The CIRI is a research center that aims to provide the scientific resources and expertises to conduct top-level fundamental research on infectious agents, associated diseases and host responses. Specific research themes, beyond those that are implemented within the teams themselves have been defined and will be collectively conducted to address explicit objectives of broad interest in the field of infectious diseases. These scientific objectives are the following:
Objective 1: Integrated immunology for vaccination and biotherapies
The development of vaccines against pathogens that cause infectious diseases was one of the most important factors in reducing child mortality and increasing life expectancy. Despite these important advances, infectious diseases remain a major public health problem. Efficient vaccines or therapies are indeed missing for a wide range of infectious diseases. We believe that the failure of previous vaccines or therapeutic approaches results from our lack of knowledge of protection mechanisms required to control a given pathogen as well as from our poor ability to design and formulate vaccines that target specific immune subsets. Our overall aim is therefore to better understand the mechanisms underlying immune responses involved in the control of several classes of pathogens. Our specific aims are:
- To understand the individual contribution of the different immune cell types in the defense against pathogens.
- To understand molecular networks underlying immune responses: how the action of the different immune effectors is coordinated and how the different genes involved in immunity are harnessed to fight infectious diseases
- To understand complex interactions between microbes and immune cells: how pathogens are sensed by immune cells and how pathogens escape this recognition to survive within their hosts.
- To understand the balance between immunity and tolerance : how the immune system spares normal cells, tissues and commensal bacteria while protecting the host against pathogens.
- To develop novel vaccinal concepts and biotherapies against infectious diseases
Objective 2: Metabolo-infectiology and non-communicable diseases
The major goal of this objective is to determine the reciprocal links existing between infections and metabolic diseasesiehow viral infections influence the metabolism of the target cell or infected host and, conversely, how pre-existing alterations in the metabolism can affect viral infection. The specific aims are:
- How viruses modify the cell and host metabolism. We will first focus on viral hepatitis for which there is strong expertise at the CIRI and for which there is already good evidence that the virus influences host metabolism. Next, others models of viral infection will be studied. Development of platforms with large-scale metabolite analysis tools and/or collaborations with such platforms will be mandatory in reaching this goal.
- The second aim is to develop joint proof of concept projects in a limited number of systems to address the two major issues rose by this objective, i.e. effect of pre-existing metabolic diseases in the natural course of viral infection and, conversely, role of viral infection in the tuning of metabolic status of the cell or the host contributing to the emergence of chronic diseases such as insulin resistance and obesity. Collaboration with nutrition and metabolic diseases centers and infectious diseases departments both in Lyon and worldwide will have to be made for reaching this goal.
- The concept of reciprocal link between viral infections and metabolism or metabolo-virology should evolve toward the extended concept of metabolo-infectiology that would include bacteria and parasites.
Objective 3: Nosocomial infections
Nosocomial infections or healthcare-associated infections (HAIs) are a major public health problem particularly with the emergence of antibiotic-resistant bacteria. The two main causes of HAIs-related death are pneumonia and bloodstream infections. The main bacterial pathogens isolated from nosocomial pneumonia areStaphylococcus aureus and Pseudomonas aeruginosa and less frequently Legionella species. Nosocomial infections are frequently caused by bacterial pathogens that can colonize healthy individuals without triggering diseases. Factors enabling colonization are thought to include bacterial virulence factors, host factors, and environmental factors (ex commensal flora). How the immune response to colonizing microbes affects the immune responses during infections with the same microbes remains to be understood. Our specific aims are:
- To focus on nosocomial pneumonia: We will characterize the virulence factors involved in nosocomial pneumonia caused by different bacteria; develop animal models to understand the factors leading to acute respiratory distress syndrome; study the environmental and host genetic factors leading to nosocomial infections in humans.
- To understand the consequences of colonization on subsequent nosocomial infections. We willcharacterize the immunity to colonizing microbes and how these mechanisms affect the translocation of the bacteria into the organism, and their ability to cause disease.
- To develop innovative therapeutic strategies. Treatment of nosocomial infections can be challenging due to the high level of antibioticresistance of nosocomial pathogens and the frequentimmunodepression of the host. We will use the knowledge gathered on both microbial factors and host responses to develop novel therapeutic strategies to prevent or fight nosocomial infections.
Objective 4: Emerging and highly pathogenic infections
Emerging diseases are communicable diseases whose incidence has increased recently. Among them, highly pathogenic viruses, classified risk-group (RG) 4, lead to limited but extremely lethal outbreaks (Filovirus, Arenavirus,etc). Although not classified RG4, some pathogens may re-assort and become highly virulent and affect a naïve population (orthomyxovirus). Other viruses and bacteria (RG3 or RG2), although less pathogenic, are responsible for large outbreaks (Flavirus, Mycobacteriaetc). They all represent a public health concern because of their endemicity in some countries and of their importation in other countries. Our specific aims are:
- To improve surveillance and anticipate disease propagation. We will improve lab tools to identify pathogens in collaboration with the CNR for Viral Hemorrhagic Fevers (VHF) and for Hantavirusthat can provide teams with viral strains. The strong connection of the CIRI with different international networkswill allow field investigation and access to new strains and samples. This includes the surveillance of viral circulation in wildlife, and livestock.
- To identify the molecular mechanisms responsible for the high pathogenicity of infectious agents in humans. At the pathogen level, the role of viral factors in pathogenesis will be determined for different pathogens (Lassa, Nipah, CCHF etc) using reverse genetic tools and by comparing closely related viruses that present different pathogenicity.
At the host level, the role of host responses in the different outcomes will be studied using in vitro human models and animal experiments for different viruses (Lassa, Nipah, LCMV etc). This knowledge of virus-host interactions will be crucial for developing therapeutic or prophylaxis and for improving the recovery status of survivors.
Objective 5: Consequences of co-infections with human pathogenic agents
Pathology associated to infection is often considered as resulting from the interaction between a given pathogen with a given host. This paradigm looks however over-simplistic since the pathology of a pathogen, relies also on the interactions between several infectious agents present within an organism or a community in the environment. The interaction between host and viral or bacterial factors may constitute severity factors, and it is crucial to consider to which extent a host infected by a first virus or bacteria is modified and whether its reaction to the infection by a second virus/bacteria is consequently altered. Our specific aims are:
- To decipher the molecular mechanisms underlying the interaction between infectious pathogens at the host cell level. Infection of a cell with an infectious agent may alter cellular pathways (innate immune response, DNA damage response, metabolismetc) resulting in either stimulation or inhibition of another agent. In addition, co-infection can also benefit or suffer from pathogen-derived molecules with complementary or neutralizing activities.
- To analyze the consequences of a co-infection at the host organism level
Studying co-infection at the level of the host organism is essential to address questions relating to pathogenesis, and the role of the immune system in the persistence and/or spread of the infection.
- To study the relevance and impact of co-infections at the level of the human population. Epidemiological and clinical studies are crucial to highlight possible interferences between pathogens and their ability to influence the propagation of the infectious agent(s) within the population. They can also reveal novel unsuspected interactions and their possible link with pathologies.