Harnessing the immunomodulatory effect of drugs for a desired immune response

The global rise of antibiotic-resistant bacteria exceeds the rate of new antibiotic discovery and leads to an urgent need for alternative therapeutic strategies. Host-directed therapies (HDT) hold the promise to optimize the immune response towards a more favorable infection outcome to the host. Surprisingly, recent evidence suggest that certain antibiotics also impact host immune processes, with either beneficial or deleterious effect that is independent of direct pathogen control. In this study, we aim to systematically screen a large number of approved therapeutic drugs, including all classes of antibiotics as well as commonly used anti-viral, anti-fungal, and anti-parasite drugs. The screen is conducted using human peripheral blood mononuclear cells (PBMCs), which enable high-throughput testing of drug effects in the context of an intact immune system and in an animal-free model. As an output, we measured changes in the secretion of 12 cytokines. We tested the immunomodulatory effect of a large panel of drugs on naive PBMCs as well as stimulated PBMCs in order to check if immunomodulatory effects are dependent on cells activation. Our data suggest that known drugs with immunomodulatory effects tested strongly in the assay, validating our approach. In addition, our screen suggests new robust hits for drugs with strong immunomodulatory effect. We plan to address the following questions for the hits from the screen: Under which conditions does the drug affect the host cells? Which cellular pathways are affected, and what are the immunomodulatory consequences of drugs beyond pathogen clearance?