Mouse neutrophils lack defensins

Eisenhauer, Patricia B.; Lehrer, RI

doi:10.1128/iai.60.8.3446-3447.1992

Cited by 198 publications

(85 citation statements)

References 13 publications

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“…A recent study demonstrated that LL-37 was capable of a dosedependent suppression of HIV reverse transcriptase activity [133]. This study also demonstrated that this function was retained by a 16 amino acid fragment of LL-37 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), with implications for production of smaller synthetic analogues. Thus, epithelial expression of LL-37 has been proposed to contribute to local protection against HIV-1 infection.…”

Section: Hiv-1mentioning

confidence: 73%

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Cationic Host Defence Peptides: Potential as Antiviral Therapeutics

2013

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There is a pressing need to develop new antiviral treatments; of the 60 drugs currently available, half are aimed at HIV-1 and the remainder target only a further six viruses. This demand has led to the emergence of possible peptide therapies, with 15 currently in clinical trials. Advancements in understanding the antiviral potential of naturally occurring host defence peptides highlights the potential of a whole new class of molecules to be considered as antiviral therapeutics. Cationic host defence peptides, such as defensins and cathelicidins, are important components of innate immunity with antimicrobial and immunomodulatory capabilities. In recent years they have also been shown to be natural, broad-spectrum antivirals against both enveloped and non-enveloped viruses, including HIV-1, influenza virus, respiratory syncytial virus and herpes simplex virus. Here we review the antiviral properties of several families of these host peptides and their potential to inform the design of novel therapeutics.

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Section: Hiv-1mentioning

confidence: 73%

“…In contrast, HD5 and 6 are expressed by Paneth cells of the small intestine [15,16] and epithelial cells of the female genital tract [12,17,18]. Interestingly, although mice express a large number of intestinal a-defensins (cryptdins) [19], in contrast to humans they do not express a-defensins in their neutrophils [20,21].…”

Section: A-defensinsmentioning

confidence: 99%

Cationic Host Defence Peptides: Potential as Antiviral Therapeutics

2013

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“…They are also expressed by monocytes, macrophages, and certain DCs, and a subset of β-defensins are only expressed in the male reproductive tract [26,28]. Although there are commonalities in expression patterns of defensins in humans and other species, one important difference relevant for experimental models of infectious disease is that mice lack myeloid α-defensins [29,30].…”

Section: Defensin Structure Expression and Physiologic Concentrationsmentioning

confidence: 99%

Antiviral Mechanisms of Human Defensins

Wilson

Wiens

Smith

2013

Journal of Molecular Biology

269

331

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Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, α- and β-defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data is known for α-defensins, molecular details for β-defensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis.

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“…Human -defensin genes exist and are transcribed, but the human genes and transcripts contain a premature stop codon that aborts translation (8), unless the cells are induced to read through the stop codon (49). Curiously, whereas rat and human PMN contain multiple ␣-defensins, murine PMN contain none (15,40).Retrocyclins inactivate anthrax lethal toxin and kill B. anthracis bacilli in vitro (51), and they are more effective than HNP 1 to 3 in preventing B. anthracis spores from germinating and commencing vegetative growth (51). Based on these findings, we performed additional in vitro studies with retrocyclins and B. anthracis and tested their ability to protect mice challenged in vivo with B. anthracis spores.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Humanized θ-Defensins (Retrocyclins) Enhance Macrophage Performance and Protect Mice from Experimental Anthrax Infections

Welkos

Cote

Hahn

et al. 2011

Antimicrob Agents Chemother

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Retrocyclins are humanized versions of the -defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal factor. We now report that retrocyclins are extensively bound by components of native mouse, human, and fetal calf sera, that heat-inactivated sera show greatly enhanced retrocyclin binding, and that native and (especially) heat-inactivated sera greatly reduce the direct activities of retrocyclins against spores and vegetative cells of B. anthracis. Nevertheless, we also found that retrocyclins protected mice challenged in vivo by subcutaneous, intraperitoneal, or intranasal instillation of B. anthracis spores. Retrocyclin 1 bound extensively to B. anthracis spores and enhanced their phagocytosis and killing by murine RAW264.7 cells. Based on the assumption that spore-bound RC1 enters phagosomes by "piggyback phagocytosis," model calculations showed that the intraphagosomal concentration of RC1 would greatly exceed its extracellular concentration. Murine alveolar macrophages took up fluorescently labeled retrocyclin, suggesting that macrophages may also acquire extracellular RC1 directly. Overall, these data demonstrate that retrocyclins are effective in vivo against experimental murine anthrax infections and suggest that enhanced macrophage function contributes to this property.The infectious form of Bacillus anthracis is the dormant spore. To cause anthrax, this spore must germinate, grow within the host, form a capsule, and release various exotoxins, which include lethal toxin, edema toxin, and anthrolysin (18,23,39,47). Without effective treatment, B. anthracis can proliferate and cause death. Agents that neutralize B. anthracis toxins, permanently prevent germination of B. anthracis spores, and/or kill or control vegetative B. anthracis growth could protect against this natural pathogen and class A bioterrorism agent.Defensins and defensin-like peptides are components of the innate immune system. (21, 31). Three defensin subfamilies, designated ␣, ␤, and , exist among mammals. Three ␣-defensins, called human neutrophil peptides (HNPs) 1, 2, and 3, collectively constitute 5 to 7% of the total protein of human neutrophils (polymorphonuclear cells [PMN]) (33) and can kill B. anthracis bacilli, inactivate anthrax lethal toxin in vitro, and protect mice injected with anthrax lethal toxin in vivo (27). The same ␣-defensins also play an important role in the potent anti-B. anthracis activity of human neutrophils (37). Retrocyclins, the synthetic peptides examined in this study, are humanized analogs of the -defensin peptides found in the leukocytes of rhesus macaques and other nonhuman primates (22, 45). -Defensin genes arose by mutation of ␣-defensin genes (22,40,45). Human -defensin genes exist and are transcribed, but the human genes and transcripts contain a premature s...

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Mouse neutrophils lack defensins

Cited by 198 publications

References 13 publications

Cationic Host Defence Peptides: Potential as Antiviral Therapeutics

Cationic Host Defence Peptides: Potential as Antiviral Therapeutics

Antiviral Mechanisms of Human Defensins

Humanized θ-Defensins (Retrocyclins) Enhance Macrophage Performance and Protect Mice from Experimental Anthrax Infections

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