Modulation of host cell death pathways by Legionella pneumophila

Simran Banga, Purdue University

Abstract

Legionella pneumophila is a facultative intracellular pathogen that infects human alveolar macrophages to cause severe pneumonia known as Legionnaires' disease. To survive and proliferate, the microorganism uses sophisticated strategies to hijack various host cell processes using bacterial proteins delivered into host cell through the Dot/Icm secretion system. As a result, the membrane bound vacuole containing Legionella, inside the macrophages escapes the default pathway to avoid fusion with the late endosomes and instead transforms the Legionella containing vacuole (LCV) into a compartment that morphologically resembles the host cell rough ER structures. These cellular perturbations lead to induction of apoptosis that can terminate L. pneumophila replication within successfully structured LCVs. Thus, the bacterium specifically employs effectors to modulate apoptotic signaling in favor of host cell survival. Here we report that SidF, an effector of Dot/Icm, functions as an anti-apoptotic protein and is required by L. pneumophila for efficient intracellular growth in macrophages. Studies on the functional characterization of SidF revealed that the protein inhibits cell death by interacting with pro-apoptotic proteins of Bcl2 family proteins, Bnip3 and Bcl-rambo thereby neutralizing their apoptotic activity. Further, in order to understand the cell death process in macrophages, we designed a screen to identify the bacterial effectors responsible for inducing cell death. We found ten effector proteins capable of inducing yeast cell death. Additional analysis showed that these effectors can be grouped into two types based on their physiological effect on host cell processes, one that target eukaryotic protein translation process and the other that interfere with vesicle trafficking network within the host cell. We identified two new substrates of Dot/Icm that target protein synthesis. Furthermore, we observed that one of these effectors G5, when expressed ectopically localizes to the nucleus of the mammalian cells. Deletion mutant analysis showed that bacterial effectors involved in inhibition of protein synthesis are collectively essential for intracellular growth of L. pneumophila in amoebae, its natural host.

Degree

Ph.D.

Advisors

Luo, Purdue University.

Subject Area

Molecular biology|Microbiology

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