With the development of multi-drug-resistant bacteria, identification of a chemical or pharmacological drug that could influence human immune response and decrease the risks of pathogens infection has become a key goal of innate immunity research. Compared with traditional in vitro assays measuring growth inhibition or killing of pathogens, Caenorhabditis elegans is a very convenient whole organism model in which to identify or assay antimicrobial drugs [9]. Since Chinese traditional herbs exhibit great advantages including fewer side effects and lower chance to generate drug resistance, more researchers focus on searching new drugs to identify potential activators of innate immunity that may confer protection against bacterial infections [36]. The traditional Chinese medicine, Schisandra chinensis, has effects on the central nervous system, such as improving learning, memory, sedation, hypnosis, anti-aging, and analgesia [30]. Schizandrin A (SA), also known as deoxyschizandrin, is one of the most biologically active lignans isolated from the traditional Chinese medicine Fructus schisandrae chinensis [11], [35]. Schisandrin A exhibits many pharmacological effects, such as anti-cancer, anti-inflammation, anti-oxidation, hepatoprotection, neuroprotection, and anti-diabetes [11]. Overall, despite the beneficial functions for Schisandrin A in multiple cellular processes, its contribution to innate immunity in animals remains unknown.

The innate immune system represents the first line of defense against pathogens infection and it is evolutionarily conserved from worms to mammals [1], [31]. During infection, the innate immune system is activated, resulting in antimicrobial response to invading pathogens [1], [14], [16], [18], [32]. Infectious pathogens, many of which are of clinical interest, provoke specific mechanisms of innate immunity, and induce the expression of antibacterial peptides such as ShK toxin protein, CUB-like protein, lysozymes and lectins [9]. Caenorhabditis elegans has been developed as a valuable genetic model for research on the animal immune response. Through using this tractable model, researchers reveal several signaling pathways that have important role in regulating the innate immunity, such as the PMK-1/p38 MAPK pathway [2], [17], the DAF-2/DAF-16 pathway [12], the MPK-1/ERK MAPK pathway [22], [37]. The p38 MAPK pathway is the primary innate immune signaling pathway that responds to pathogen infection, which has been found to be conserved from worms to mammals [14]. In this pathway, NSY-1/ASK1(MAPK kinase kinase) signals to SEK-1/MKK3/MKK6 (MAPK kinase), which signals to PMK-1/p38 (MAPK) [6], [17]. Previous studies have demonstrated that PMK-1/p38 MAPK signaling pathway can regulate the expression of antibacterial peptide genes [14], [28].

In this study, we investigated the role of Schisandrin A to modulate C. elegans host defense. Through genetic screening in C. elegans, we found that Schisandrin A protects host against pathogens through PMK-1/p38 MAPK. Furthermore, Schisandrin A increased the expression of antibacterial peptide genes, such as K08D8.5, lys-2, F35E12.5, T24B8.5, and C32H11.12 by activation PMK-1/p38 MAPK. This ancient Schisandrin A response pathway was conserved from worms to mammals. These findings revealed that the Schisandrin A-promoted innate immunity would significantly boost its application to improve the patients of infectious diseases.