高福院士,病原体防控 z-bio 2025-09-25 4055

　　In recent years, global public health has been threatened by new and re-occurring infectious diseases and drug-resistant pathogens, and the analysis of pathogen mechanisms and the development of prevention and control methods have become the focus. In 2025, Academician Gao Fu's team and top institutions won new theoretical and technological achievements in breakthrough prevention and control of infectious diseases, and appeared in top journals such as STM and PNAS.

　　On September 17, 2025, Academician Gao Fu, together with Shenzhen Children's Hospital, Director Ma Xiaopeng, Associate Researcher Zhao Xin, Institute of Microbiology, Chinese Academy of Sciences, and Researcher Lu Xuancheng, the Chinese Center for Disease Control and Prevention, published an article titled "A complete Sigmodon hispidus genome and dynamic single-cell transcriptome reveals evolutionarily conserved responses to RSV infection" in Science Translational Medicine.

　　This study focused on the host-pathogen interaction mechanism of respiratory syncytial virus (RSV) infection using cotton mouse (Sigmodon hispidus) as a model. Cotton mice are a key model organism in this field, but there has been no in-depth analysis at the cellular level in the past. Therefore, the research and integration of cotton mice chromosomal genome and single-cell transcriptome technology aims to map the dynamic map of the whole cycle of RSV infection, reveal the evolutionary conservative immune response, and provide theoretical support for the research on cross-species transmission of RSV and the development of broad-spectrum antiviral strategies.

　　The research team first integrated PCR-free whole genome sequencing, strand read sequencing and RNA-seq technology to successfully complete the chromosome-level genome assembly of cotton rats - this genome contains 25 chromosomes and 24,878 protein-encoded genes. Subsequent comparative genomic analysis confirmed that it is highly homologous to human genes, laying the foundation for validation of cross-species models.

　　Subsequently, the team tracked the dynamic changes of respiratory cells 0-7 days after RSV infection through single-cell transcriptome sequencing, and found that epithelial cells, immune cells and stromal cells all showed significant phenotypic differentiation: for example, ciliary epithelial cells initiate innate immune defense by upregulating interferon stimulating genes (ISGs), and macrophages rely on metabolic reprogramming and regulating virus clearance.

　　In-depth analysis also came to two key conclusions: First, RSV can use G protein mutation to avoid attacks on main neutralizing antibodies, but core structural proteins such as F protein are highly conserved across species, which is the core reason why cotton mouse models have universality in RSV research; second, it is observed for the first time that cotton mice and humans will activate the Nrf2-HMOX1 antioxidant pathway after infection with RSV, suggesting that this pathway may be a potential target for antiviral intervention.

　　In summary, these findings not only deepen the understanding of the pathogenic mechanism of RSV, but also open up new directions for the development of host-oriented therapies-related drugs.

　　On September 10, 2025, Academician Gao Fu, together with Researcher Qi Jianxun, Researcher Zhao Xin and Researcher Fang Jingyuan of Shanghai Jiaotong University, published an article titled "Binding of Fusobacterium nuclearatum autotransporter adhesin CbpF to human CEACAM1 and CEACAM5: A Velcro model for bacterial adhesion" in PNAS Proceedings of American Academy of Sciences.

　　The adhesion process between Fusobacterium nucleatum and host cells is a key initial link in which the bacteria colonizes and induces infection in the intestine and oral cavity, and then participates in the pathological progress of diseases such as colorectal cancer. This research revolves around this core mechanism. The research team took CbpF as the core research object and for the first time explained that it can mediate the strong adhesion between bacteria and host cells by specifically binding to human carcinoembryonic antigen-related cell adhesion molecules (CEACAM1 and CEACAM5). At the same time, it innovatively proposed the "Velcro model" to explain this dynamic multivalent binding process. This achievement not only provides new clues for analyzing the pathogenic mechanism of F. nucleus, but also opens up a new perspective for the development of targeted intervention strategies.

　　On September 9, 2025, Professor Wang Quanyi, Academician Gao Fu and his team of professors Wang Quanyi, the Beijing Center for Disease Control and Prevention, published a research article titled "Epidemiological and phylogenetic characteristics of human metapneumovirus in Beijing, China, 2014-2024" in Signal Transduction and Targeted Therapy.

　　The adhesion process between Fusobacterium nucleatum and host cells is a key initial link in which the bacteria colonizes and induces infection in the intestine and oral cavity, and then participates in the pathological progress of diseases such as colorectal cancer. This research revolves around this core mechanism. The research team took CbpF as the core research object and for the first time explained that it can mediate the strong adhesion between bacteria and host cells by specifically binding to human carcinoembryonic antigen-related cell adhesion molecules (CEACAM1 and CEACAM5). At the same time, it innovatively proposed the "Velcro model" to explain this dynamic multivalent binding process. This achievement not only provides new clues for analyzing the pathogenic mechanism of F. nucleus, but also opens up a new perspective for the development of targeted intervention strategies.

　　On September 9, 2025, Professor Wang Quanyi, Academician Gao Fu and his team of professors Wang Quanyi, the Beijing Center for Disease Control and Prevention, published a research article titled "Epidemiological and phylogenetic characteristics of human metapneumovirus in Beijing, China, 2014-2024" in Signal Transduction and Targeted Therapy.

　　African swine fever (ASF) can be regarded as the "number one threat" to the global pig farming industry. Its prevention and control system has long been centered on biosafety measures, and safe and effective vaccine research and development has not made breakthrough progress. In response to this industry pain point, the research takes genetic engineering technology as the core means and is committed to developing live attenuated vaccines (LAVs), and focuses on two major technical bottlenecks: First, how to reduce the virulence of the virus while ensuring that it can still stimulate the body to produce an effective immune response (i.e., balance virility and immunogenicity); second, how to block the attenuated strains from recovering pathogenicity during the transmission of the pig herd (i.e., avoiding the return of virulence to strong).

　　After target screening, the research team finally determined to delete two key functional genes, CD2v and A137R: the protein encoded by the CD2v gene can mediate the binding of viruses to red blood cells, thereby affecting the occurrence of viremia and the spread of viruses in the population; the A137R gene plays a key role in the regulation of viral DNA replication and directly determines the replication efficiency of the virus. Through this innovative strategy of dual gene deletion, the research team has built a safe and efficient ASF vaccine candidate strain, providing new practical solutions for solving the problems of ASF vaccine research and development.

　　On August 31, 2025, Researcher Qi Jianxun, Academician Gao Fu and Wang Qihui, Researcher at the Institute of Microbiology, Chinese Academy of Sciences, teams of researchers from EBioMedicine (an international authoritative journal focusing on translational medicine under The Lancet), jointly published an article titled "Rational design of respiratory syncytial virus dimeric F-subunit vaccines in protein and mRNA forms" "Rational design of protein and mRNA form of respiratory syncytial virus dimer F subunit vaccines".

　　As the primary pathogenic virus that causes acute lower respiratory tract infection in infants and young children and the elderly, the development of efficient vaccines for respiratory syncytial virus (RSV) has always been a key problem in the medical field. In more than 60 years of research and development, the core obstacle that the vaccine has not been broken through is the difficulty in stably inducing powerful neutralizing antibodies against viral fusion protein (F protein). The study focused on this core obstacle, and used the pre-F conformational dimer as the core structure of the vaccine (including two types of vector forms of protein subunit vaccine and mRNA vaccine). Through the protein engineering transformation technology guided by structural biology theory, it not only overcomes the technical problems of pre-F conformational change and poor stability, but also further analyzes the different characteristics of different vaccine forms in the process of stimulating the body's protective immune response. This study laid an important theoretical foundation and provided a new research and development direction for the subsequent development of RSV vaccines covering all age groups and having broad-spectrum protection effects.

　　On August 15, 2025, Academician Gao Fu's team, Wang Han's team from Peking University, and Liu Zhida's team from Shanxi Institute of Advanced Innovation, published a research paper titled "Sterilized protected immunity induced by DAM and DAM+ in mouse models for both VACV and MPXV" in Science Bulletin's "Sterilized protective immunity induced by DAM and DAM+ in mouse models for both VACV and MPXV".

　　The research aims to develop a new generation of orthopoxvirus vaccines, and the core design concept is to "achieve complete inactivation of the virus while completely retaining the natural conformation of the antigen." To achieve this goal, the research team adopted innovative viral particle processing technology - namely DAM process and DAM+ process. The key advantage of this technology is that it can not only completely inactivate the virus (to ensure the safety of the vaccine), but also retain the natural spatial structure of key antigens such as A27, B5, and H3 on the surface of the virus to the greatest extent (to ensure that the antigen can effectively stimulate the immune response). This design directly hits the core pain point of traditional inactivated vaccines with "low immunogenicity", and ultimately provides new means to prevent and control the epidemics of orthopox viruses such as monkeypox, which are both safe and efficient.

　　On July 31, 2025, Academician Gao Fu, together with Researcher Gao Feng from the Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Researcher Haixia and others, published a research article titled "Cryo-EM structures of mycobacteria MmpL5-AcpM complex" in Science China Life Sciences "China Science: Life Sciences".

　　As the single pathogen with the highest mortality rate in the world, the spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb) has posed a severe challenge to the global public health system. This study has developed a technical bottleneck in the structure analysis of the key protein complex of Mycobacterium, and finally achieved an important breakthrough: using cryo-electron microscopy (Cryo-EM) technology, the three-dimensional structure of the MmpL5 and the acyl carrier protein M (AcpM) complex was analyzed for the first time, and the structural resolution was as high as 2.81 Å. Through the analysis of this high-resolution structure, the research team clearly explained the core mechanism of MmpL5 in iron carrier transportation - iron carrier, as a key molecule for mycobacteria to obtain iron, its transportation process directly affects the growth and pathogenic ability of bacteria. This research result not only provides a new perspective for a deep understanding of the physiological metabolism and pathogenic mechanism of Mycobacteria, but more importantly, it has laid a solid structural biology foundation for the research and development of anti-tuberculosis drugs targeting the MmpL5 protein.

　　What core directions did Academician Gao Fu’s team and collaborators focus on in 2025? At the basic research level, the team completed the assembly of chromosomal genomes of cotton rats, revealing the dynamic differentiation and evolution of conservative immune pathways of host cells in RSV infection, laying the foundation for a broad-spectrum anti-RSV strategy; analyzing the "Velcro model" binding mechanism with F. nucleus CbpF-CEACAM, providing targets for antibacterial and anti-tumor drugs; sorting out the ten-year epidemic cycle of hMPV in Beijing, and finding that the clinical symptoms of B2 subtype are mild, providing a basis for precise prevention and control; analyzing the structure of MmpL5-AcpM complex of Mycobacterium tuberculosis, revealing the acylation pathway of iron carriers, and opening up a new direction for anti-tuberculosis drugs.

　　How do these basic discoveries be transformed into "practical weapons"? Vaccine and drug development give answers: build the CD2v/A137R double-deletion mutant strain of ASFV to achieve complete protection of the pig herd and non-virulent recovery, break through the bottleneck of ASF vaccine; lock in the pre-F dimer conformation of RSV, develop protein and mRNA vaccines, and induce long-term immunity; innovate the orthopoxvirus DAM+ inactivation process, retain the natural conformation of the antigen, and achieve complete protection of VACV/MPXV through single immunity.

　　These achievements form a "basic-transformation" closed loop, which not only answers scientific questions, but also provides implementation solutions, contributing Chinese wisdom to global infectious disease prevention and control.