Functional analysis of Coxiella burnetii type IV effector-induced inhibition of host cell apoptosis

• Applicant: Professorin Dr. Anja Lührmann
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 164906395

Coxiella burnetii is a Gram-negative, obligate intracellular pathogen that causes Q-fever, a worldwide zoonotic disease. Q-fever is a mild flu-like illness, but can be associated with chronic or even fatal outcomes. The type IV secretion system (T4SS) expressed by C. burnetii is thought to deliver bacterial proteins into the host cell in order to manipulate host cell pathways and to establish intracellular infection. A host pathway targeted by several intracellular pathogens is the apoptosis pathway. For C. burnetii, inhibition of host cell apoptosis is important to ensure a productive infection and may play a role in establishing chronic disease. My previous work indicates that the T4SS effector AnkG inhibits host cell apoptosis by interfering with alternative splicing of the apoptosis regulator Bcl-x, through binding the host cell protein p32. However, the temporal and spatial regulation of the AnkG-induced modulation of p32 activity and Bcl-x splicing is unknown. This study aims to (1) elucidate how AnkG inhibits apoptosis and will answer (1a) how AnkG trafficking inside the host cell is regulated and (1b) how AnkG modulates the activity of p32. Additionally, we hypothesize that not only AnkG but also other T4SS effector proteins are involved in inhibition of host cell apoptosis. Therefore, this study aims to (2) determine the diverse mechanisms employed by C. burnetii to prevent host cell apoptosis. We will identify and characterize the functions of additional T4SS substrates that interfere with the intrinsic and extrinsic apoptosis pathways.

• DFG Programme: Research Grants