1 Department of Systems Biology, Technical University of Denmark2 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark
Latent infections with the human pathogenic microorganisms Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are creating some of the most devastating pandemics to date, with great impact on the infected people’s lives, their expected lifetime, as well as general costs for society. Consequently there is a pressing need to search for new treatment strategies. Nowadays it is known that HIV-1 and Mtb have acquired the ability to escape the removal from the body by exploiting the immune system for their own benefits. Dendritic cells (DCs) determine the way the immune response unfolds by signaling other immune cells how to respond. An early deregulation of the DCs may therefore propagate into detrimental effects in later stages of the immune response, and may permit HIV-1 and Mtb to become latent. Hence, understanding the way HIV-1 and Mtb interacts with DCs could lead to novel treatment strategies. In the present work this has been examined in purified human plasmacytoid DCs (pDCs) and monocyte-derived DCs (moDCs). First it is demonstrated how Mtb exploits plasticity in moDCs to avoid production of the cytokine IL-12p70 necessary for protection against Mtb. Then it is shown that Mtb induces signaling in moDCs that misdirects the immune response into an extracellular Th17 response, even though the bacteria hide inside immune cells. Finally it is demonstrated how HIV-1 strains, capable of provoking sustained infection, induce a highmannose-independent complete necrotic eradication of the pDCs that is needed to inhibit initial infection. The results presented in this thesis provide novel insights into immune evasion strategies employed by HIV-1 and Mtb. These findings could eventually be utilized for better treatment strategies against AIDS and tuberculosis disease when specific strategies for immune cell perturbations are established.