Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberculosis Beijing strain

Thanida Laopanupong,Tegar Adriansyah Putra Siregar,Tanapat Palaga,Suparerk Borwornpinyo,Pongsak Utaisincharoen,Stephane Méresse,Marisa Ponpuak,Jiraporn Paha,Angkana Chaiprasert,Atsadang Boonmee,Phongthon Kanjanasirirat,Tanawadee Khumpanied,Pinidphon Prombutara,Salisa Benjaskulluecha

doi:10.1038/s41598-021-83835-4

Thanida Laopanupong, Tegar Adriansyah Putra Siregar + Show 12 more

Open Access

https://doi.org/10.1038/s41598-021-83835-4

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Abstract

Induction of host cell autophagy by starvation was shown to enhance lysosomal delivery to mycobacterial phagosomes, resulting in the restriction of Mycobacterium tuberculosis reference strain H37Rv. Our previous study showed that strains belonging to M. tuberculosis Beijing genotype resisted starvation-induced autophagic elimination but the factors involved remained unclear. Here, we conducted RNA-Seq of macrophages infected with the autophagy-resistant Beijing strain (BJN) compared to macrophages infected with H37Rv upon autophagy induction by starvation. Results identified several genes uniquely upregulated in BJN-infected macrophages but not in H37Rv-infected cells, including those encoding Kxd1 and Plekhm2, which function in lysosome positioning towards the cell periphery. Unlike H37Rv, BJN suppressed enhanced lysosome positioning towards the perinuclear region and lysosomal delivery to its phagosome upon autophagy induction by starvation, while depletion of Kxd1 and Plekhm2 reverted such effects, resulting in restriction of BJN intracellular survival upon autophagy induction by starvation. Taken together, these data indicated that Kxd1 and Plekhm2 are important for the BJN strain to suppress lysosome positioning towards the perinuclear region and lysosomal delivery into its phagosome during autophagy induction by starvation to evade starvation-induced autophagic restriction.

Highlights

Induction of host cell autophagy by starvation was shown to enhance lysosomal delivery to mycobacterial phagosomes, resulting in the restriction of Mycobacterium tuberculosis reference strain H37Rv
RNA-Seq analyses were performed under three biological conditions: (1) macrophages induced to undergo autophagy by starvation without infection (S versus F), (2) macrophages infected with the autophagy-sensitive H37Rv strain followed by autophagy induction by starvation (HS versus HF) and (3) macrophages infected with the autophagy-resistant Beijing strain (BJN) followed by autophagy induction by starvation (BS versus BF)
Induction of autophagy leads to enhanced mycobacterial phagosome acquisition of lysosomal hydrolases, resulting in the digestion of intracellular M. tuberculosis reference strains such as H37Rv and strains belonging to the East African Indian g enotype[15,25,27,28,38]