Project: Exit of Mycobacterium avium from granuloma macrophagesCopyright: © Henneke
M. avium is a widely present environmental organism with an intracellular life-style. M. avium causes three distinct human diseases, a) chronic suppurative lymphadenitis in preschool children, b) pneumonia in patients with chronic lung disease, and c) disseminated disease in immunodeficient patients. We previously identified a novel circulating monocyte progenitor type, which is induced in mice with mycobacterial lung and liver infections (denominated iMoP). iMoP are restricted precursors and give rise to granuloma Mφ, in particular multinucleated giant cells. Yet, they are distinct from differentiated monocytes and Mφ, i.e. they are largely resistant to apoptosis and exhibit alterations in lipid and glucose metabolism.
The specific hypothesis underlying this proposal holds that resident tissue Mφ are infected with M. avium. This leads to the parallel processes of Mφ apoptosis and phenotypic adaptation of M. avium to increased virulence and resistance to oxidative stress. At the same time, iMoP are mobilized from the bone-marrow, reach the tissue and undergo first steps to MGC transformation, e.g. upon activation by TLR2-stimulating mycobacterial effectors. This allows them to effectively take up apoptotic infected Mφ and apoptotic bodies. Thus M. avium exits primarily infected Mφ and is transferred to a more permissive environment and nascent granulomas seeded. Deciphering of the basic mechanisms underlying exit and secondary entry, i.e. M. avium transfer between Mφ species can be expected to reveal novel strategies to boost mycobacterial immunity