The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins

Tripathi, Shweta; Tecle, Tesfaldet; Verma, Anamika; Crouch, Erika C.; White, Mitchell R.; Hartshorn, Kevan L.

doi:10.1099/vir.0.045013-0

Cited by 168 publications

(171 citation statements)

References 33 publications

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“…Hence, the peptide appears to mainly act on the virus itself rather than on the cell to achieve neutralization. In agreement with prior findings obtained with defensins, retrocyclins and LL-37, βA peptides did not inhibit HA activity of IAV [15], [21]. Our results further suggest that the ability of βA42 to cause viral aggregation may in part account for viral inhibition.…”

Section: Discussionsupporting

confidence: 93%

“…We have proposed a similar mechanism for the ability of HNPs and retrocyclins to induce viral aggregation [21], [22]. In contrast, LL-37 does not induce any viral aggregation and inhibits infectivity at a step after viral internalization in the cell [15]. The mechanism of antiviral activity of βA peptides involves reduced viral uptake by epithelial cells, possibly as a result of viral aggregation.…”

Section: Discussionmentioning

confidence: 88%

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Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes

et al. 2014

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Accumulation of β-Amyloid (βA) is a key pathogenetic factor in Alzheimer's disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of βA (βA42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 88%

Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes

et al. 2014

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“…Synergistic activity in triple combinations of lysozyme, lactoferrin, and the protease inhibitor secreted by leukocytes has also been reported (17). Moreover, SP-A and SP-D have been shown to have additive neutralizing activity with cathelicidin against influenza A virus (18). Our results suggest that synergistic interaction of SP-A and SP-B N might be important to overcome Gram-negative bacterial infections in the alveolar airspaces.…”

Section: Discussionmentioning

confidence: 99%

Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN

Coya

Akinbi

Sáenz

et al. 2015

The Journal of Immunology

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The anionic antimicrobial peptide SP-BN, derived from the N-terminal saposin-like domain of the SP-B proprotein, and SP-A are lung anti-infective proteins. SP-A-deficient mice are more susceptible than WT mice to lung infections, and bacterial killing is enhanced in transgenic mice overexpressing SP-BN. Despite their potential anti-infective action, in vitro studies indicate that several microorganisms are resistant to SP-A and SP-BN. In this study we test the hypothesis that these proteins act synergistically or cooperatively to strengthen each other’s microbicidal activity. The results indicate that the proteins acted synergistically in vitro against SP-A- and SP-BN-resistant capsulated Klebsiella pneumoniae (serotype K2) at neutral pH. SP-A and SP-BN were able to interact in solution (Kd = 0.4 μM), which enabled their binding to bacteria with which SP-A or SP-BN alone could not interact. In vivo, we found that treatment of K. pneumoniae-infected mice with SP-A and SP-BN conferred more protection against K. pneumoniae infection than each protein individually. SP-A/SP-BN-treated infected mice showed significant reduction of bacterial burden, enhanced neutrophil recruitment, and ameliorated lung histopathology with respect to untreated infected mice. In addition, the concentrations of inflammatory mediators in lung homogenates increased early in infection in contrast with the weak inflammatory response of untreated K. pneumoniae-infected mice. Finally, we found that therapeutic treatment with SP-A and SP-BN 6h or 24h after bacterial challenge conferred significant protection against K. pneumoniae infection. These studies show novel anti-infective pathways that could drive development of new strategies against pulmonary infections.

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“…It exhibits hemolytic activity [24,25] and is cytotoxic against Gram-positive and Gram-negative bacteria [20,25] as well as tumor cells [26]. LL-37 is also active against viruses [27]. Furthermore, LL-37 can bind and neutralize lipopolysaccharides (LPS) from the cell membrane of Gram-negative bacteria [28,29].…”

Section: Introductionmentioning

confidence: 99%

Interactions of Two Fragments of the Human Antimicrobial Peptide LL-37 with Zwitterionic and Anionic Lipid Monolayers

Dannehl

Brezesinski

Möhwald

2014

Zeitschrift Für Physikalische Chemie

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The interactions of two fragments of the human antimicrobial LL-37 with lipid monolayers at the soft liquid/air interface have been characterized. To model the interaction with mammalian cell membranes, lipid monolayers composed of the zwitterionic DPPC and DOPC were used. To investigate the interaction with bacterial cell membranes, lipid monolayers of anionic DPPG and POPG were used. DPPC and DPPG exhibit a first-order phase transition from the disordered liquid to the ordered condensed state, whereas POPG and DOPC monolayers are in the fluid disordered state at all surface pressures studied. Therefore, the influence of the monolayer phase state on peptide-lipid interactions can be studied. To obtain insight into the peptide structure and their influence on phospholipid membranes, film balance measurements were coupled with surface sensitive Infrared Reflection-Absorption Spectroscopy (IRRAS). The results were compared to CD measurements in bulk. LL-32 is more surface active and can better intercalate into lipid monolayers than LL-20. Even though LL-32 has no cell-selectivity, our results show how the peptide interacts differently with zwitterionic compared to anionic membrane models. The interaction with DPPC monolayers is based on simple intercalation of the peptides between the lipid molecules. However, the peptides bind in a two-step process to DPPG monolayers, which results in a fluidization of the lipid film. This can be related to a membrane thinning.

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The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins

Cited by 168 publications

References 33 publications

Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes

Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes

Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN

Interactions of Two Fragments of the Human Antimicrobial Peptide LL-37 with Zwitterionic and Anionic Lipid Monolayers

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