Abstract Acne is an important skin disorder believed to be caused by skin commensal P. acnes, although how P. acnes contributes to acne is unclear. We have identified two types of hyaluronidase enzymes, made by different strains of P. acnes, that are either pro- or anti-inflammatory. Importantly, skin colonization by P. acnes strains that encode the pro-inflammatory hyaluronidase is associated with development of acne, whereas colonization with P. acnes strains that express the anti-inflammatory hyaluronidase is associated with healthy skin. In preliminary experiments, we have shown that the pro- or anti-inflammatory property of the hyaluronidases is related to the size of hyaluronan fragments generated by the enzymes. Therefore, we hypothesize that hyaluronidases influence the acne-genic potential of P. acnes by degrading hyaluronan to different sizes. To address our hypothesis, 1) we propose to investigate the structural basis of hyaluronan degradation by P. acnes hyaluronidases, binding of hyaluronan fragments to TLR2/4 and host immune responses to the hyaluronan fragments. 2) We propose to determine the contribution of both hyaluronidases to acne by testing well characterized clinical strains of P. acnes and mutant strains of P. acnes that do not express hyaluronidase, in a new mouse acne model. 3) We will also investigate hyaluronidase-based strategies for preventing or treating acne.