Methicillin-resistant Staphylococcus aureus (MRSA) remains a major public health problem worldwide because of its strong resistance to a variety of antibiotics. Natural immunoglobulin (Ig) M antibodies have been reported to protect against microbial infections. In the present study, the function of a monoclonal natural anti-keratin antibody IgM (named 3B4) in MRSA infection was evaluated. The binding of 3B4 to MRSA was studied using immunofluorescence assay and flow cytometry (FCM). The binding of 3134 to mannose-binding lectin (MBL) and complement activation were detected by ELISA. For the in vivo study, transgenic mice for the V-H gene from 3B4 (TgV(H) 3B4) were used. After infection, the bacterial burden was examined in the kidney, spleen and enterocelia. Inflammatory cytokine levels and the neutrophil ratio in peritoneal lavage fluid (PLF) were assessed by ELISA and FCM, respectively. Additionally, the total serum hemolytic activity (CH50) in the early stage of infection was detected by ELISA. The results showed that 3B4 bound directly to MRSA and MBL, and the interaction between 3B4 and MRSA/MBL led to the activation of the classic and the MBL pathway in vitro. After 48 h of MRSA infection, the bacterial load in the kidney, spleen and enterocelia was significantly decreased in TgV(H) 3B4 mice (P < 0.05) compared with wild-type mice. Levels of IL-6, TNF-alpha, and IFN-gamma were increased after MRSA infection. The levels of IL-6 and TNF-alpha in TgV(H) 3B4 mice were decreased by 49.1% and 59.4% compared to wild-type mice. Additionally, the neutrophil ratio in the PLF of TgV(H) 3B4 mice was decreased by 65.9%. The CHSO value was significantly higher in TgV(H) 3B4 mice than in wild-type mice, indicating that 3B4 promoted the activation of the complement system in MRSA infected mice. The results reveal an important role of 384 in the anti-MRSA immune response, and the complement activation contributes to this effect. (C) 2015 Elsevier Inc. All rights reserved.