Publications by authors named "William J Liu"

69 Publications

Peptide Presentations of Marsupial MHC Class I Visualize Immune Features of Lower Mammals Paralleled with Bats.

J Immunol 2021 Sep 17. Epub 2021 Sep 17.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China;

Marsupials are one of three major mammalian lineages that include the placental eutherians and the egg-laying monotremes. The marsupial brushtail possum is an important protected species in the Australian forest ecosystem. Molecules encoded by the MHC genes are essential mediators of adaptive immune responses in virus-host interactions. Yet, nothing is known about the peptide presentation features of any marsupial MHC class I (MHC I). This study identified a series of possum MHC I Trvu-UB*01:01 binding peptides derived from wobbly possum disease virus (WPDV), a lethal virus of both captive and feral possum populations, and unveiled the structure of marsupial peptide/MHC I complex. Notably, we found the two brushtail possum-specific insertions, the 3-aa IleGluArg and 1-aa Arg insertions are located in the Trvu-UB*01:01 peptide binding groove (PBG). The 3-aa insertion plays a pivotal role in maintaining the stability of the N terminus of Trvu-UB*01:01 PBG. This aspect of marsupial PBG is unexpectedly similar to the bat MHC I Ptal-N*01:01 and is shared with lower vertebrates from elasmobranch to monotreme, indicating an evolution hotspot that may have emerged from the pathogen-host interactions. Residue Arg insertion, located in the α2 helix, is available for TCR recognition, and it has a particular influence on promoting the anchoring of peptide WPDV-12. These findings add significantly to our understanding of adaptive immunity in marsupials and its evolution in vertebrates. Our findings have the potential to impact the conservation of the protected species brushtail possum and other marsupial species.
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http://dx.doi.org/10.4049/jimmunol.2100350DOI Listing
September 2021

A novel potentially recombinant rodent coronavirus with a polybasic cleavage site in the spike protein.

J Virol 2021 Aug 25:JVI0117321. Epub 2021 Aug 25.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reignited global interest in animal coronaviruses and their potential for human transmission. While bats are thought to be the wildlife reservoir of SARS-CoV and SARS-CoV-2, the widespread human coronavirus OC43 is thought to have originated in rodents. We sampled 297 rodents and shrews representing eight species in three municipalities of southern China. We report coronavirus prevalence of 23.3% and 0.7% in Guangzhou and Guilin, respectively, with samples from urban areas having significantly higher coronavirus prevalence than those from rural areas. We obtained three coronavirus genome sequences from , including a RCoV-GCCDC3, an RCoV-GCCDC5 and a novel RCoV-GCCDC4. Recombination analysis suggests that there was a potential recombinant event involving RCoV-GCCDC4, Murine hepatitis virus and Longquan Rl rat coronavirus. Furthermore, we uncovered a polybasic cleavage site RARR in the spike (S) protein of RCoV-GCCDC4, which is dominant in RCoV. These findings provide further information on the potential for inter-species transmission of coronaviruses and demonstrate the value of a One Health approach to virus discovery. Surveillance of viruses among rodents within rural and urban areas of South China identified three rodent coronaviruses RCoV-GCCDC3, 4 and 5, one of which was identified as a novel potentially recombinant coronavirus with a polybasic cleavage site in the spike (S) protein. Through reverse transcription PCR screening of coronaviruses, we found that coronavirus prevalence in urban areas is much higher than that in rural areas. Subsequently, we obtained three coronavirus genome sequences by deep sequencing. After different method-based analyses, we found that RCoV-GCCDC4 was a novel potentially recombinant coronavirus with a polybasic cleavage site in S protein, dominant in RCoV. This newly identified coronavirus RCoV-GCCDC4 with its potentially recombinant genome and polybasic cleavage site provides a new insight into the evolution of coronaviruses. Furthermore, our results provide further information on the potential for inter-species transmission of coronaviruses and demonstrate the necessity of a One Health approach for zoonotic disease surveillance.
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http://dx.doi.org/10.1128/JVI.01173-21DOI Listing
August 2021

Recombinant chimpanzee adenovirus AdC7 expressing dimeric tandem-repeat spike protein RBD protects mice against COVID-19.

Emerg Microbes Infect 2021 Dec;10(1):1574-1588

Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Haikou, People's Republic of China.

A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus-vectored vaccines expressing spike (S) protein have been approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD), or tandem-repeat dimeric RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular immune responses. AdC7-RBD-tr2 showed higher antibody responses compared to either AdC7-S or AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. AdC7-RBD-tr2-elicted sera preserved the neutralizing activity against the circulating variants, especially the Delta variant. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.
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http://dx.doi.org/10.1080/22221751.2021.1959270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366625PMC
December 2021

Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Institut Pasteur of Shanghai, Guangzhou Women and Children's Medical Center Joint Center for Infection and Immunity, Chinese Academy of Sciences, 200031 Shanghai, China;

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.
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http://dx.doi.org/10.1073/pnas.2019798118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092388PMC
April 2021

Avian influenza A (H7N9) virus: from low pathogenic to highly pathogenic.

Front Med 2021 Aug 16;15(4):507-527. Epub 2021 Apr 16.

Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, 518114, China.

The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.
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http://dx.doi.org/10.1007/s11684-020-0814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190734PMC
August 2021

More diversified antibiotic resistance genes in chickens and workers of the live poultry markets.

Environ Int 2021 08 30;153:106534. Epub 2021 Mar 30.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Background: Poultry farms and LPMs are a reservoir of antimicrobial resistant bacteria and resistance genes from feces. The LPM is an important interface between humans, farm animals, and environments in a typical urban environment, and it is considered a reservoir for ARGs and viruses. However, the antibiotic resistomes shared between chicken farms and LPMs, and that of LPM workers and people who have no contact with the LPMs remains unknown.

Methods: We characterized the resistome and bacterial microbiome of farm chickens and LPMs and LPM workers and control subjects. The mobile ARGs identified in chickens and the distribution of the mcr-family genes in publicly bacterial genomes and chicken gut metagenomes was analyzed, respectively. In addition, the prevalence of mcr-1 in LPMs following the ban on colistin-positive additives in China was explored.

Results: By profiling the microbiomes and resistomes in chicken farms, LPMs, LPM workers, and LPM environments, we found that the bacterial community composition and resistomes were significantly different between the farms and the LPMs, and the LPM samples possessed more diversified ARGs (59 types) than the farms. Some mobile ARGs, such as mcr-1 and tet(X3), identified in chicken farms, LPMs, LPM workers, and LPM environments were also harbored by human clinical pathogens. Moreover, we found that the resistomes were significantly different between the LPM workers and those who have no contact with the LPMs, and more diversified ARGs (188 types) were observed in the LPM workers. It is also worth noting that mcr-10 was identified in both human (5.2%, 96/1,859) and chicken (1.5%, 14/910) gut microbiomes. Although mcr-1 prevalence decreased significantly in the LPMs across the eight provinces in China, from 190/333 (57.1%) samples in September 2016-March 2017 to 208/544 (38.2%) samples in August 2018-May 2019, it is widespread and continuous in the LPMs.

Conclusion: Live poultry trade has a significant effect on the diversity of ARGs in LPM workers, chickens, and environments in China, driven by human selection with the live poultry trade. Our findings highlight the live poultry trade as ARG disseminators into LPMs, which serve as an interface of LPM environments even LPM workers, and that could urge Government to have better control of LPMs in China. Further studies on the factors that promote antibiotic resistance exchange between LPM environments, human commensals, and pathogens, are warranted.
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http://dx.doi.org/10.1016/j.envint.2021.106534DOI Listing
August 2021

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β2-Microglobulin.

J Vis Exp 2021 03 10(169). Epub 2021 Mar 10.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University; NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention;

The major histocompatibility complex (MHC) plays a pivotal role in antigen peptide presentation and T cell immune responses against infectious disease and tumor development. The hybrid MHC I complexed with heterologous β2-microglobulin (β2m) substitution from different species can be stabilized in vitro. This is a feasible means to study MHC I of mammals, when the homologous β2m is not available. Meanwhile, it is indicated that mammalian β2m substitution does not significantly affect peptide presentation. However, there is limited summarization regarding the methodology and the technology for the hybrid MHC I complexed with heterologous β2-microglobulin (β2m). Herein, methods to evaluate the feasibility of heterologous β2m substitution in MHC I study are presented. These methods include preparation of expression constructs; purification of inclusion bodies and refolding of the MHC complex; determination of protein thermostability; crystal screening and structure determination. This study provides a recommendation for understanding function and structure of MHC I, and is also significant for T cell response evaluation during infectious disease and tumor immunotherapy.
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http://dx.doi.org/10.3791/61462DOI Listing
March 2021

Effective virus-neutralizing activities in antisera from the first wave of survivors of severe COVID-19.

JCI Insight 2021 02 22;6(4). Epub 2021 Feb 22.

State Key Laboratory of Virology, Institute of Medical Virology and School of Basic Medical Sciences, Wuhan University, Wuhan, China.

The coronavirus disease 19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst public health crisis in a century. However, knowledge about the dynamics of antibody responses in patients with COVID-19 is still poorly understood. In this study, we performed a serological study with serum specimens collected at the acute and the convalescent phases from 104 patients with severe COVID-19 who were part of the first wave of COVID-19 cases in Wuhan, China. Our findings revealed that neutralizing antibodies to SARS-CoV-2 are persistent for at least 6 months in patients with severe COVID-19, despite that IgG levels against the receptor binding domain (RBD) and nucleocapsid protein (N) IgG declined from the acute to the convalescent phase. Moreover, we demonstrate that the level of RBD-IgG is capable of correlating with SARS-CoV-2-neutralizing activities in COVID-19 serum. In summary, our findings identify the magnitude, functionality, and longevity of antibody responses in patients with COVID-19, which sheds light on the humoral immune response to COVID-19 and would be beneficial for developing vaccines.
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http://dx.doi.org/10.1172/jci.insight.146267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934937PMC
February 2021

Recent Insights into Emerging Coronavirus: SARS-CoV-2.

ACS Infect Dis 2021 06 9;7(6):1369-1388. Epub 2020 Dec 9.

Frontiers Science Center for Flexible Electronics (FSCFE), Xian Institute of Flexible Electronics (IFE) & Xi'an Institute of Biomedical Materials and Engineering (IBME), Northwestern Polytechnical University (NPU), Xi'an 710072, China.

The SARS-CoV-2 outbreak that emerged at the end of 2019 has affected more than 58 million people with more than 1.38 million deaths and has had an incalculable impact on the world . Extensive prevention and treatment measures have been implemented since the pandemic. In this Review, we summarize current understanding on the source, transmission characteristics, and pathogenic mechanism of SARS-CoV-2. We also detail the recent development of diagnostic methods and potential treatment strategies of COVID-19 with focus on the ongoing clinical trials of antibodies, vaccines, and inhibitors for combating the emerging coronavirus.
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http://dx.doi.org/10.1021/acsinfecdis.0c00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737536PMC
June 2021

Convincing the confidence to conquer COVID-19: From epidemiological intervention to laboratory investigation.

Biosaf Health 2020 Dec 27;2(4):185-186. Epub 2020 Nov 27.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

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http://dx.doi.org/10.1016/j.bsheal.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694464PMC
December 2020

Cold-chain transportation in the frozen food industry may have caused a recurrence of COVID-19 cases in destination: Successful isolation of SARS-CoV-2 virus from the imported frozen cod package surface.

Biosaf Health 2020 Dec 19;2(4):199-201. Epub 2020 Nov 19.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

Coronavirus disease 2019 (COVID-19) pandemic has spread in 220 countries/regions to wreak havoc to human beings around the world. At present, the second wave of COVID-19 has begun in many European countries. The complete control of COVID-19 is very urgent. Although China quickly brought the virus under control, there have been eight sporadic outbreaks in China since then. Both in Xinfadi of Beijing and Dalian outbreak of COVID-19, environmental swab samples related to imported cold chain food were tested nucleic acid positive for SARS-CoV-2. In this outbreak in Qingdao, we directly isolated SARS-CoV-2 from the cod outer package's surface swab samples. This is the first time worldwide, SARS-CoV-2 were isolated from the imported frozen cod outer package's surface, which showed that imported frozen food industry could import SARS-CoV-2 virus.
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http://dx.doi.org/10.1016/j.bsheal.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676848PMC
December 2020

Dominant subtype switch in avian influenza viruses during 2016-2019 in China.

Nat Commun 2020 11 20;11(1):5909. Epub 2020 Nov 20.

Federal Research Center of Fundamental and Translational Medicine, Federal State Budget Scientific Institution, Siberian Branch of Russian Academy of Sciences, Novosibirsk State University, Novosibirsk, Russia, 630090.

We have surveyed avian influenza virus (AIV) genomes from live poultry markets within China since 2014. Here we present a total of 16,091 samples that were collected from May 2016 to February 2019 in 23 provinces and municipalities in China. We identify 2048 AIV-positive samples and perform next generation sequencing. AIV-positive rates (12.73%) from samples had decreased substantially since 2016, compared to that during 2014-2016 (26.90%). Additionally, H9N2 has replaced H5N6 and H7N9 as the dominant AIV subtype in both chickens and ducks. Notably, novel reassortants and variants continually emerged and disseminated in avian populations, including H7N3, H9N9, H9N6 and H5N6 variants. Importantly, almost all of the H9 AIVs and many H7N9 and H6N2 strains prefer human-type receptors, posing an increased risk for human infections. In summary, our nation-wide surveillance highlights substantial changes in the circulation of AIVs since 2016, which greatly impacts the prevention and control of AIVs in China and worldwide.
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http://dx.doi.org/10.1038/s41467-020-19671-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679419PMC
November 2020

Emerging HxNy Influenza A Viruses.

Cold Spring Harb Perspect Med 2020 Sep 14. Epub 2020 Sep 14.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.

The continuous emergence and reemergence of diverse subtypes of influenza A viruses, which are known as "HxNy" and are mediated through the reassortment of viral genomes, account for seasonal epidemics, occasional pandemics, and zoonotic outbreaks. We summarize and discuss the characteristics of historic human pandemic HxNy viruses and diverse subtypes of HxNy among wild birds, mammals, and live poultry markets. In addition, we summarize the key molecular features of emerging infectious HxNy influenza viruses from the perspectives of the receptor binding of Hx, the inhibitor-binding specificities and drug-resistance features of Ny, and the matching of the gene segments. Our work enhances our understanding of the potential threats of novel reassortant influenza viruses to public health and provides recommendations for effective prevention, control, and research of this pathogen.
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http://dx.doi.org/10.1101/cshperspect.a038406DOI Listing
September 2020

Genomic characterization of SARS-CoV-2 identified in a reemerging COVID-19 outbreak in Beijing's Xinfadi market in 2020.

Biosaf Health 2020 Dec 2;2(4):202-205. Epub 2020 Sep 2.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

After 56 days without coronavirus disease 2019 (COVID-19) cases, reemergent cases were reported in Beijing, China on June 11, 2020. Here, we report the genetic characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequenced from the clinical specimens of 4 human cases and 2 environmental samples. The nucleotide similarity among six SARS-CoV-2 genomes ranged from 99.98% to 99.99%. Compared with the reference strain of SARS-CoV-2 (GenBank No. NC_045512), all six genome sequences shared the same substitutions at nt241 (C → T), nt3037 (C → T), nt14408 (C → T), nt23403 (A → G), nt28881 (G → A), nt28882 (G → A), and nt28883 (G → C), which are the characteristic nucleotide substitutions of L-lineage European branch I. This was also proved by the maximum likelihood phylogenetic tree based on the full-length genome of SARS-CoV-2. They also have a unique shared nucleotide substitution, nt6026 (C → T), which is the characteristic nucleotide substitution of SARS-CoV-2 in Beijing's Xinfadi outbreak. It is noteworthy that there is an amino acid D614G mutation caused by nt23403 substitution in all six genomes, which may enhance the virus's infectivity in humans and help it become the leading strain of the virus to spread around the world today. It is necessary to continuously monitor the genetic variation of SARS-CoV-2, focusing on the influence of key mutation sites of SARS-CoV-2 on viral transmission, clinical manifestations, severity, and course of disease.
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http://dx.doi.org/10.1016/j.bsheal.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467064PMC
December 2020

Dynamic PB2-E627K substitution of influenza H7N9 virus indicates the in vivo genetic tuning and rapid host adaptation.

Proc Natl Acad Sci U S A 2020 09 1;117(38):23807-23814. Epub 2020 Sep 1.

Shenzhen Key Laboratory of Pathogen and Immunity, State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, 518112 Shenzhen, China;

Avian-origin influenza viruses overcome the bottleneck of the interspecies barrier and infect humans through the evolution of variants toward more efficient replication in mammals. The dynamic adaptation of the genetic substitutions and the correlation with the virulence of avian-origin influenza virus in patients remain largely elusive. Here, based on the one-health approach, we retrieved the original virus-positive samples from patients with H7N9 and their surrounding poultry/environment. The specimens were directly deep sequenced, and the subsequent big data were integrated with the clinical manifestations. Unlike poultry/environment-derived samples with the consistent dominance of avian signature 627E of H7N9 polymerase basic protein 2 (PB2), patient specimens had diverse ratios of mammalian signature 627K, indicating the rapid dynamics of H7N9 adaptation in patients during the infection process. In contrast, both human- and poultry/environment-related viruses had constant dominance of avian signature PB2-701D. The intrahost dynamic adaptation was confirmed by the gradual replacement of 627E by 627K in H7N9 in the longitudinally collected specimens from one patient. These results suggest that host adaptation for better virus replication to new hosts, termed "genetic tuning," actually occurred in H7N9-infected patients in vivo. Notably, our findings also demonstrate the correlation between rapid host adaptation of H7N9 PB2-E627K and the fatal outcome and disease severity in humans. The feature of H7N9 genetic tuning in vivo and its correlation with the disease severity emphasize the importance of testing for the evolution of this avian-origin virus during the course of infection.
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http://dx.doi.org/10.1073/pnas.2013267117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519270PMC
September 2020

Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients.

Immunity 2020 09 19;53(3):685-696.e3. Epub 2020 Jul 19.

BGI-Shenzhen, 518103 Shenzhen, China; BGI Education Center, University of Chinese Academy of Sciences, 518083 Shenzhen, China.

The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
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http://dx.doi.org/10.1016/j.immuni.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368915PMC
September 2020

Strict Assembly Restriction of Peptides from Rabbit Hemorrhagic Disease Virus Presented by Rabbit Major Histocompatibility Complex Class I Molecule RLA-A1.

J Virol 2020 08 17;94(17). Epub 2020 Aug 17.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China

Rabbits are pivotal domestic animals for both the economy and as an animal model for human diseases. A large number of rabbits have been infected by rabbit hemorrhagic disease virus (RHDV) in natural and artificial pandemics in the past. Differences in presentation of antigenic peptides by polymorphic major histocompatibility complex (MHC) molecules to T-cell receptors (TCR) on T lymphocytes are associated with viral clearance in mammals. Here, we screened and identified a series of peptides derived from RHDV binding to the rabbit MHC class I molecule, RLA-A1. The small, hydrophobic B and F pockets of RLA-A1 capture a peptide motif analogous to that recognized by human class I molecule HLA-A*0201, with more restricted aliphatic anchors at P2 and PΩ positions. Moreover, the rabbit molecule is characterized by an uncommon residue combination of Gly53, Val55, and Glu56, making the 3 helix and the loop between the 3 and α1 helices closer to the α2 helix. A wider A pocket in RLA-A1 can induce a special conformation of the P1 anchor and may play a pivotal role in peptide assembly and TCR recognition. Our study broadens the knowledge of T-cell immunity in domestic animals and also provides useful insights for vaccine development to prevent infectious diseases in rabbits. We screened rabbit MHC class I RLA-A1-restricted peptides from the capsid protein VP60 of rabbit hemorrhagic disease virus (RHDV) and determined the structures of RLA-A1 complexed with three peptides, VP60-1, VP60-2, and VP60-10. From the structures, we found that the peptide binding motifs of RLA-A1 are extremely constraining. Thus, there is a generally restricted peptide selection for RLA-A1 compared to that for human HLA-A*0201. In addition, uncommon residues Gly53, Val55, and Glu56 of RLA-A1 are located between the 3 helix and α1 helix, which makes the steric position of the 3 helix in RLA-A1 much closer to the α2 helix than that found in other mammalian MHC class I molecules. This special conformation between the 3 helix and α1 helix plays a pivotal role in rabbit MHC class I assembly. Our results provide new insights into MHC class I molecule assembly and peptide presentation of domestic mammals. Furthermore, these data also broaden our knowledge on T-cell immunity in rabbits and may also provide useful information for vaccine development to prevent infectious diseases in rabbits.
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http://dx.doi.org/10.1128/JVI.00396-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431782PMC
August 2020

Identification of causing an unexplained disease cluster in Matthews Ridge, Guyana.

Biosaf Health 2019 Dec 17;1(3):150-154. Epub 2019 Dec 17.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

Here, we report the identification of causing an unexplained disease cluster in Matthews Ridge, Guyana. In March 2019, 14 employees of Chongqing Bosai Mining Company, China, working in a manganese mining of Guyana, had unexplained fever, and two of them died. We obtained lung and brain tissues as well as the blood samples from the two deceased cases (patient No. 1 and 2), and bronchoscopy lavages and cerebrospinal fluid samples from one severe case (patient No. 3), respectively. All samples were tested by pathological examination, high-throughput sequencing, and real-time PCR. Pathological detection showed the presence of spore-like structures in the lung tissue of patient No. 1, indicating a fungal infection in this patient. Nanopore sequencing identified the existing of in the lung tissue sample within 13 h. Next-generation sequencing identified specific fragments of in all of the samples tested (lung, brain and blood serum from the deceased cases, and plasma from the severe case). Real-time PCR assays did not reveal any viral infection related to transmission from bat feces. We conclude that was the causative pathogen of this disease cluster based on epidemiologic, clinical, pathological and nucleic acid evidence.
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http://dx.doi.org/10.1016/j.bsheal.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148593PMC
December 2019

It's not just science: Challenges for public health intervention in Ebola epidemics in the Democratic Republic of Congo.

Sci China Life Sci 2020 Jul 10;63(7):1079-1081. Epub 2020 Mar 10.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.

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http://dx.doi.org/10.1007/s11427-019-1670-6DOI Listing
July 2020

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

Lancet 2020 02 30;395(10224):565-574. Epub 2020 Jan 30.

Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.

Background: In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.

Methods: We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.

Findings: The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.

Interpretation: 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.

Funding: National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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http://dx.doi.org/10.1016/S0140-6736(20)30251-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159086PMC
February 2020

Individual-Specific Analysis for Psychoradiology.

Neuroimaging Clin N Am 2020 Feb 11;30(1):45-51. Epub 2019 Nov 11.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Suite 2301, Charlestown, MA 02129, USA.

In neuroimaging research, averaging data at the level of the group results in blurring of potentially meaningful individual differences. A more widespread use of an individual-specific approach is advocated for, which involves a more thorough investigation of each individual in a group, and characterization of idiosyncrasies at the level of behavior, cognition, and symptoms, as well as at the level of brain organization. It is hoped that such an approach, focused on individuals, will provide convergent findings that will help identify the underlying pathologic condition in various psychiatric disorders and help in the development of treatments individualized for each patient.
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http://dx.doi.org/10.1016/j.nic.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884424PMC
February 2020

Avian Influenza A Viruses among Occupationally Exposed Populations, China, 2014-2016.

Emerg Infect Dis 2019 12;25(12):2215-2225

To determine the seroprevalence and seroconversion of avian influenza virus (AIV) antibodies in poultry workers, we conducted a seroepidemiologic study in 7 areas of China during December 2014-April 2016. We used viral isolation and reverse transcription PCR to detect AIVs in specimens from live poultry markets. We analyzed 2,124 serum samples obtained from 1,407 poultry workers by using hemagglutination inhibition and microneutralization assays. We noted seroprevalence of AIV antibodies for subtypes H9N2, H7N9, H6N1, H5N1-SC29, H5N6, H5N1-SH199, and H6N6. In serum from participants with longitudinal samples, we noted seroconversion, with >4-fold rise in titers, for H9N2, H7N9, H6N1, H5N1-SC29, H6N6, H5N6, and H5N1-SH199 subtypes. We found no evidence of H10N8 subtype. The distribution of AIV antibodies provided evidence of asymptomatic infection. We found that AIV antibody prevalence in live poultry markets correlated with increased risk for H7N9 and H9N2 infection among poultry workers.
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http://dx.doi.org/10.3201/eid2512.190261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874249PMC
December 2019

Genetic and Phylogenetic Characterization of a Chikungunya Virus Imported into Shenzhen, China.

Virol Sin 2020 Feb 21;35(1):115-119. Epub 2019 Oct 21.

Shenzhen Key Laboratory of Pathogen and Immunity, Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, State Key Discipline of Infectious Disease, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Third People's Hospital, Shenzhen, 518112, China.

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http://dx.doi.org/10.1007/s12250-019-00166-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035398PMC
February 2020

Peptide presentation by bat MHC class I provides new insight into the antiviral immunity of bats.

PLoS Biol 2019 09 9;17(9):e3000436. Epub 2019 Sep 9.

NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Bats harbor many zoonotic viruses, including highly pathogenic viruses of humans and other mammals, but they are typically asymptomatic in bats. To further understand the antiviral immunity of bats, we screened and identified a series of bat major histocompatibility complex (MHC) I Ptal-N*01:01-binding peptides derived from four different bat-borne viruses, i.e., Hendra virus (HeV), Ebola virus (EBOV), Middle East respiratory syndrome coronavirus (MERS-CoV), and H17N10 influenza-like virus. The structures of Ptal-N*01:01 display unusual peptide presentation features in that the bat-specific 3-amino acid (aa) insertion enables the tight "surface anchoring" of the P1-Asp in pocket A of bat MHC I. As the classical primary anchoring positions, the B and F pockets of Ptal-N*01:01 also show unconventional conformations, which contribute to unusual peptide motifs and distinct peptide presentation. Notably, the features of bat MHC I may be shared by MHC I from various marsupials. Our study sheds light on bat adaptive immunity and may benefit future vaccine development against bat-borne viruses of high impact on humans.
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http://dx.doi.org/10.1371/journal.pbio.3000436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752855PMC
September 2019

Divergent Peptide Presentations of HLA-A30 Alleles Revealed by Structures With Pathogen Peptides.

Front Immunol 2019 23;10:1709. Epub 2019 Jul 23.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A30:01 and -A30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A30:01 and -A30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A30:01, and -A30:03 were similar to those of HLA-A11:01 in the A3 supertype. However, HLA-A30:03, but not -A30:01, also showed binding with the HLA01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A30:01 and -A30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A30:01 and -A30:03. Interchanging residue 77 between HLA-A30:01 and HLA-A30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.
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http://dx.doi.org/10.3389/fimmu.2019.01709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664060PMC
November 2020

Co-circulation and persistence of multiple A/H3N2 influenza variants in China.

Emerg Microbes Infect 2019 ;8(1):1157-1167

a Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing , People's Republic of China.

The spread of influenza A/H3N2 variants possessing the hemagglutinin 121 K mutation and the unexpectedly high incidence of influenza in the 2017-2018 northern hemisphere influenza season have raised serious concerns about the next pandemic. We summarized the national surveillance data of seasonal influenza in China and identified marked differences in influenza epidemics between northern and southern China, particularly the predominating subtype and the presence of an additional summer peak in southern China. Notably, a minor spring peak of influenza caused by a different virus subtype was also observed. We also revealed that the 3C.2a lineage was dominant from the summer of 2015 to the end of the 2015-2016 peak season in China, after which the 3C.2a2 lineage predominated despite the importation and co-circulation of the 121 K variants of 3C.2a1 and 3C.2a3 lineages at the global level. Finally, an analysis based on genetic distances revealed a delay in A/H3N2 vaccine strain update. Overall, our results highlight the complicated circulation pattern of seasonal influenza in China and the necessity for a timely vaccine strain update worldwide.
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http://dx.doi.org/10.1080/22221751.2019.1648183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713139PMC
December 2019

Salt bridge-forming residues positioned over viral peptides presented by MHC class I impacts T-cell recognition in a binding-dependent manner.

Mol Immunol 2019 08 18;112:274-282. Epub 2019 Jun 18.

NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. Electronic address:

The viral peptides presentation by major histocompatibility complex class I (MHC I) molecules play a pivotal role in T-cell recognition and the subsequent virus clearance. This process is delicately adjusted by the variant residues of MHC I, especially the residues in the peptide binding groove (PBG). In a series of MHC I molecules, a salt bridge is formed above the N-terminus of the peptides. However, the potential impact of the salt bridge on peptide binding and T-cell receptor (TCR) recognition of MHC I, as well as the corresponding molecular basis, are still largely unknown. Herein, we determined the structures of HLA-B*4001 and H-2K in which two different types of salt bridges (Arg62-Glu163 or Arg66-Glu163) across the PBG were observed. Although the two salt bridges led to different conformation shifts of both the MHC I α helix and the peptides, binding of the peptides with the salt bridge residues was relatively conserved. Furthermore, through a series of in vitro and in vivo investigations, we found that MHC I mutations that disrupt the salt bridge alleviate peptide binding and can weaken the TCR recognition of MHC I-peptide complexes. Our study may provide key references for understanding MHC I-restricted peptide recognition by T-cells.
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http://dx.doi.org/10.1016/j.molimm.2019.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112684PMC
August 2019

Intra-host Ebola viral adaption during human infection.

Biosaf Health 2019 Jun 20;1(1):14-24. Epub 2019 Feb 20.

NHC Key Laboratory of Biosafety National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

The onsite next generation sequencing (NGS) of Ebola virus (EBOV) genomes during the 2013-2016 Ebola epidemic in Western Africa provides an opportunity to trace the origin, transmission, and evolution of this virus. Herein, we have diagnosed a cohort of EBOV patients in Sierra Leone in 2015, during the late phase of the outbreak. The surviving EBOV patients had a recovery process characterized by decreasing viremia, fever, and biochemical parameters. EBOV genomes sequenced through the longitudinal blood samples of these patients showed dynamic intra-host substitutions of the virus during acute infection, including the previously described short stretches of 13 serial T>C mutations. Remarkably, within individual patients, samples collected during the early phase of infection possessed Ts at these nucleotide sites, whereas they were replaced by Cs in samples collected in the later phase, suggesting that these short stretches of T>C mutations could emerge independently. In addition, up to a total of 35 nucleotide sites spanning the EBOV genome were mutated coincidently. Our study showed the dynamic intra-host adaptation of EBOV during patient recovery and gave more insight into the complex EBOV-host interactions.
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http://dx.doi.org/10.1016/j.bsheal.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347341PMC
June 2019
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