Abstract
Antimicrobial peptides (AMPs) contribute to host innate immune defense and are a critical component to control bacterial infection. Nontypeable Haemophilus influenzae (NTHI) is a commensal inhabitant of the human nasopharyngeal mucosa, yet is commonly associated with opportunistic infections of the upper and lower respiratory tracts. An important aspect of NTHI virulence is the ability to avert bactericidal effects of host-derived antimicrobial peptides (AMPs). The Sap (sensitivity to antimicrobial peptides) ABC transporter equips NTHI to resist AMPs, although the mechanism of this resistance has remained undefined. We previously determined that the periplasmic binding protein SapA bound AMPs and was required for NTHI virulence in vivo. We now demonstrate, by antibody-mediated neutralization of AMP in vivo, that SapA functions to directly counter AMP lethality during NTHI infection. We hypothesized that SapA would deliver AMPs to the Sap inner membrane complex for transport into the bacterial cytoplasm. We observed that AMPs localize to the bacterial cytoplasm of the parental NTHI strain and were susceptible to cytoplasmic peptidase activity. In striking contrast, AMPs accumulated in the periplasm of bacteria lacking a functional Sap permease complex. These data support a mechanism of Sap mediated import of AMPs, a novel strategy to reduce periplasmic and inner membrane accumulation of these host defense peptides.
Highlights
Host-derived antimicrobial peptides (AMPs) are typically amphipathic, cationic innate immune defense molecules that target bacterial membranes, disrupt transmembrane potential and trigger cytoplasmic leakage resulting in bacterial cell death [1,2]
The opportunistic pathogen Haemophilus influenzae is a normal inhabitant of the human nasopharynx, and is commonly implicated in respiratory tract infections, of the middle ear, sinuses, and lung
We have identified a multifunctional bacterial uptake system that is required for critical mechanisms of bacterial survival in the host
Summary
Host-derived antimicrobial peptides (AMPs) are typically amphipathic, cationic innate immune defense molecules that target bacterial membranes, disrupt transmembrane potential and trigger cytoplasmic leakage resulting in bacterial cell death [1,2]. Bacteria adapt to resist AMP lethality through a series of countermeasures: remodeling the bacterial outer membrane surface to dampen charge and alter hydrophobicity [1,12,13,14], export of AMPs via multiple transferable resistance (MTR)-mediated efflux pumps [15], secretion of exoproteases for AMP degradation [16], secretion of bacterial molecules to suppress host innate defense [17,18], and release of proteins that function to adsorb extracellular AMPs [19]. NTHI outer membrane remodeling provides a first line of defense against cationic AMPs. Lysenko and colleagues demonstrated that the presence of phosphorylcholine, a phase variable modification of NTHI lipooligosaccharide, alters outer membrane hydrophobicity that confers resistance to the cathelicidin LL-37 [26]. HtrB is required for hexaacylation of NTHI lipid A, mutants lacking htrB are unable to fully acylate their lipid A rendering NTHI susceptible to AMP mediated killing [27]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
