Mycobacterium tuberculosis (Mtb) uses efficient
strategies to evade the eradication by professional phagocytes, involving—as
recently confirmed—escape from phagosomal confinement. While
Mtb determinants, such as the ESX-1 type VII secretion system,
that contribute to this phenomenon are known, the host cell factors governing this
important biological process are yet unexplored. Using a newly developed
flow-cytometric approach for Mtb, we show that macrophages
expressing the phagosomal bivalent cation transporter Nramp-1, are much less
susceptible to phagosomal rupture. Together with results from the use of the
phagosome acidification inhibitor bafilomycin, we demonstrate that restriction of
phagosomal acidification is a prerequisite for mycobacterial phagosomal rupture and
cytosolic contact. Using different in vivo approaches including an
enrichment and screen for tracking rare infected phagocytes carrying the CD45.1
hematopoietic allelic marker, we here provide first and unique evidence of M.
tuberculosis-mediated phagosomal rupture in mouse spleen and lungs and in
numerous phagocyte types. Our results, linking the ability of restriction of
phagosome acidification to cytosolic access, provide an important conceptual advance
for our knowledge on host processes targeted by Mtb evasion
strategies.
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