Abstract
Mycobacterium tuberculosis is an intracellular pathogen that can survive within phagocytic cells by inhibiting phagolysosome biogenesis. However, host cells can control the intracellular M. tuberculosis burden by the induction of autophagy. The mechanism of autophagosome formation to M. tuberculosis has been well studied in macrophages, but remains unclear in dendritic cells. We therefore characterized autophagosome formation in response to M. tuberculosis infection in dendritic cells. Autophagy marker protein LC3, autophagy adaptor protein p62/SQSTM1 (p62) and ubiquitin co-localized to M. tuberculosis in dendritic cells. Mycobacterial autophagosomes fused with lysosomes during infection, and major histcompatibility complex class II molecules (MHC II) also localized to mycobacterial autophagosomes. The proteins p62 and Atg5 function in the initiation and progression of autophagosome formation to M. tuberculosis, respectively; p62 mediates ubiquitination of M. tuberculosis and Atg5 is involved in the trafficking of degradative vesicles and MHC II to mycobacterial autophagosomes. These results imply that the autophagosome formation to M. tuberculosis in dendritic cells promotes the antigen presentation of mycobacterial peptides to CD4+ T lymphocytes via MHC II.
Highlights
Mycobacterium tuberculosis is the causative agent of tuberculosis and infects one-third of the world’s population
To assess whether autophagosomes are formed around M. tuberculosis bacilli in macrophages and dendritic cells (DC), we infected bone marrow-derived macrophages (BMM) or BMDC with M. tuberculosis and by immunofluorescence microscopy, we examined the localization of the autophagic marker protein, LC3 [27], around M. tuberculosis (Figure 1A– C)
We further examined the localization of an autophagy adaptor protein, p62/SQSTM1 (p62) and ubiquitin to mycobacteria in BMM or BMDC (Figure 1D–I). p62 is involved in targeting ubiquitinated intracellular bacteria to the selective autophagic pathway [29] and is responsible for autophagic elimination of mycobacteria in macrophages [30]
Summary
Mycobacterium tuberculosis is the causative agent of tuberculosis and infects one-third of the world’s population. M. tuberculosis is an intracellular bacterium that can survive within infected the phagocytic cells and its ability to block phagolysosome biogenesis [1] may contribute to its persistence within host cells. Our studies have supported these findings by showing that M. tuberculosis infection modulates the trafficking of Rab GTPases that regulate phagosome maturation, resulting in the inhibition of phagolysosome biogenesis in macrophages [3,4,5,6]. Despite the intracellular proliferation of M. tuberculosis in macrophages, the interaction of infected macrophages and T lymphocytes promotes the elimination of M. tuberculosis [7,8]. This process illustrates the close interaction between the innate and adaptive immunity systems in pathogens clearance. The contribution of directly infected DC in the activation of T lymphocytes remains unclear
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