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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.

Abstract

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.

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Figure 1: Pattern recognition receptors of the innate immune system and their signalling pathways.
Figure 2: Bacterial quorum sensing second-messenger molecules stimulate innate immune activation in mammalian cells.

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Acknowledgements

The authors gratefully acknowledge funding from the Canadian Institutes for Health Research (CIHR) for their research on immunomodulators. R.E.W.H. holds a Canada Research Chair. A.N. was a recipient of postdoctoral fellowships from the CIHR and the Michael Smith Foundation. D.J.P. is a Howard Hughes International Research Scholar.

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Robert E. W. Hancock, Anastasia Nijnik & Dana J. Philpott

Modulating immunity as a therapy for bacterial infections

Nature Reviews Microbiology 10, 243–254 (2012); doi:10.1038/nrmicro2745

Robert E. W. Hancock is developing innate defence regulator (IDR) peptides as immune modulators and treatments for infection and inflammation, and has assigned several patents covering his research to his employer, the University of British Columbia (UBC), Canada. All of the recently derived peptides must be made available free of charge to developing countries under the terms of the Grand Challenges in Global Health Program. Two of the IDR peptides covered in these patents have been licensed to Elanco for use against infections of animals. Hancock is consulting with Elanco to advise them on the development of these peptides. One IDR peptide has been selected by the Cystic Fibrosis Canada Translational Initiative for development as a treatment for hyperinflammatory lung disease in cystic fibrosis. A peptide derived from those out-licensed by UBC to Inimex Pharmaceuticals has completed Phase I clinical trials for unexplained fevers in chemotherapy patients. Hancock was a co-founder of Inimex and remains a minor shareholder, but has no current formal links to this company. Other peptides have been licensed to the Pan-Provincial Vaccine Enterprise in Saskatchewan, Canada, for use as components of an adjuvant formulation for vaccines against RSV infections in animals.

Anastasia Nijnik and Dana J. Philpott declare no competing financial interests.

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Glossary

Adjunctive therapies

Treatments that are used together with a primary treatment to increase its potency. For example, an immunomodulatory treatment can be adjunctive to primary treatment with an antibiotic.

Pattern recognition receptors

(PRRs). Host receptors, such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs), that can sense pathogen signatures (pathogen-associated molecular patterns) and endogenous damage-associated molecular patterns and then initiate signalling cascades that lead to an innate immune response. These proteins can be membrane-bound receptors (such as TLRs) or cytoplasmic receptors (such as NLRs).

Bacteriocin

A small ribosomally synthesized, heat-stable peptide that is produced by one bacterium and is active against another bacterium, either of the same species (narrow spectrum) or across species and even genera (broad spectrum).

Inflammasome

A molecular complex of several proteins that, following its assembly, cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18, thereby producing active IL-1β and IL-18.

TH1 immunity

An immune response that is characterized by a subset of T helper (TH) cells that secrete a particular set of cytokines, including interleukin2 and interferon-γ, the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.

Freund's complete adjuvant

A mixture of heat-killed mycobacteria with mineral oil. When animals are immunized with antigen mixed with Freund's complete adjuvant, a strong immune response to the antigen is induced.

TH2 immunity

A type of immune response that is characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, and by humoral immunity mediated by B cells and immunoglobulin A (IgA) and IgE antibody classes; this response is mediated by T helper 2 (TH2) cells.

Intestinal crypts

Tubular invaginations of the intestinal epithelium. Crypts contain intestinal stem cells that continuously divide and are the source of all intestinal epithelial cells. Paneth cells are found at the base of the crypts and produce antimicrobial proteins and peptides, including phospholipase A2 and defensins.

Dendritic cells

Professional antigen-presenting cells that are found in the T cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched, or dendritic, morphology and are the most potent stimulators of naive T cell responses.

Quorum sensing

A microbial cell–cell communication process that uses small signalling molecules to allow bacteria to coordinate population behaviour, in part in response to cell density.

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Hancock, R., Nijnik, A. & Philpott, D. Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10, 243–254 (2012). https://doi.org/10.1038/nrmicro2745

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