Microbial drug resistance is a serious threat to the global health. It is essential to explore new anti-infective strategies that avoid the emergence of new drug resistance. One promising approach is the host-directed immunotherapy, which aims at boosting the innate immunity to prevent/treat infectious diseases. The approach avoids the emergence of resistance by targeting the host instead of the pathogen. Several host-directed immunotherapeutics are currently in clinical use, including monophosphoryl lipid A (MPL), which is used as a vaccine adjuvant. While the concept is promising, there is one major challenge in the development of new immunotherapeutics. Stimulation of the innate immunity activates the signaling pathways for inflammation as well as for protective immunity. Although inflammation is important for rapid eradication of invading pathogens, its hyperactivation can be very harmful to the host. Thus, the challenge is how to control inflammation without compromising protective immunity. To find a new approach to safely promote protective immunity, the proposed SC3 project will examine Juzen-taiho-to (JTT), an immune-boosting herbal formulation with long- tested clinical efficacy and safety. Recently, our group found that the immunostimulatory activity of JTT arises from lipopolysaccharides (LPSs) of plant-associated bacteria. Since LPSs are pro-inflammatory toxins, JTT must have a mechanism to effectively control the pro-inflammatory pathway. The objective of the proposed SC3 project is to clarify the mechanism by which pro-inflammatory effect of LPSs is controlled in JTT. The central hypothesis is that the pro-inflammatory effect is controlled by dual mechanisms, namely, (1) the LPSs in JTT, which is administered orally, are hydrolyzed by the stomach acid to benign forms that can still promote protective immunity, and (2) anti-inflammatory phytochemicals in JTT selectively attenuate the pro- inflammatory effect without compromising protective immunity. Both of these mechanisms are based on our strong preliminary results. To accomplish the objective, the following aims will be pursued. Aim 1: Characterize the structures and immunological effects of acid-treated LPSs in JTT. A combination of mass spectrometry cell-based assays, and in vivo cytokine profiling will be employed to characterize the impact of acid-treatment on the structures and immunological effects of phytobacterial LPSs. Aim 2: Determine the roles of anti- inflammatory phytochemicals in JTT. Here, anti-inflammatory phytochemicals will be subjected to cell-based assays and in vivo cytokine profiling to determine their effects on inflammation and other immunological pathways. It is our expectation that the proposed work will reveal a time-tested, but hitherto uncharacterized, approach to generate safe immunotherapeutics, which will expand our ability to develop new anti-infective strategies that avoid microbial resistance. The developmental objective of the PI is to build a strong collaborative research program focused on the discovery of novel immunomodulatory agents. Based on the results obtained from the proposed SC3 project, the collaborative team will aggressively seek extramural funding for future studies.

SC3GM130409

2020-09-15

2024-08-31