Naslov
Modulation of biogenesis of the Francisella tularensis subsp novicida-containing phagosome in quiescent human macrophages and its maturation into a phagolysosome upon activation by IFN-gamma

Autori
Šantić, Marina ; Molmeret, Maelle ; Abu Kwaik, Yousef

Izvornik
Cellular microbiology (1462-5814) 7 (2005), 7; 957-967

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
trafficking; tularemia; endosome; lysosomes

Sažetak
Francisella tularensis is a highly virulent facultative intracellular pathogen that has been categorized as a class A bioterrorism agent, and is classified into four subsp, tularensis, holarctica, mediasiatica, and novicida. Although the ability of F. tularensis subsp. novicida to cause tularemia in mice is similar to the virulent subsp tularensis and holarctica, it is attenuated in humans. It is not known whether attenuation of F. tularensis subsp novicida in humans is due to a different route of trafficking within human macrophages, compared to the tularensis or holarctica subsp. Here we show that in quiescent human monocytes-derived macrophages (hMDMs), the F. tularensis subsp. novicida containing phagosome (FCP) matures into a late endosome like-stage that acquires the late endosomal marker LAMP-2 but does not fuse to lysosomes. This modulation of phagosome biogenesis by F. tularensis is followed by disruption of the phagosome at 4-12h and subsequent bacterial escape into cytoplasm where the organism replicates. In IFN- activated hMDMs, intracellular replication of F. tularensis is completely inhibited, and is associated with failure of the organism to escape from the phagosome into the cytoplasm for up to 24h after infection. In IFN- activated hMDMs, the FCPs acquire the lysosomal enzymes Cathepsin D, which is excluded in quiescent hMDMs. When the lysosomes of IFN- -activated hMDMs are pre-load with Texas Red Ovalbumin or BSA-gold, the FCPs acquire both lysosomal tracers. In contrast, both lysosomal tracers are excluded from the FCPs within quiescent hMDMs. We conclude that although F. tularensis subsp. novicida is attenuated in humans, it modulates biogenesis of its phagosome into a late endosome-like compartment followed by bacterial escape into the cytoplasm within quiescent hMDMs, similar to the virulent subsp tularensis. In IFN- -activated hMDMs, the organism fails to escape into the cytoplasm and its phagosome fuses to lysosomes, similar to inert particles.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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