Abstract:
:Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.
journal_name
Infect Immunjournal_title
Infection and immunityauthors
Elphinstone RE,Besla R,Shikatani EA,Lu Z,Hausladen A,Davies M,Robbins CS,Husain M,Stamler JS,Kain KCdoi
10.1128/IAI.00371-17subject
Has Abstractpub_date
2017-08-18 00:00:00issue
9eissn
0019-9567issn
1098-5522pii
IAI.00371-17journal_volume
85pub_type
杂志文章abstract::Modification of three or four of the five histidine residues in the toxic shock syndrome toxin 1 (TSST-1) with diethylpyrocarbonate did not inhibit the precipitin reaction of the modified TSST-1 with polyvalent antisera to the toxin. Monoclonal antibody 7T did not react with the modified TSST-1, but monoclonal antibod...
journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.57.7.1901-1905.1989
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abstract::The relationship between hypersensitivity and cellular resistance to infection with facultative intracellular parasites was studied in mice by using infection-immunity in tularemia as a model system. Delayed hypersensitivity to antigenic fractions of Francisella tularensis was first detected 6 to 7 days after immuniza...
journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.5.3.311-318.1972
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journal_title:Infection and immunity
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doi:10.1128/IAI.00701-07
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.11.6.1174-1181.1975
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abstract::LT-IIa and LT-IIb, the type II heat-labile enterotoxins of Escherichia coli, are closely related in structure and function to cholera toxin and LT-I, the type I heat-labile enterotoxins of Vibrio cholerae and E. coli, respectively. Recent studies from our group demonstrated that LT-IIa and LT-IIb are potent systemic a...
journal_title:Infection and immunity
pub_type: 杂志文章
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journal_title:Infection and immunity
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doi:10.1128/iai.70.1.412-415.2002
更新日期:2002-01-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.58.4.1106-1113.1990
更新日期:1990-04-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.72.11.6318-6323.2004
更新日期:2004-11-01 00:00:00
abstract::Association of Salmonella typhimurium with MDCK epithelial cells in monolayers, represented primarily by intracellular bacteria after 30 min of contact, with centrifugation followed by vigorous washing, was measured during aerobic and anaerobic growth of the bacteria in brain heart infusion broth. Cell association was...
journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.63.4.1462-1467.1995
更新日期:1995-04-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.36.2.504-509.1982
更新日期:1982-05-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.66.11.5543-5546.1998
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.9.4.764-765.1974
更新日期:1974-04-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/iai.71.6.3206-3212.2003
更新日期:2003-06-01 00:00:00
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journal_title:Infection and immunity
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doi:10.1128/IAI.00025-11
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.61.7.2952-2959.1993
更新日期:1993-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.01434-08
更新日期:2009-04-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.27.3.798-803.1980
更新日期:1980-03-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.67.1.16-21.1999
更新日期:1999-01-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.38.2.694-698.1982
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.60.3.1150-1155.1992
更新日期:1992-03-01 00:00:00
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journal_title:Infection and immunity
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.62.8.3122-3128.1994
更新日期:1994-08-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.37.1.222-226.1982
更新日期:1982-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.25.1.127-132.1979
更新日期:1979-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.57.7.1984-1989.1989
更新日期:1989-07-01 00:00:00
abstract::Infection with Trypanosoma cruzi, the agent of Chagas' disease, may induce antibodies and T cells reactive with self antigens (autoimmunity). Because autoimmunity is generally thought to develop during the chronic phase of infection, one hypothesis is that autoimmunity develops only after long-term, low-level stimulat...
journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/iai.69.9.5643-5649.2001
更新日期:2001-09-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.10.1.284-285.1974
更新日期:1974-07-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.00700-09
更新日期:2009-12-01 00:00:00
abstract::Helicobacter pylori mutants devoid of urease activity fail to colonize the gastric mucosa of mice; however, the effect of decreased levels of urease on colonization has not been examined. The nixA gene, required for full urease activity, encodes a cytoplasmic membrane nickel transporter that imports nickel ions and le...
journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/iai.70.2.685-691.2002
更新日期:2002-02-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.28.1.54-64.1980
更新日期:1980-04-01 00:00:00