Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major nosocomial pathogen that is deeply entrenched in both health care facilities and the community at large by direct host-to-host transmission.Several virulence factors are associated with pathogen transmission to naive hosts.Immunodominant surface antigen B (IsaB) is a virulence factor that helps Staphylococcus aureus to evade the host defense system.However, the mechanism of IsaB on host transmissibility remains unclear.In this study, we found that IsaB expression levels were elevated in transmissible MRSA, which showed increased inflammatory cytokine MIP-2 and enhanced colonization in infected mice.The wild-type isaB strain inhibited autophagy and augmented colonization and inflammation in THP-1 cells or mice skins compared to cells or mice skins infected with isaB deletion mutant strain.In contrast to the clinical MRSA isolate with the lowest IsaB expression, MRSA isolates with higher IsaB expression inhibited autophagic flux to survive and caused inflammation in THP-1 cells.Additionally, recombinant IsaB recovered the virulence of the isaB deletion mutant strain for host susceptibility to group A streptococcus (GAS) in vivo.Together, these results reveal that IsaB may diminish autophagy to evade host degradation, providing IsaB as a suitable target for preventing or treating MRSA infection.