Targeting lung epithelial cells or type 3 innate lymphoid cells for the treatment of respiratory infections induced by Klebsiella pneumoniae – TargetInnate
Rationale: Bacterial infections of the lower respiratory tract, i.e. pneumonia represent a major cause of mortality worldwide. The high rate of mortality and morbidity is due to debilitating effects on respiratory functions and the frequent evolution of pneumonia into sepsis, a severe disease with poor prognosis. The respiratory infections are acquired in community or in hospital and affect civil populations (especially children and immunosuppressed individuals) as well as military personnel, particularly soldiers in operation. In addition, in the context of bioterrorism or war, the weaponization of bacterial agents like Yersinia pestis or Bacillus anthracis remains a threat of respiratory infections for both civilians and soldiers. The bacteria Klebsiella pneumoniae is a main causative agent of pneumonia and represent an excellent model of pneumonia and sepsis. Antibiotics are used as a first line treatment against K. pneumoniae-mediated pneumonia. However, emergence of resistance to one or multiple antibiotics is largely responsible for treatment failure. Therefore, there is an urgent need of alternative strategies to antibiotics. From this perspective, manipulation of innate immunity represents an interesting medical countermeasure since it is activated rapidly to enable, through a multiplicity of effectors, defense against a broad spectrum of microorganisms. Previous studies found that stimulation of innate immunity by nasal or systemic route with flagellin, the only known agonist for the Toll-like receptor 5 (TLR5), promotes the clearance of Streptococcus pneumoniae, Pseudomonas aeruginosa, or Burkholderia cepacia in the lower respiratory tract and the rapid shift to homeostasis. The nasal and systemic treatments induce preferentially a TLR5-specific signaling in respiratory epithelial cells and in pulmonary dendritic cells (DC), respectively. It is assumed that the epithelial activation induces protection via secretion of neutrophil-specific chemokines and antimicrobial peptides. In contrast, the dendritic cell activation engages pulmonary type 3 innate lymphoid cells (ILC3) and interleukin 22 (IL-22). TLR5 signaling is however ubiquitous and triggers unwanted effects due to activation of many host cells that are not required for protection.
Objectives: The main objective of this project is to demonstrate by preclinical studies that specific targeting of flagellin to epithelial cells or to dendritic cells is highly potent to prevent and to cure antibiotic-resistant K. pneumoniae-induced respiratory infections and sepsis. To this aim, recombinant flagellins conjugated to antibodies specific for respiratory epithelial cells and dendritic cells will be produced. The experiments will determine in a mouse model of infection the appropriate target and dose of these immunoconjugates that:
• improve the clearance of bacteria and animal survival in early and severe grades of infection
• improve recovery from pneumonia, and
• reduce any undesired effects.
The project will also consider developing conjugates with antibodies specific for human cell counterparts and validate proof-of-concept in human primary cells. Regarding technology transfer, the filing of new patents is planned in the aim to find an industrial partner.
Expected results: The project aims at providing new pharmaceutical products based on therapy targeting specific host innate cells to better prevent and/or cure antibiotic-resistant K. pneumoniae infections and potentially reduce treatment failure. Moreover, it opens new prospects for prophylaxis and treatments of weaponized bacterial agents such as Y. pestis or B. anthracis.
Monsieur Jean-Claude SIRARD (Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IRCM Institut de Recherche en Cancérologie de Montpellier
CIIL Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille
Help of the ANR 298,510 euros
Beginning and duration of the scientific project: - 36 Months