The dual role of macrophages in mycobacterial- and HIV disease: host cell and generator of protective mediators with therapeutic potential.

HIV and Mycobacterium tuberculosis top the WHO list of deaths caused by infectious agents. Millons of people are co-infected, and drug resistance among pathogenic mycobacteria is a serious problem. To discover new therapies we need thorough knowledge abou t the interplay between the pathogens and cells of the immune system. The overall goal of this project is to characterise the role of effector responses resulting from activation of Toll-like receptors (TLRs) on macrophages in mycobacterial- and HIV disea se. Both mycobacteria and the HIV-virus are recognised by TLRs. We hypothesise that distortions in the TLR signalling pathways may contribute to immunodeficiency, HIV replication and increased susceptibility of HIV-infected individuals to mycobacterial di seases. We therefore propose as our first Objective to compare TLR-initiated effector responses in healthy individuals with those in HIV/AIDS patients with or without accompanying mycobacterial disease. During infection, bacteria acquire much of their iro n by synthesising siderophores that scavenge iron from the host and transport it into the pathogen. However, upon encountering invading bacteria the TLRs on innate immune cells stimulate the secretion of lipocalin 2; lipocalin 2 then limits bacterial grow th by sequestering the iron-laden siderophore. We predict that lipocalin 2 may have a bacteriostatic effect against mycobacteria by starving them for iron. If this holds true, lipocalin 2 will represent a promising candidate as a therapeutic agent against mycobacterial diseases. We want to establish the importance of lipocalin 2 in infections with mycobacteria and to study the binding and intracellular transport of lipocalin 2 in macrophages, the host cell of mycobacteria (Objectives 2 and 3). The propose d studies will contribute to a better understanding of the pathogenesis of mycobacteria in HIV-infected individuals, as well as to discovery of new therapeutic modalities for HIV and mycobacterial diseases.