Effects of mycobacteria or HIV on the host antimicrobial peptide cathelicidin

Abstract

The incidence of nontuberculous mycobacteria (NTM) infections is rising particularly in immunocompromised hosts. Understanding host‐pathogen interactions that allow NTM to gain a foothold is crucial. Antimicrobial peptides (AMPs) are novel host innate antibiotics whose increased production at sites of infection limits bacterial growth and dissemination. The human AMP cathelicidin (LL‐37) is found at mucosal surfaces, neutrophils and bodily fluids and is bactericidal for a variety of bacteria. We tested the activity of LL‐37 against a panel of 4 clinical and 1 environmental NTM isolates and found that although synthetic LL‐37 killed gram‐negative E. coli, it had no effect on NTM. Importantly, whereas the LL‐37 in E. coli culture media (CM) retained antibacterial activity, LL‐37 in NTM CM did not, suggesting a soluble factor in the NTM CM inactivates LL‐37. This factor is partially resistant to heat‐inactivation and is found in the de‐lipidated fraction of NTM cell wall and whole cell extracts. These findings suggest a novel NTM virulence mechanism for evasion of innate immunity. We then measured circulating LL‐37 levels in plasma from HIV−/+ donors. LL‐37 levels were considerably lower in HIV+ compared to HIV‐ (p=0.015). In contrast, PBMC from HIV+ contained more intracellular LL‐37 compared to HIV‐ (p=0.004). Neutralization of LL‐37 activity or altered levels will have significant clinical consequences.