed. High levels of immune responses were detected after AdC68-F, pVAX1-F, and a prime-boost strategy (pVAX1-F/AdC68-F) in mice. After high titers of humoral responses were induced, the hamsters were challenged by the lethal NiV-M and NiV-B strains separately. The vaccinated hamsters did not show any clinical signs and survived 21 days after infection with either strain of NiV, and no virus was detected in different tissues. These results indicate that the vaccines provided complete protection against representative strains of NiV infection and have the potential to be developed as a broad-spectrum vaccine for human use.
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Infecções por Henipavirus , Vírus Nipah , Vacinas Virais , Cricetinae , Animais , Humanos , Camundongos , Mesocricetus , Infecções por Henipavirus/prevenção & controleRESUMO
Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that poses a severe threat to humans due to its high morbidity and the lack of viable countermeasures. Vaccines are the most crucial defense against NiV infections. Here, a recombinant chimpanzee adenovirus-based vaccine (AdC68-G) and a DNA vaccine (DNA-G) were developed by expressing the codon-optimized full-length glycoprotein (G) of NiV. Strong and sustained neutralizing antibody production, accompanied by an effective T-cell response, was induced in BALB/c mice by intranasal or intramuscular administration of one or two doses of AdC68-G, as well as by priming with DNA-G and boosting with intramuscularly administered AdC68-G. Importantly, the neutralizing antibody titers were maintained for up to 68 weeks in the mice that received intramuscularly administered AdC68-G and the prime DNA-G/boost AdC68-G regimen, without a significant decline. Additionally, Syrian golden hamsters immunized with AdC68-G and DNA-G via homologous or heterologous prime/boost immunization were completely protected against a lethal NiV virus challenge, without any apparent weight loss, clinical signs, or pathological tissue damage. There was a significant reduction in but not a complete absence of the viral load and number of infectious particles in the lungs and spleen tissue following NiV challenge. These findings suggest that the AdC68-G and DNA-G vaccines against NiV infection are promising candidates for further development.
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As one of the deadliest viruses, Ebola virus (EBOV) causes lethal hemorrhagic fevers in humans and nonhuman primates. The suppression of innate immunity leads to robust systemic virus replication of EBOV, leading to enhanced transmission. However, the mechanism of EBOV-host interaction is not fully understood. Here, we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis, which are highly clustered to Jak-STAT signaling. EBOV VP35 and VP30 were found to inhibit type I interferon (IFN) signaling. Moreover, exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1, and suppresses nuclear translocation of STAT1. Using serial truncated mutations of VP35, N-terminal 1-220 amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling. Remarkably, VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus (BDBV) and Marburg virus (MARV), resulting in stable replication to facilitate the pathogenesis. Altogether, this study enriches understanding on EBOV evasion of innate immune response, and provides insights into the interplay between filoviruses and host.
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Ebolavirus , Doença pelo Vírus Ebola , Interferon Tipo I , Humanos , Animais , Proteínas Virais/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Imunidade Inata , Ebolavirus/genética , Replicação ViralRESUMO
The ongoing pandemic caused by mpox virus (MPXV) has become an international public health emergency that poses a significant threat to global health. The vaccinia virus Tiantan strain (VTT) was used to vaccinate against smallpox in China 42 years ago. It is urgent to assess the level of immunity to smallpox in individuals vaccinated 43 or more years ago and evaluate their immunological susceptibility to MPXV. Here, we recruited 294 volunteers and detected the level of residual humoral immunity, including the vaccinia-specific IgG level and neutralizing antibody titer, and the cross-antibodies of MPXV A29L, B6R, A35R, and M1R. Our results showed that the humoral immunity from the smallpox vaccine in the population still remains, and VTT-specific NAb levels wane with age. The majority of the population pre-1981 who should be immunized with VTT still maintains certain levels of MPXV-specific antibodies, in particular, targeting A35R and B6R antigens. Furthermore, we separately analyzed the correlations between the OD450 values of VTT-specific IgG and A35R-specific IgG, B6R-specific IgG, and A29L-specific IgG with plasma samples diluted 1:40, showing a linear correlation (p < 0.0001). Our findings suggest that most Chinese populations still maintain VTT-specific IgG antibodies for 42 or more years after smallpox vaccination and could provide some level of protection against MPXV.
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Imunidade Humoral , Mpox , Vacina Antivariólica , Humanos , Anticorpos Neutralizantes , Imunoglobulina G , Monkeypox virus , Varíola/prevenção & controle , Vacinação , Vacina Antivariólica/imunologia , Mpox/prevenção & controleRESUMO
SARS-CoV-2, a type of respiratory virus, has exerted a great impact on global health and economy over the past three years. Antibody-based therapy was initially successful but later failed due to the accumulation of mutations in the spike protein of the virus. Strategies that enable antibodies to resist virus escape are therefore of great significance. Here, we engineer a bispecific SARS-CoV-2 neutralizing nanobody in secretory Immunoglobulin A (SIgA) format, named S2-3-IgA2m2, which shows broad and potent neutralization against SARS-CoV-1, SARS-CoV-2 and its variants of concern (VOCs) including XBB and BQ.1.1. S2-3-IgA2m2 is â¼1800-fold more potent than its parental IgG counterpart in neutralizing XBB. S2-3-IgA2m2 is stable in mouse lungs at least for three days when administrated by nasal delivery. In hamsters infected with BA.5, three intranasal doses of S2-3-IgA2m2 at 1 mg/kg significantly reduce viral RNA loads and completely eliminate infectious particles in the trachea and lungs. Notably, even at single dose of 1 mg/kg, S2-3-IgA2m2 prophylactically administered through the intranasal route drastically reduces airway viral RNA loads and infectious particles. This study provides an effective weapon combating SARS-CoV-2, proposes a new strategy overcoming the virus escape, and lays strategic reserves for rapid response to potential future outbreaks of "SARS-CoV-3".
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Anticorpos , SARS-CoV-2 , Animais , Cricetinae , Camundongos , Surtos de Doenças , Imunoglobulina A Secretora , RNA Viral , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Sorafenibe/farmacologia , Mutação , GenótipoRESUMO
Fusion with host cell membrane is the main mechanism of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 µM, while the IC50 in delta variant decreased to 0.101 µM, the IC50 in Omicron BA.1 variant was 0.042 µM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 µM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.