Dampening the Inflammatory Response to P. aeruginosa Infection using a Synthetic Immunomodulatory Peptide

By Dr. Georgina Butler, Research Associate, Overall Lab

Antibiotic resistance and the lack of novel antibiotics pose a real threat to health, and therefore new solutions to fight resistant bacteria are required. The Hancock Lab at UBC is using host defense peptides to tackle the problem of antibiotic resistance: These peptides, which occur naturally, are also known as Innate Defense Regulator (IDR) peptides. IDRs do not kill bacteria directly like traditional antibiotics, but rather, modulate our innate immune system to downplay excessive inflammation and enhance protective immune functions. Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia. P. aeruginosa lung infections are particularly problematic in cystic fibrosis patients whose lungs are already compromised, and the infections are not easily treated due to increasing drug resistance of this Gram negative bacterium.

In a recent study published in Infection and Immunity, Kelli Wuerth, a former graduate student in the Hancock lab, used a 12 amino acid synthetic host defense peptide, IDR-1002, in a murine model of acute P. aeruginosa lung infection. Changes in gene expression in lungs and blood following infection with P. aeruginosa were analysed by RNA sequencing followed by comprehensive bioinformatics studies to determine  which pathways are affected. Bacterial infection altered the expression of over 4700 genes in lungs and over 1300 in blood (about half upregulated and half downregulated in both tissues) with 59 pathways being differentially regulated. These included hemostasis, axon guidance (cell migration), and chemokine signalling. As expected, the upregulated proteins that included, for example, chemokines and matrix metalloproteinases, were involved in inflammation and immune responses. In keeping with the RNA-seq data, neutrophils, white blood cells that destroy bacteria, were increased in the infected lungs.

Mice treated with IDR-1002 without any infection showed few changes in gene expression, indicating the potential safety of this compound. When mice were treated with IDR-1002 prophylactically, before P. aeruginosa infection, the altered expression of genes induced by the bacterial infection was greatly reduced (2111 genes vs 4739 in lungs). Also, the inflammatory-response genes were downregulated, there were reduced proinflammatory chemokines and cytokines and fewer bacteria in the lungs. The types of white blood cells present were altered, i.e., there were fewer neutrophils and more monocytes/macrophages, cells that help to resolve inflammation by clearing dead neutrophils after an immune response.

Thus, treatment with IDR-1002 prior to infection with P. aeruginosa dampened the overwhelming inflammatory response whilst reducing the bacterial burden in the lungs. This is important since it is often the exaggerated host response to infection that causes the damage or disease, rather than the infection itself. The results of this study suggest that IDR-1002 primes the immune response to respond to infection. Future research in the Hancock lab will address whether IDR-1002 could be used as an adjuvant or in combination with antibiotics to improve the host response and promote the elimination of P. aeruginosa lung infection.

  1. Wuerth et al. Characterization of Host Responses during Pseudomonas aeruginosa Acute Infection in the Lungs and Blood and after Treatment with the Synthetic Immunomodulatory Peptide IDR-1002. Infection and Immunity 87 (1), (2018).