Naslov
Incomplete activation of macrophage apoptosis during intracellular replication of L. pneumophila

Autori
Abu-Zant, Alaeddin ; Šantić, Marina ; Molmeret Maelle ; Jones, Snake ; Helbig, Jurgen ; Abu Kwaik, Yousef

Izvornik
Infection and Immunity (0019-9567) 73 (2005), 9; 5339-5349

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

Ključne riječi
Legionnaires'; intracellular

Sažetak
The ability of the intracellular bacterium L. pneumophila to cause disease is totally dependent on its ability to modulate biogenesis of its phagosome and to replicate within alveolar cells. Upon invasion, L. pneumophila activates caspase-3 in macrophages, monocytes, and alveolar epithelial cells in a Dot/Icm-dependent manner, and independent of the extrinsic or intrinsic pathways of apoptosis, suggesting a novel mechanism of caspase-3 activation by this intracellular pathogen. We have shown that inhibition of caspase-3 prior to infection results in altered biogenesis of the L. pneumophila-containing phagosome and in inhibition of intracellular replication. In this report, we show that pre-activation of caspase-3 prior to infection does not rescue intracellular replication of L. pneumophila icmS, icmR and icmQ mutant strains. Interestingly, pre-activation of caspase-3 through the intrinsic and extrinsic pathways of apoptosis, in both human and mouse macrophages, inhibits intracellular replication of the parental stain of L. pneumophila. Using single-cell analysis, we show that intracellular L. pneumophila induces robust activation of caspase-3 during exponential replication. Surprisingly, despite this robust activation of caspase-3 in the infected the cell, the host cell does not undergo apoptosis till late stages of infection. In a sharp contrast, activation of caspase-3 by apoptosisinducing agents results in activation of caspase-3 concomitant with apoptotic death of the cells in all cells that exhibit caspase-3 activation. Only at later stage of infection, and concomitant with termination of intracellular replication, that the L. pneumophila-infected cells undergo apoptotic death. We conclude that although robust activation of caspase-3 is exhibited throughout exponential intracellular replication of L. pneumophila, apoptotic cell death is not executed till late stages of the infection, concomitant with the termination of intracellular replication.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA