Education & Certifications
Doctor, Chinese Academy of Science, Biology (2013)
The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination.
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.
View details for DOI 10.1016/j.cell.2021.05.039
View details for PubMedID 34174187
Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.
The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike receptor binding domain displayed on a protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing oil-in-water emulsion; AS37, a TLR-7 agonist adsorbed to Alum; CpG1018-Alum, a TLR-9 agonist formulated in Alum; and Alum. RBD-NP immunization with AS03, CpG1018-Alum, AS37 or Alum induced substantial nAb and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. Live-virus nAb response was maintained up to 180 days post-vaccination with RBD/AS03, and correlated with protection. RBD-NP immunization cross-neutralized the B.1.1.7 variant efficiently but showed a reduced response against the B.1.351 variant. While RBD-NP/AS03 demonstrated a 4.5-fold reduction in neutralization of B.1.351, the RBD-NP/AS37 group showed a 16-fold reduction, suggesting differences in the breadth of the nAb response induced by these adjuvants. Furthermore, RBD-NP/AS03 was as immunogenic as a prefusion stabilized Spike immunogen (Hexapro) adjuvanted with AS03. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2, and have paved the way for the clinical evaluation of this vaccine in Phase I/II clinical trials (NCT04742738 and NCT04750343).
View details for DOI 10.1038/s41586-021-03530-2
View details for PubMedID 33873199
Type-IInterferon-Inducible SERTAD3 Inhibits Influenza A Virus Replication by Blocking the Assembly of Viral RNA Polymerase Complex.
2020; 33 (5): 108342
Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication invitro. More importantly, Sertad3-/- mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.
View details for DOI 10.1016/j.celrep.2020.108342
View details for PubMedID 33147462
- Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors in Mice and Children ADVANCED SCIENCE 2020
Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors in Mice and Children.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
2020; 7 (18): 1901996
Zika virus (ZIKV) has evolved into a global health threat because of its causal link to congenital Zika syndrome. ZIKV infection of pregnant women may cause a spectrum of abnormalities in children. In the studies in Brazil, a large cohort of children with perinatal exposure to ZIKV is followed, and a spectrum of neurodevelopmental abnormalities is identified. In parallel, it is demonstrated that infection of the mouse neonatal brain by a contemporary ZIKV strain instead of an Asian ancestral strain can cause microcephaly and various abnormal neurological functions. These include defects in social interaction and depression, impaired learning and memory, in addition to severe motor defects, which are present in adult mice as well as in the prospective cohort of children. Importantly, although mouse brains infected later after birth do not have apparent abnormal brain structure, those mice still show significant impairments of visual cortical functions, circuit organization, and experience-dependent plasticity. Thus, the study suggests that special attention should be paid to all children born to ZIKV infected mothers for screening of abnormal behaviors and sensory function during childhood.
View details for DOI 10.1002/advs.201901996
View details for PubMedID 32999822
View details for PubMedCentralID PMC7509663
Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses.
Antimicrobial agents and chemotherapy
Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection in vitro by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes (ISGs) in response to ZIKV infection. In particular, we found that AZM upregulates the expression of MDA5 and RIG-I, pathogen recognition receptors (PRRs) induced by ZIKV infection, and increases the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulates phosphorylation of TBK1, without inducing phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and prevent ZIKV associated devastating clinical outcomes, such as congenital microcephaly.
View details for DOI 10.1128/AAC.00394-19
View details for PubMedID 31527024
Development of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone
2018; 9: 673
The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. Here we report the development and characterization of a recombinant chimeric ZIKV vaccine candidate (termed ChinZIKV) that expresses the prM-E proteins of ZIKV using the licensed Japanese encephalitis live-attenuated vaccine SA14-14-2 as the genetic backbone. ChinZIKV retains its replication activity and genetic stability in vitro, while exhibiting an attenuation phenotype in multiple animal models. Remarkably, immunization of mice and rhesus macaques with a single dose of ChinZIKV elicits robust and long-lasting immune responses, and confers complete protection against ZIKV challenge. Significantly, female mice immunized with ChinZIKV are protected against placental and fetal damage upon ZIKV challenge during pregnancy. Overall, our study provides an alternative vaccine platform in response to the ZIKV emergency, and the safety, immunogenicity, and protection profiles of ChinZIKV warrant further clinical development.
View details for PubMedID 29445153
Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate.
2018; 9 (5)
Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy.IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.
View details for DOI 10.1128/mBio.01683-18
View details for PubMedID 30228241
View details for PubMedCentralID PMC6143740
E90 subunit vaccine protects mice from Zika virus infection and microcephaly.
Acta neuropathologica communications
2018; 6 (1): 77
Zika virus (ZIKV) became a global threat due to its unprecedented outbreak and its association with congenital malformations such as microcephaly in developing fetuses and neonates. There are currently no effective vaccines or drugs available for the prevention or treatment of ZIKV infection. Although multiple vaccine platforms have been established, their effectiveness in preventing congenital microcephaly has not been addressed. Herein, we tested a subunit vaccine containing the 450 amino acids at the N-terminus of the ZIKV envelope protein (E90) in mouse models for either in utero or neonatal ZIKV infection. In one model, embryos of vaccinated dams were challenged with a contemporary ZIKV strain at embryonic day 13.5. The other model infects neonatal mice from vaccinated dams by direct injection of ZIKV into the developing brains. The vaccine led to a substantial reduction of ZIKV-infected cells measured in the brains of fetal or suckling mice, and successfully prevented the onset of microcephaly compared to unvaccinated controls. Furthermore, E90 could protect mice from ZIKV infection even at 140 days post-immunization. This work directly demonstrates that immunization of pregnant mice protects the developing brains of offspring both in utero and in the neonatal period from subsequent ZIKV infection and microcephaly. It also supports the further development of the E90 subunit vaccine towards clinical trials.
View details for DOI 10.1186/s40478-018-0572-7
View details for PubMedID 30097059
View details for PubMedCentralID PMC6086021
25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.
2017; 46 (3): 446–56
Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.
View details for DOI 10.1016/j.immuni.2017.02.012
View details for PubMedID 28314593
View details for PubMedCentralID PMC5957489
Screening for Novel Small-Molecule Inhibitors Targeting the Assembly of Influenza Virus Polymerase Complex by a Bimolecular Luminescence Complementation-Based Reporter System.
Journal of virology
2017; 91 (5)
Influenza virus RNA-dependent RNA polymerase consists of three viral protein subunits: PA, PB1, and PB2. Protein-protein interactions (PPIs) of these subunits play pivotal roles in assembling the functional polymerase complex, which is essential for the replication and transcription of influenza virus RNA. Here we developed a highly specific and robust bimolecular luminescence complementation (BiLC) reporter system to facilitate the investigation of influenza virus polymerase complex formation. Furthermore, by combining computational modeling and the BiLC reporter assay, we identified several novel small-molecule compounds that selectively inhibited PB1-PB2 interaction. Function of one such lead compound was confirmed by its activity in suppressing influenza virus replication. In addition, our studies also revealed that PA plays a critical role in enhancing interactions between PB1 and PB2, which could be important in targeting sites for anti-influenza intervention. Collectively, these findings not only aid the development of novel inhibitors targeting the formation of influenza virus polymerase complex but also present a new tool to investigate the exquisite mechanism of PPIs. IMPORTANCE Formation of the functional influenza virus polymerase involves complex protein-protein interactions (PPIs) of PA, PB1, and PB2 subunits. In this work, we developed a novel BiLC assay system which is sensitive and specific to quantify both strong and weak PPIs between influenza virus polymerase subunits. More importantly, by combining in silico modeling and our BiLC assay, we identified a small molecule that can suppress influenza virus replication by disrupting the polymerase assembly. Thus, we developed an innovative method to investigate PPIs of multisubunit complexes effectively and to identify new molecules inhibiting influenza virus polymerase assembly.
View details for DOI 10.1128/JVI.02282-16
View details for PubMedID 28031371
View details for PubMedCentralID PMC5309938
Integrating computational modeling and functional assays to decipher the structure-function relationship of influenza virus PB1 protein.
2014; 4: 7192
The influenza virus PB1 protein is the core subunit of the heterotrimeric polymerase complex (PA, PB1 and PB2) in which PB1 is responsible for catalyzing RNA polymerization and binding to the viral RNA promoter. Among the three subunits, PB1 is the least known subunit so far in terms of its structural information. In this work, by integrating template-based structural modeling approach with all known sequence and functional information about the PB1 protein, we constructed a modeled structure of PB1. Based on this model, we performed mutagenesis analysis for the key residues that constitute the RNA template binding and catalytic (TBC) channel in an RNP reconstitution system. The results correlated well with the model and further identified new residues of PB1 that are critical for RNA synthesis. Moreover, we derived 5 peptides from the sequence of PB1 that form the TBC channel and 4 of them can inhibit the viral RNA polymerase activity. Interestingly, we found that one of them named PB1(491-515) can inhibit influenza virus replication by disrupting viral RNA promoter binding activity of polymerase. Therefore, this study has not only deepened our understanding of structure-function relationship of PB1, but also promoted the development of novel therapeutics against influenza virus.
View details for DOI 10.1038/srep07192
View details for PubMedID 25424584
View details for PubMedCentralID PMC4244630
A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly.
The FEBS journal
2013; 280 (4): 1139–49
Efficient assembly of the influenza virus RNA-dependent RNA polymerase, a heterotrimeric complex formed by three subunits (PA, PB1 and PB2) is critical for virus replication and pathogenicity. Therefore, interfering with the assembly of the RNA-dependent RNA polymerase complex could offer novel and effective anti-influenza therapeutics. In the present study, we show that a short peptide derived from amino acids 731-757 of PB1 (PB1(731-757)) can disrupt the interaction between the C-terminal part of PB1 (denoted as PB1c corresponding to PB1(676-757)) and the N-terminal part of PB2 (denoted as PB2n corresponding to PB2(1-40) ). We further show that PB1(731-757) is capable of inhibiting viral polymerase activity and viral replication. Interestingly, we find that PB1(731-757) interacts with PB1c rather than PB2n. Furthermore, mutational analyses show that the hydrophobic sites of PB1c play an essential role in the PB1c-PB1(731-757) interaction. The characterization of the inhibitory effect of PB1(731-757) on viral polymerase activity and viral replication could offer a potential target for anti-influenza drug development.
View details for DOI 10.1111/febs.12107
View details for PubMedID 23279951