"Group AStreptococcus (GAS) is a predominant Gram-positive bacterium causing a substantial burden of diseases in humans. Autophagy is a starvation-induced response that provides nutrients by degrading long-living proteins and recycling intracellular organelles. In 2004, autophagy was identified as a new immune mechanism for killing and clearing invading GAS in epithelial cells. It is regulated by host proteins such as Beclin1, ATG 5, ATG6 and LC3. On the other hand, host proteases such as calpain, caspase and cathepsin inhibit autophagy activation by degrading these proteins.GAS virulence factors that can affect host autophagy have never been identified or described so far. The first part of this proposal will focus on the GAS virulence factors that can initiate degradation of host autophagy proteins. Potential GAS virulence factors listed in this proposal are Streptolysin S (SLS) and Streptolysin O (SLO) which are playing a role in host protease activation. Streptococcal Pyrogenic Exotoxin B (SpeB) and Group A streptococcus protease (SpyCEP) are also going to be investigated for their potential to directly degrade host autophagy proteins. Degradation of host proteins involved in autophagy, by these proteases can influence autophagy regulation. The second part of this proposal is aiming to study the role of autophagy in zoonotic streptococci infection. As increasing numbers of invasive infection caused by zoonotic streptococci are recently reported, this would be a first and an important study. The third part will be to study the role of autophagy in bacterial killing in neutrophils. Neutrophils are known to be one of the most important immune cells to clear GAS infection. However the role of autophagy in neutrophils against GAS infection has never been studied. The understanding of mechanisms underlying autophagy regulation by GAS has the potential to contribute towards the discovery of targets for novel therapeutic agents against GAS infections."