Differential Microbicidal Effects of Human Histone Proteins H2A and H2B on
            <i>Leishmania</i>
            Promastigotes and Amastigotes

Wang, Yingwei; Chen, Yang; Luo, Xin; Beverley, Stephen M.; Carlsen, Eric D.; Popov, Vsevolod L.; Chang, Kwang-Poo; Wang, Ming; Soong, Lynn

doi:10.1128/iai.00658-10

Cited by 65 publications

(67 citation statements)

References 56 publications

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“…However, we observed that amastigotes are highly resistant to neutrophil microbicidal mechanisms and induce anti-inflammatory IL-10 release, while promastigotes trigger more TNF-␣ secretion and are more susceptible to killing by neutrophils. Collectively, this study supports and expands upon our previous understanding of the role of neutrophils during leishmaniasis (10,22) and highlights the possible cross talk between neutrophils and other immune cells involved in parasite recognition and clearance.…”

Section: Discussionsupporting

confidence: 67%

“…However, the immunological ramifications of amastigote-neutrophil interactions remain largely uncharacterized. We have recently demonstrated that L. amazonensis amastigotes are highly resistant to the antimicrobial effects of purified human histone proteins (22), which are known to be released together with other microbicidal agents when neutrophils undergo NETosis (23). Currently, it is unclear whether neutrophils recognize amastigotes and influence amastigote clearance or persistence (24).…”

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confidence: 99%

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Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms

et al. 2013

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Neutrophils are the first cells to infiltrate to the site of Leishmania promastigote infection, and these cells help to reduce parasite burden shortly after infection is initiated. Several clinical reports indicate that neutrophil recruitment is sustained over the course of leishmaniasis, and amastigote-laden neutrophils have been isolated from chronically infected patients and experimentally infected animals. The goal of this study was to compare how thioglycolate-elicited murine neutrophils respond to L. amazonensis metacyclic promastigotes and amastigotes derived from axenic cultures or from the lesions of infected mice. Neutrophils efficiently internalized both amastigote and promastigote forms of the parasite, and phagocytosis was enhanced in lipopolysaccharide (LPS)-activated neutrophils or when parasites were opsonized in serum from infected mice. Parasite uptake resulted in neutrophil activation, oxidative burst, and accelerated neutrophil death. While promastigotes triggered the release of tumor necrosis factor alpha (TNF-␣), uptake of amastigotes preferentially resulted in the secretion of interleukin-10 (IL-10) from neutrophils. Finally, the majority of promastigotes were killed by neutrophils, while axenic culture-and lesion-derived amastigotes were highly resistant to neutrophil microbicidal mechanisms. This study indicates that neutrophils exhibit distinct responses to promastigote and amastigote infection. Our findings have important implications for determining the impact of sustained neutrophil recruitment and amastigote-neutrophil interactions during the late phase of cutaneous leishmaniasis.

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Section: Discussionsupporting

confidence: 67%

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confidence: 99%

Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms

et al. 2013

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“…In an analysis of histone toxicity to L. major, a cutaneous leishmaniasis-causing agent, it was demonstrated that lpg1 Ϫ mutants, which lack LPG, were equally as susceptibility to histone killing as the wild-type promastigotes (48). Also, preincubation of histone with purified L. major LPG reduced the rate of death of wild-type promastigotes without affecting lpg1 Ϫ mutants (48). LPG is highly polymorphic, varying among different Leishmania species and even strains (45).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the role of LPG in protecting parasites from NET killing mediated by histones associated with these traps is complex and remains to be established. Moreover, Leishmania surface metalloprotease (GP63) seems to participate in promastigote escape from NET histone killing, since it has been shown that knockdown of L. amazonensis GP63 increased parasite susceptibility to histone killing (48).…”

Section: Discussionmentioning

confidence: 99%

3′-Nucleotidase/Nuclease Activity Allows Leishmania Parasites To Escape Killing by Neutrophil Extracellular Traps

et al. 2014

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Leishmaniasis is a widespread neglected tropical disease caused by parasites of the Leishmania genus. These parasites express the enzyme 3=-nucleotidase/nuclease (3=NT/NU), which has been described to be involved in parasite nutrition and infection. Bacteria that express nucleases escape the toxic effects of neutrophil extracellular traps (NETs). Hence, we investigated the role of 3=NT/NU in Leishmania survival of NET-mediated killing. Promastigotes of Leishmania infantum were cultured in high-phosphate (HP) or low-phosphate (LP) medium to modulate nuclease activity. We compared the survival of the two different groups of Leishmania during interaction with human neutrophils, assessing the role of neutrophil extracellular traps. As previously reported, we detected higher nuclease activity in parasites cultured in LP medium. Both LP and HP promastigotes were capable of inducing the release of neutrophil extracellular traps from human neutrophils in a dose-and time-dependent manner. LP parasites had 2.4 times more survival than HP promastigotes. NET disruption was prevented by the treatment of the parasites with ammonium tetrathiomolybdate (TTM), a 3=NT/NU inhibitor. Inhibition of 3=NT/NU by 3=-AMP, 5=-GMP, or TTM decreased promastigote survival upon interaction with neutrophils. Our results show that Leishmania infantum induces NET release and that promastigotes can escape NET-mediated killing by 3=-nucleotidase/nuclease activity, thus ascribing a new function to this enzyme. N eutrophils are short-lived cells and the most abundant leukocytes in the blood circulation; they constitute one of the first lines of defense against invading microorganisms (1). These granulocytes can kill microorganisms by phagocytosis, degranulation, and neutrophil extracellular traps (NETs). NETs are weblike structures composed of chromatin, granules, and cytoplasmic proteins that are extruded when neutrophils undergo NETosis, a unique cell death mechanism (2-5). However, recent work challenges NETosis as a cell death mechanism because live neutrophils were detected after NET extrusion in in vivo studies (6). NETs function by killing and containing pathogens, thereby preventing the pathogen's dissemination through the organism. In addition, some studies have indicated that NETs play a role in autoimmune diseases (7-10).A diverse group of stimuli has been described as activating NETosis (5, 11). Among the parasites, Leishmania promastigotes were demonstrated to activate release of NETs (12, 13). Leishmania amazonensis promastigotes interact intimately with NETs and are killed by web-associated histones (12). However, although promastigotes of Leishmania donovani trigger NET release, these parasites escape the toxicity of NETs (13). Groups of microorganisms have evolved different mechanisms of escaping the toxic effects of NETs. Streptococcus pneumoniae, group A Streptococcus, Streptococcus agalactiae, Staphylococcus aureus, and Vibrio cholerae express endonucleases that efficiently degrade DNA filaments from NETs, allowing these bacteria...

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“…Immunoneutralization of histones can abrogate killing of the parasites, supporting the antiparasitic activity of histones. In addition, purified H2A and H2B, but not H1, can kill Leishmania promastigotes [33].…”

Section: Antiparasitic Activitymentioning

confidence: 99%

Histones as Mediators of Host Defense, Inflammation and Thrombosis

et al. 2016

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Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of animal hosts. In addition, histones can trigger inflammatory responses in some cases acting through Toll-like receptors or inflammasome pathways. Extracellular histones mediate organ injury (lung, liver), sepsis physiology, thrombocytopenia and thrombin generation and some proteins can bind histones and reduce these potentially harmful effects.

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Differential Microbicidal Effects of Human Histone Proteins H2A and H2B on Leishmania Promastigotes and Amastigotes

Cited by 65 publications

References 56 publications

Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms

Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms

3′-Nucleotidase/Nuclease Activity Allows Leishmania Parasites To Escape Killing by Neutrophil Extracellular Traps

Histones as Mediators of Host Defense, Inflammation and Thrombosis

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