Biophysical Society Thematic Meeting

Mechanobiology of Disease

Wednesday Speaker Abstracts

Bacterial Pathogen Induces Host Cell Fusion and Triggers the Type I Interferon Response

through cGAS and STING

Yunn Hwen Gan

1,3

, Joanne Wei-Kay Ku

1,2

Yong Loo Lin School of Medicine, National University of Singapore, Singapore,

NUS

Graduate School for Integrative Sciences and Engineering, National University of Singapore,

Singapore,

Immunology Program , National University of Singapore, Singapore.

The bacterial pathogen Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, an

endemic disease in Southeast Asia, Northern Australia and many areas in the tropics. It is unique

among bacterial pathogens in its ability to induce Multinucleated Giant Cell (MNGC) formation

through one of its Type Six Secretion Systems (T6SS-1, also known as T6SS-5). After the

pathogen enters the host cell and escapes into the cytosol, it turns on T6SS-1 through the sensing

of glutathione present abundantly in the cytosol. The induction of cell fusion is important for

facilitating cell-to-cell spread by the pathogen. Based on work conducted on Bp and the

surrogate model organism, Burkholderia thailandensis, we discovered that late kinetics of Type I

interferon (IFN) relied on a functional T6SS-1 and correlated with the extent and time of MNGC

formation. Further investigations revealed the involvement of stimulator of interferon genes

(STING), an ER-residing pattern recognition receptor, as well as cGAS, which resides in the

cytosol and binds double stranded DNA. Engagement of cGAS leads to STING activation and

the downstream Type I IFN response. I will discuss our efforts in trying to decipher the

relationship between T6SS, cell fusion and the cytosolic DNA response. This represents an

attempt by the host to respond to the danger signals of a pathogen invading the cytosol and

causing massive remodelling of the host cell membrane.