Axis 1. Flagellin as an adjunct for antibiotic treatment of infections
We previously showed the proof-of-concept that respiratory administration of a recombinant TLR5 agonist, i.e. flagellin in association with antibiotics protects mice against S. pneumoniae infection. The universality of the adjunct therapy combining TLR agonist and antibiotic will be challenged in a clinically relevant respiratory model of infection in mice using multidrug-resistant (MDR) S. pneumoniae as well as susceptible and MDR Klebsiella pneumoniae. These Gram+ and Gram- bacteria are major causes of community-acquired and hospital care-associated pneumonia and treatment failure due to MDR. This axis is part of the European H2020 project "FAIR" coordinated by our team.
The objectives are to :
- develop appropriate delivery systems and formulations for aerosol therapy in human
- demonstrate the proof-of-concept of safety/tolerability/activity and determine the pharmacokinetics and pharmacodynamics of nebulized flagellin
- and perform a placebo-controlled, double-blind phase I safety trial in adult volunteers, as a primary step to further clinical development.
Axis 2- Defining the contribution of myeloid lineage in the effectiveness of antibiotic treatment of infections
The direct effect of antibiotics on bacteria is well studied worldwide. Interestingly, increasing evidence suggests that many antibiotics also directly modulate activities/functions of immune cells like myeloid cells (monocytes, dendritic cells) and mainly function as anti-inflammatory agents. However, the indirect effects of antibiotics on host immunity in the context of infections remain largely unexplored. Bacterial infections trigger the mobilization of myeloid cells from the bone marrow to infected tissues, a process called “emergency myelopoiesis”. This is accompanied by an expansion/differentiation of hematopoietic stem cells into myeloid progenitors to maintain the supply of myeloid cells, a process crucial to control infection. This emergency process is thus commonly associated with alterations in the cellular and/or functional characteristics of bone marrow stem and progenitor cells. We plan to study the changes in myeloid cells during antibiotic treatment of infections and thereby define how emergency myelopoiesis impacts on protection.
We propose to investigate the impact of antibiotic treatment in the modulation of host immunity in S. pneumoniae as well as K. pneumoniae (susceptible or MDR) pulmonary infection using high throughput analyses. To obtain a complete picture of how antibiotics impact on the host immune system during infection, we will identify the innate signaling pathways and the cells required to clear the infection. Finally, the impact of antibiotics on the myeloid population will be also tested in human.