Abstract
Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15–30 µg/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.
Highlights
Mycobacterium tuberculosis (Mtb), the cause of human tuberculosis (TB) is one of the major killers among the infectious organisms causing around 1.5 to 3 million deaths per year [1]
We were able to demonstrate that HH2, like 1002 and 1018, induced large amounts of the macrophage/monocyte chemokines macrophage chemotactic protein-1 (MCP-1) and Gro-a in human peripheral blood mononuclear cells (Table 1) and was protective when applied prophylactically in an invasive Staphylococcus aureus model in mice (Fig. 1; cf. the control peptide HH-17 - KIWVRWK-NH2 - that showed minimal immunomodulatory activity, Table 1)
The present study demonstrates that two different Innate Defence Regulator (IDR) peptides showed notable anti-infective activity in an animal model against both a drug-sensitive and multi drug-resistant (MDR) strain (Fig. 4,5)
Summary
Mycobacterium tuberculosis (Mtb), the cause of human tuberculosis (TB) is one of the major killers among the infectious organisms causing around 1.5 to 3 million deaths per year [1]. It has been estimated that one third of the human population carries Mtb and 10% of these people will develop active disease at some time in their lives, creating an enormous reservoir. In the past 40 years there has no broadly successful new Mtb drug developed. There is a strong incentive to develop new treatments for TB and/or improve the ones currently in use to enable significant reductions in the duration of therapy and enhance patient survival. In addition to the development of new anti-tubercular drugs, immunotherapy has strong potential in treatment of this significant disease [2]
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