Phase-Variable Expression of
            <i>lptA</i>
            Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

Kandler, Justin L.; Joseph, Sandeep J.; Balthazar, Jacqueline T.; Dhulipala, Vijaya; Read, Timothy D.; Jerse, Ann E.; Shafer, William M.

doi:10.1128/aac.03108-14

Cited by 22 publications

(19 citation statements)

References 13 publications

(18 reference statements)

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“…We now provide evidence that Gc producing PEA-lipid A not only have a survival advantage when associated with phagocytes, but that they most likely also have an enhanced ability to dysregulate autophagy in infected macrophages and can influence host cell chemokine production. Taken together, the present work and past studies [ 11 , 12 , 14 , 16 ] implicate Gc PEA-lipid A as a Gc virulence factor.…”

Section: Introductionsupporting

confidence: 86%

Phosphoethanolamine Modification of Neisseria gonorrhoeae Lipid A Reduces Autophagy Flux in Macrophages

et al. 2015

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Autophagy, an ancient homeostasis mechanism for macromolecule degradation, performs an important role in host defense by facilitating pathogen elimination. To counteract this host defense strategy, bacterial pathogens have evolved a variety of mechanisms to avoid or otherwise dysregulate autophagy by phagocytic cells so as to enhance their survival during infection. Neisseria gonorrhoeae is a strictly human pathogen that causes the sexually transmitted infection, gonorrhea. Phosphoethanolamine (PEA) addition to the 4' position of the lipid A (PEA-lipid A) moiety of the lipooligosaccharide (LOS) produced by gonococci performs a critical role in this pathogen’s ability to evade innate defenses by conferring decreased susceptibility to cationic antimicrobial (or host-defense) peptides, complement-mediated killing by human serum and intraleukocytic killing by human neutrophils compared to strains lacking this PEA decoration. Heretofore, however, it was not known if gonococci can evade autophagy and if so, whether PEA-lipid A contributes to this ability. Accordingly, by using murine macrophages and human macrophage-like phagocytic cell lines we investigated if PEA decoration of gonococcal lipid A modulates autophagy formation. We report that infection with PEA-lipid A-producing gonococci significantly reduced autophagy flux in murine and human macrophages and enhanced gonococcal survival during their association with macrophages compared to a PEA-deficient lipid A mutant. Our results provide further evidence that PEA-lipid A produced by gonococci is a critical component in the ability of this human pathogen to evade host defenses.

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Section: Introductionsupporting

confidence: 86%

Phosphoethanolamine Modification of Neisseria gonorrhoeae Lipid A Reduces Autophagy Flux in Macrophages

et al. 2015

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“…Kandler et al found that high-frequency mutation in a polynucleotide repeat of the lptA gene influences bacterial resistance. An lptA mutant is highly susceptible to cationic peptides [ 122 ]. In addition, the PEA-modification of lipid A has an immunostimulatory role during infection [ 123 ].…”

Section: Mechanisms Of Action Of Antimicrobial Peptides and Genetimentioning

confidence: 99%

Antimicrobial Peptides in 2014

et al. 2015

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This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.

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“…Many of the LOS outer core biosynthetic genes are phase variable, and components of LOS can be enzymatically modified (Gotschlich, 1994;Shell et al, 2002;Cox et al, 2003). One of these modifications is the addition of phosphoethanolamine (PEA) to the 4′ phosphate on lipid A, catalysed by the phase variable LOS PEA transferase A (LptA) (Cox et al, 2003;Lewis et al, 2009;Kandler et al, 2014). lptA mutant Gc is more susceptible to bacteriolysis by human complement, and both Gc and N. meningitidis lacking lptA are more susceptible to killing by cationic antimicrobial proteins (CAMPs) (Tzeng et al, 2005;Lewis et al, 2009;.…”

Section: Introductionmentioning

confidence: 99%

The lipooligosaccharide-modifying enzyme LptA enhances gonococcal defence against human neutrophils

Handing

Criss

2015

Cell Microbiol

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Summary Infection with Neisseria gonorrhoeae (Gc) is marked by an influx of neutrophils to the site of infection. Despite a robust immune response, viable Gc can be recovered from neutrophil-rich gonorrheal secretions. Gc enzymatically modifies the lipid A portion of lipooligosaccharide by the addition of phosphoethanolamine (PEA) to the phosphate group at the 4’ position. Loss of LptA, the enzyme catalyzing this reaction, increases bacterial sensitivity to killing by human complement and cationic antimicrobial peptides. Here, we investigated the importance of LptA for interactions between Gc and human neutrophils. We found that lptA mutant Gc was significantly more sensitive to killing by human neutrophils. Three mechanisms underlie the increased sensitivity of lptA mutant Gc to neutrophils. 1) lptA mutant Gc is more likely to reside in mature phagolysosomes than LptA-expressing bacteria. 2) lptA mutant Gc is more sensitive to killing by components found in neutrophil granules, including CAP37/azurocidin, human neutrophil peptide 1, and the serine protease cathepsin G. 3) lptA mutant Gc is more susceptible to killing by antimicrobial components that are exocytosed from neutrophils, including those decorating neutrophil extracellular traps. By increasing the resistance of Gc to the bactericidal activity of neutrophils, LptA-catalyzed modification of lipooligosaccharide enhances survival of Gc from the human inflammatory response during acute gonorrhea.

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Phase-Variable Expression of lptA Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

Cited by 22 publications

References 13 publications

Phosphoethanolamine Modification of Neisseria gonorrhoeae Lipid A Reduces Autophagy Flux in Macrophages

Phosphoethanolamine Modification of Neisseria gonorrhoeae Lipid A Reduces Autophagy Flux in Macrophages

Antimicrobial Peptides in 2014

The lipooligosaccharide-modifying enzyme LptA enhances gonococcal defence against human neutrophils

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