Role of mitochondrial homeostasis in group A streptococcus infected muscle cells

Abstract

Group A streptococcus (GAS) causes a wide range of infections on human, including skin, throat, blood, and muscles. The most severe form of invasive group A streptococcal disease is necrotizing fasciitis described as rapidly muscular destruction. Muscles are responsible for energetic functions provided by abundant mitochondria. Mitochondria homeostasis is essential for the regulation of its function and the dysfunctional mitochondria can be eliminated through Parkin/PINK1-dependent mitophagy. Mitochondria play an important role in innate immunity that pathogens target to mitochondria as a strategy for preserving intracellular survival. Thus, we hypothesized that GAS induced muscular destruction that increases the intracellular bacterial survival is through damaging mitochondria. First, we infected mouse myoblasts, C2C12, with GAS and found that GAS caused loss of mitochondrial contents and permeabilized mitochondrial membrane thus increased mitophagy. Attenuation of mitophagy preserved mitochondrial contents and decreased intracellular bacterial number, suggesting inhibiting mitophagy was beneficial for intracellular bacterial clearance. To assess which bacterial virulence factor contributed to the disturbance of mitochondria, we found that streptolysin S (SLS) mutant induced less mitochondrial loss and mitophagy. Due to SLS is a pore-forming toxin, we found that SLS mutant caused less mitochondrial permeabilization, cytochrome c release, OPA1 degradation and mitochondrial fission, suggesting the effect of SLS was similar to that of the protonophore CCCP. In addition, CCCP pre-treatment and infection with SLS mutant could enhance intracellular bacterial survival. Furthermore, we found that GAS with SLS led to severe muscular damage and the alteration of mitochondrial morphology in vivo. Taken together, we found that GAS infection triggered mitophagy mediated by mitochondrial damage which contributed by SLS and further promoted intracellular bacterial survival, suggesting mitochondria played a critical innate protective role during GAS infection.

Date of Award	2014
Original language	English
Supervisor	Pei-Jane Tsai (Supervisor)