Lipocalin 2 - a novel antimicrobial protein: Role in mycobacterial disease, urinary tract infection and in wound healing

Infectious diseases remain the main cause of premature death worldwide and antimicrobial resistance is increasing. Consequently, the WHO stresses that there is an urgent need for new drugs and supplementary treatment regimens against infectious agents. We have recently discovered a novel mechanism by which the innate immune system curbs bacteraemia and protects against infection (Flo TH et al., Nature 2004). During infection, bacteria acquire much of their iron by synthesizing siderophores that scavenge i ron from the host and transport it into the pathogen. However, upon encountering invading bacteria the Toll-like receptors on immune cells stimulate a massive induction and secretion of lipocalin 2. Lipocalin 2 then limits bacterial growth by sequestering the iron-laden siderophore, thereby preventing the establishment of tissue infections and/or septic shock resulting from an overwhelming bacterial load. By utilizing siderophores with a different chemistry, pathogens can escape lipocalin 2-mediated iron- deprivation. The specificity of siderophore-neutralizing proteins like lipocalin 2 may thus explain why some siderophores (e.g. mycobactins by M. tuberculosis, and aerobactin and yersiniabactin by uropathogenic E. coli) are associated with virulence. The formation of chronic wounds also involves poly-microbial colonization, and several antimicrobial proteins, including lipocalin 2, have been identified in human skin that may also be important for wound healing. In our approach we focus on the role and the rapeutic potential of lipocalin 2 in mycobacterial diseases, urinary tract infection and in wound healing. The acquisition of iron is recognized as one of the key steps in the development of any pathogen in its host. Lipocalin 2 thus represents an effecto r molecule with potential as a bacteriostatic drug candidate.