Sap transporter mediated import and subsequent degradation of antimicrobial peptides in Haemophilus.
Sap transporter mediated import and subsequent degradation of antimicrobial peptides in Haemophilus.
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DOI：
10.1371/journal.ppat.1002360
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Mason KM
中科院分区：
文献类型：
--
作者：
Shelton CL;Raffel FK;Beatty WL;Johnson SM;Mason KM
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. The opportunistic pathogen Haemophilus influenzae is a normal inhabitant of the human nasopharynx, and is commonly implicated in respiratory tract infections, particularly of the middle ear (otitis media), sinuses, and lung (pneumonia, chronic obstructive pulmonary disease and cystic fibrosis). We have identified a multifunctional bacterial uptake system that is required for critical mechanisms of bacterial survival in the host. This Sap transporter system recognizes and transports host immune defense molecules and is involved in uptake of an iron-containing nutrient (heme) that is host-limited, yet required for bacterial growth and survival. We propose that bacteria utilize this, and likely other similar transport systems, for numerous functions that are important for bacterial survival in the host, including host immune evasion and metabolism. Our findings significantly advance our understanding of how single bacterial protein systems co-operate and coordinate multiple functions to equip bacteria to survive and cause disease in the hostile host environment. Our long-range goal is to block this uptake system thereby starving the bacterium of essential nutrients and also promoting clearance by the host immune response. Removal of this important bacterial survival mechanism will thwart the ability for Haemophilus to survive as a pathogen and thus decrease the incidence of disease development.
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影响因子：
6.7
作者：
Attia AS;Benson MA;Stauff DL;Torres VJ;Skaar EP
通讯作者：
Skaar EP
影响因子：
4.8
作者：
Harder, J;Bartels, J;Schröder, JM
通讯作者：
Schröder, JM
影响因子：
4.8
作者：
Frick, IM;Åkesson, P;Björck, L
通讯作者：
Björck, L
影响因子：
82.9
作者：
Chromek, Milan;Slamova, Zuzana;Brauner, Annelie
通讯作者：
Brauner, Annelie
DOI：
10.1006/bbrc.1999.1506
发表时间：
2000-03-24
影响因子：
3.1
作者：
Chen, HY;Weng, SF;Lin, JW
通讯作者：
Lin, JW