Abstract
Securinine, a GABAA receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABAA receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5′-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca2+ binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.
Highlights
It was recently reported by Lubick, et al, that Securinine enhanced monocytic cell killing of phase II Coxiella burnetii [1]
Recent proteomic analysis of lipopolysaccharide (LPS) stimulated Toll-like receptor (TLR) in monocytes gave distinctly different proteome changes compared to those we find for Securinine exposure [6,7], providing direct evidence that TLRs, and GABAA receptors have different influences on the monocyte immune response
Our results on differential protein expression combined with information from the literature suggest that GABAA receptors and TLRs have different regulatory functions in the monocyte immune responses
Summary
It was recently reported by Lubick, et al, that Securinine enhanced monocytic cell killing of phase II Coxiella burnetii [1]. Small molecules, such as Securinine, that activate the innate immune response are adjuvants, and represent an alternative and/ or complimentary method to vaccines as a means to protect against infection. GABAA receptors are important inhibitory neurotransmitter receptors in the CNS, and recent reports have suggested that they have a role in modulating the immune response in both monocytes and T cells [4,5]. Lubick et al, demonstrated that Securinine modulates the monocyte immune response in a manner distinct from that of Toll-like receptor (TLR) activation, and that Securinine does not trigger TLRs [1]. Securinine represents a novel class of innate immune adjuvant that may have applications in strategies protecting against C. burnetii and other pathogens
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