Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is the major pathogen responsible for community and hospital bacterial infections. Sublancin, a glucosylated antimicrobial peptide isolated from Bacillus subtilis 168, possesses antibacterial infective effects. In this study, we investigated the role and anti-infection mechanism of sublancin in a mouse model of MRSA-induced sublethal infection. Sublancin could modulate innate immunity by inducing the production of IL-1β, IL-6, TNF-α, and nitric oxide, enhancing phagocytosis and MRSA-killing activity in both RAW264.7 cells and mouse peritoneal macrophages. The enhanced macrophage function by the peptide in vitro correlated with stronger protective activity in vivo in the MRSA-invasive sublethal infection model. Macrophage activation by sublancin was found to be partly dependent on TLR4 and the NF-κB and MAPK signaling pathways. Moreover, oral administration of sublancin increased the frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes. The protective activity of sublancin was associated with in vivo augmenting phagocytic activity of peritoneal macrophages and partly improving T cell-mediated immunity. Macrophages thus represent a potentially pivotal and novel target for future development of innate defense regulator therapeutics against S. aureus infection.
Highlights
Concurrent with the success of antibiotics for treating infections, their excessive use contributes to the emergence of antibiotic-resistant bacteria [1]
Methicillin-resistant Staphylococcus aureus (MRSA) is widespread and multiresistant; it has challenged the effectiveness of antibiotics including β-lactams, macrolides, and quinolones, as well as vancomycin which has been accepted as the first-line option for treating infections due to MRSA [2]
We investigated whether sublancin can (i) activate macrophages and the signaling pathway involved in this process, (ii) inhibit bacterial growth in a model of MRSA-infected mice and macrophages, and (iii) improve immune function in mice under healthy and MRSA-induced sublethal infection conditions
Summary
Concurrent with the success of antibiotics for treating infections, their excessive use contributes to the emergence of antibiotic-resistant bacteria [1]. Antibiotic resistance has become an increasingly serious health care problem in the world [3]. This has been aggravated by a collapse in the number of approvals of new antibacterials in the past three decades [4]. Macrophages are professional phagocytes of the innate immune system, providing a first line of defense against infections. It has been reported that macrophages play an important role in the clearance of S. aureus in the infected mice [5]. Mice that have been depleted of macrophages are susceptible to MRSA infection [6]. Macrophages can kill bacteria directly through phagocytosis and indirectly via releasing inflammatory
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