Modulating immunity as a therapy for bacterial infections

Key Points Immunomodulatory therapies for the treatment of bacterial infections act on the host rather than the pathogen and are intended for use as adjunctive treatments together with conventional antimicrobial drugs, particularly in the face of increasing antibiotic resistance. Toll-like receptor (TLR) agonists can be used to stimulate innate immune responses against bacterial infections and as components of vaccine adjuvants. By contrast, there are challenges facing the ongoing development of TLR antagonists for the treatment of sepsis. NOD-like receptor (NLR) agonists can also be applied as adjuvants and adjunctive anti-infectious therapies. Innate defence regulator (IDR) peptides are another class of compound in clinical trials for the prevention and treatment of infections, and are being developed for both their capacity to stimulate some mechanisms of antimicrobial immunity and their anti-inflammatory properties. The potential of using bacterial signalling molecules, which are used in quorum sensing, to modify virulence could be explored as an anti-infective strategy. Given the rise of antibiotic resistance and the decreasing rate of discovery of new antimicrobials, exploring new paradigms for antimicrobial therapy is essential. Here, Hancock, Nijnik and Philpott describe the promise of one such alternative approach: host-directed immunomodulatory therapies for enhancing protective antimicrobial immunity. Despite our efforts to halt the increase and spread of antimicrobial resistance, bacteria continue to become less susceptible to antimicrobial drugs over time, and rates of discovery for new antibiotics are declining. Thus, it is essential to explore new paradigms for anti-infective therapy. One promising approach involves host-directed immunomodulatory therapies, whereby natural mechanisms in the host are exploited to enhance therapeutic benefit. The objective is to initiate or enhance protective antimicrobial immunity while limiting inflammation-induced tissue injury. A range of potential immune modulators have been proposed, including innate defence regulator peptides and agonists of innate immune components such as Toll-like receptors and NOD-like receptors.