Application for the Project ＂Host Adaptation and Immune Intervention of Pathogens＂ of Chinese Academy of Sciences

China Academy of Sciences’ strategic pioneer science and technology class B special project "Host Adaptation and Immune Intervention of Pathogens" (hereinafter referred to as "special project") has been approved and will soon enter the implementation stage (2018-2022).　

　

With the core demand of "pathogen host adaptation and immune intervention", the project focuses on solving the following scientific problems. Clarify the source and transmission mechanism of pathogens of emerging infectious diseases such as influenza and SARS, and provide theoretical basis for early warning and forecasting of emerging infectious diseases; Clarify the drug resistance mechanism of drug-resistant pathogens such as tuberculosis and find new targets of pathogenic drugs; To clarify the mechanism of immune recognition and response, immune memory and organ damage caused by excessive immunity in the process of acute infection, and provide theoretical basis for vaccine development and clinical treatment; To clarify the mechanism of immune escape and immune exhaustion in the process of chronic infection, and provide theoretical basis for immunotherapy strategies; Based on the study of the interaction mechanism between acute and chronic infection and host, this paper puts forward new immune intervention strategies, and puts forward ideas and strategies for the long-standing world problems such as the design of AIDS vaccine and influenza universal vaccine.　

　

According to the special management regulations of strategic pilot science and technology of China Academy of Sciences, around the special objectives, the top-level design is adopted, and the implementation of special research tasks and team building are organized by combining key tasks with free bidding.　　

　

I. Scope of application and research content　　

　

According to the framework of the overall implementation plan of the special project and the regulations of the pilot project of China Academy of Sciences, there are five special projects, including: 1. Tracing the source of the virus, cross-species transmission and pathogenic mechanism; 2. Pathogenicity and drug resistance mechanism of pathogenic bacteria; 3. Pathogen immune response and immune escape; 4. New ideas and strategies of immune intervention; 5. New methods and technologies for infection and immunity research. Declare according to the bidding direction under the affiliated project, and the same research content cannot be declared repeatedly in different projects.　

　

Based on the above-mentioned projects, the special project aims at major scientific issues and sets up three special teams to jointly tackle key problems: universal influenza vaccine, immunotherapy based on NK cells, and early warning of emerging infectious diseases. Specially encourage and support the research group to participate in joint research, and participate in joint research teams to give priority to selected projects at the same level and give priority to raising the funding level.　

　

Project 1: To study the origin, cross-species transmission and pathogenic mechanism of the virus.

　

Targeting of this project“Early warning, prevention and control of emerging infectious diseases"This frontier scientific problem, aiming at the internationally recognized scientific problems such as the complexity of viruses in nature, the diversity of transmission routes and pathogenic mechanisms, has been studied from three aspects: the molecular epidemiology of viruses, the cross-species transmission mechanism and the interaction between viruses and hosts, thus changing the passive response situation of emerging infectious diseases into active monitoring and early warning. Proposed for the followingthreeA key direction for bidding:

　

1. The origin, evolution and transmission mechanism of new pathogens:　

　

In view of the new outbreak of infectious virus, the virus and its variants carried by its natural hosts (birds, bats and rodents, etc.) and vector hosts (mosquitoes and ticks, etc.) were tracked to understand its temporal and spatial distribution and analyze its origin, evolution and variation in nature. For patients with unexplained diseases, as well as sick and healthy animals (including samples from China’s surrounding areas and the Belt and Road area), unknown pathogen detection and pathogen group research were carried out to explore and determine pathogens with potential risks of infecting people and animals. Including: virus traceability and new virus discovery, virus origin and evolution, virus spread and diffusion mechanism, etc.　

　

2. Molecular mechanism of virus cross-species infection and pathogenicity:　

　

Aiming at important new outbreaks and virulent viruses (influenza virus, Ebola virus, coronavirus, Marburg virus, arenavirus, etc.), the key molecules affecting their cross-species infection and their pathogenic mechanisms were analyzed by studying their ability to invade and replicate in different host cells. Including: virus invasion, virus replication and assembly, and infection model.　

　

3. Interaction mechanism between virus and host:　

　

For acute and chronic infected viruses, the interaction between pathogen and host (including natural host, vector host and human) was studied, the important host factors regulating virus infection and replication were analyzed, the molecular mechanism of the occurrence, development and prognosis of infectious diseases was clarified, and the basic research on the application of new antiviral means was carried out. Including: host factors and their mechanism of action, virus mutation and escape mechanism.　

　

Item 2: Pathogenicity and drug resistance mechanism of pathogenic bacteria

　

This project intends to systematically and deeply study the molecular mechanism of infection, pathogenicity, adaptation and regulation of host immune response, drug resistance and other important pathogens, as well as the interaction and regulation mechanism between pathogens, human microbiota and host. Committed to achieving breakthroughs in the study of pathogenic bacteria and drug resistance mechanisms, and discovering potential new drug targets for pathogen diagnosis and treatment. Proposed for the followingthreeA key direction for bidding:

　

1. Systematic discovery and functional study of pathogenic factors of pathogenic bacteria;　

　

Systematically discover pathogenic factors of important pathogenic bacteria such as Mycobacterium tuberculosis and confirm their relationship with pathogenicity; Construct an interaction network of pathogenic factors of pathogenic bacteria and verify its function; To clarify the structural basis and function of key pathogenic factors of pathogenic bacteria.　

　

2. Study on the interaction mechanism between pathogen and host;　

　

Identification and confirmation of pathogenic factors (including secretory effector proteins and bacterial surface proteins) and host factors (including host limiting factors and susceptible factors) closely related to infection and pathogenicity of important pathogenic bacteria such as Mycobacterium tuberculosis; Clarify the structural basis and biochemical mechanism of the interaction between pathogenic bacteria and host protein; To explore the regulatory effect and molecular mechanism of pathogenic factors on host signal pathway and cell function during infection; To study the influence of host factors and human microbiome on the infection and pathogenicity of pathogenic bacteria and its molecular mechanism.　

　

3. Study on drug resistance mechanism of pathogenic bacteria:　

　

Identify and verify new genes related to drug resistance of important pathogens; Clarify the structural basis and function of drug resistance-related factors; Explore new mechanisms of drug resistance and develop new technologies for rapid detection of drug resistance.　　

　

Item 3: Immune Recognition Activation and Immune Memory of Pathogens

　

In this project, the natural immune recognition receptor (intracellular) of virus is deeply studied/) and its immune signaling pathway, trying to find new receptors, new pathways and new mechanisms; Enhance toxicity to memory cellsTCell and memoryBThe study of the formation mechanism of cells has found the key immune molecules and regulatory pathways that can enhance the antiviral ability. Proposed for the followingthreeA key direction for bidding:

　

1. Immune recognition and regulation of pathogens:　

　

In-depth study of the virus’s natural immune recognition mechanism, and discovery of new receptors and new pathways of antiviral natural immunity; To study the regulatory effects of acquired immunity, metabolic system or nervous system on the natural immune response of anti-virus, and to reveal the prognosis mechanism of viral immune response.　

　

2. Immune escape and immune exhaustion of pathogens:　

　

Establish an international leading animal model of chronic virus infection; Describe the key cellular and molecular mechanisms of virus-induced immune tolerance/depletion; To verify the new card control points that mediate immune tolerance/exhaustion in major chronic virus diseases, and obtain the means and schemes to adjust the card control points.　

　

3. Immune damage and malignant transformation mechanism of pathogens:　

　

To compare the different pathological mechanisms of immune damage caused by acute and chronic virus infection; To compare the characteristics, common rules and intermodulation mechanism of tissues and organs caused by different pathogens; To find the effector cells and key molecules that block the persistent infection of pathogens, and to reveal their role and mechanism in the malignant transformation caused by persistent infection.　

　

Fourth, study new strategies and theories of immune intervention.

　

On the basis of the above three projects, this project puts forward new ideas and strategies of immune intervention based on pathogen infection and immune mechanism. Develop new vaccines and new immunotherapy methods. with“Universal influenza vaccine"This world problem is a breakthrough, focusing on solving.1-2A scientific problem, and realize1-2Industrialization of application results. Proposed for the followingthreeA key direction for bidding:

　

1. Functional transformation of various cells in immune microenvironment during acute inflammation-chronic inflammation-cancer transformation:　

　

To understand the regulatory mechanism of the interaction network between various immune cells and interstitial cells and tumor cells and their effects on inflammation-cancer transformation; Aiming at the immune microenvironment, we developed a multi-target immunotherapy strategy that systematically blocked the transformation from inflammation to cancer. Including: specific antibody immunomodulation for various targets and new strategies and concepts of cell therapy such as CAR-T, TCR-T and CAR-NK.　

　

2. Mechanism of neutralizing antibody production and screening of monoclonal neutralizing antibody during pathogen infection;　

　

In view of different pathogen infections, various new technologies are used to separate neutralizing antibodies and identify antigenic epitopes in patients recovering from pathogen infections, which on the one hand provides a basis for the design of new vaccines; On the other hand, monoclonal neutralizing antibodies were prepared for the prevention and treatment of pathogen infection, and the preclinical experiments of some antibodies were completed.　

　

3. New strategies for designing new vaccines and adjuvants:　

　

Design a safe, rapid and effective vaccine against the pathogens of emerging infectious diseases; Under the guidance of the new immune theory, new vaccine design strategies (such as synthetic vaccine based on neutralizing antibody production characteristics, new vaccine based on dendritic cells, nano-vaccine, genetic engineering vaccine based on structural biology and antibody design) are put forward for pathogens and cancers with long-term slow progress in vaccine research and development. At the same time, research on new immune adjuvants was carried out.　

　

Project 5: New methods and technologies for infection and immunity research

　

This project will combine special important scientific issues, especially the visualization of pathogen infection and host cell immune process, the heterogeneity of pathogenic microorganisms and host cells, the occurrence and development law of drug-resistant bacteria, and the research methods and evaluation methods of new drugs and vaccines. The methods used include super-resolution imaging technology, biosensor technology, nano-biology technology, organ chip technology, single cell technology, synthetic biology technology and so on. The breakthrough of new technologies and methods will not only solve the scientific problems in this field, but also promote the development of new industries. Proposed for the followingsixA key direction for bidding:

　

1. High time-space resolution tracing of pathogen infection process:　

　

Aiming at the scientific problems of virus and bacterial infection and host immune process, a high time-space resolution monitoring technique is established to visualize the key steps of pathogen infection process, trace and interpret the infected cells and tissues and host immune process in real time, and reveal the pathogen infection and pathogenic mechanism in depth.　

　

2. Humanized tissue and organ chip and humanized small animal model;　

　

Develop human-like tissue and organ chip, establish in vitro pathogenic infection and immune model, and carry out drug evaluation and pharmacodynamic research; Aiming at the infection and immune research of important pathogens, a humanized small animal model was established.　

　

3. Raman fingerprint and single cell biology of pathogenic bacteria:　

　

Establish a single cell Raman fingerprint library of pathogenic microorganisms to realize rapid identification of pathogenic microorganisms and rapid determination of drug resistance; To study single cell biology such as drug resistance and pathogenicity of pathogenic bacteria.　

　

4. Rapid evolution of bacteriophage molecules resistant to bacterial drug resistance:　

　

In view of the increasingly serious drug resistance in clinic, and the speed of new drug research and development can’t keep up, according to the bacterial specificity of phage, a new strategy of rapid, efficient and broad-spectrum drug research and development of phage resistant bacteria was established by using synthetic biology and directed molecular evolution technology.　

　

5, nano antigen and antigen binding genomics:　

　

Rational design of pathogen-like nano-antigen, study of its specific immune cell response in vivo, and development of new vaccine technology; Carry out pathogen-host combinatorics, systematically find and identify receptors and immune factors, and reveal the mechanism of pathogen-host interaction and immune response.　

　

6, new technology of pathogen screening and new technology principle of infection and immunity research:　

　

In view of the high incidence of infectious diseases and public emergencies, a new rapid, highly sensitive and Qualcomm-rich pathogen immunoassay method was established to provide support for the monitoring and early warning of emerging infectious diseases; Aiming at the bottleneck problem in the research of infection and immunity, through interdisciplinary research, we explore the establishment of advanced new technical principles.　　　　　

　

Second, the reporting requirements　　

　

1. All applicants are required to obtain the recommendation of the project leader.