Effective Adjunctive Therapy by an Innate Defense Regulatory Peptide in a Preclinical Model of Severe Malaria

被引：66

作者：

Achtman, Ariel H. ^{[1
,2
]}

Pilat, Sandra ^{[1
,2
]}

Law, Charity W. ^{[1
,2
]}

Lynn, David J. ^{[3
,4
,5
]}

Janot, Laure ^{[3
]}

Mayer, Matt L. ^{[3
]}

Ma, Shuhua ^{[3
]}

Kindrachuk, Jason ^{[3
]}

Finlay, B. Brett ^{[6
]}

Brinkman, Fiona S. L. ^{[4
]}

Smyth, Gordon K. ^{[1
,7
]}

Hancock, Robert E. W. ^{[3
]}

Schofield, Louis ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia

[3] Univ British Columbia, Ctr Microbial Dis & Immun Res, Vancouver, BC V6T 1Z4, Canada

[4] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada

[5] AGRIC, Anim & Biosci Res Dept, Dunsany, Meath, Ireland

[6] Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada

[7] Univ Melbourne, Dept Math & Stat, Melbourne, Vic 3010, Australia

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2012年 / 4卷 / 135期

基金：

英国医学研究理事会;

关键词：

TUMOR-NECROSIS-FACTOR; PLASMODIUM-FALCIPARUM MALARIA; CEREBRAL MALARIA; MONOCLONAL-ANTIBODY; IFN-GAMMA; T-CELLS; CHILDREN; INTERFERON; EXPRESSION; RESPONSES;

D O I：

10.1126/scitranslmed.3003515

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. We assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (IDR) peptides, based on host defense peptides. The Plasmodium berghei ANKA model of experimental cerebral malaria was adapted to use as a preclinical screen by combining late-stage intervention in established infections with advanced bioinformatic analysis of early transcriptional changes in co-regulated gene sets. Coadministration of IDR-1018 with standard first-line antimalarials increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. Thus, IDR peptides provided host-directed adjunctive therapy for severe disease in combination with antimalarial treatment.

引用

页数：10

共 61 条

[1] Increased levels of inflammatory mediators in children with severe Plasmodium falciparum malaria with respiratory distress [J].

Awandare, Gordon A. ;

Goka, Bamenla ;

Boeuf, Philippe ;

Tetteh, John K. A. ;

Kurtzhals, Jorgen A. L. ;

Behr, Charlotte ;

Akanmori, Bartholomew D. .

JOURNAL OF INFECTIOUS DISEASES, 2006, 194 (10) :1438-1446

[2] Control of pathogenic CD8+ T cell migration to the brain by IFN-γ during experimental cerebral malaria [J].

Belnoue, E. ;

Potter, S. M. ;

Rosa, D. S. ;

Mauduit, M. ;

Gruener, A. C. ;

Kayibanda, M. ;

Mitchell, A. J. ;

Hunt, N. H. ;

Renia, L. .

PARASITE IMMUNOLOGY, 2008, 30 (10) :544-553

[3] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4] P-VALUES MAXIMIZED OVER A CONFIDENCE SET FOR THE NUISANCE PARAMETER [J].

BERGER, RL ;

BOOS, DD .

JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION, 1994, 89 (427) :1012-1016

[5] A comparison of normalization methods for high density oligonucleotide array data based on variance and bias [J].

Bolstad, BM ;

Irizarry, RA ;

Åstrand, M ;

Speed, TP .

BIOINFORMATICS, 2003, 19 (02) :185-193

[6] Immunomodulatory activities of small host defense peptides [J].

Bowdish, DME ;

Davidson, DJ ;

Scott, MG ;

Hancock, REW .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, 49 (05) :1727-1732

[7] Cytokine expression in the brain in human cerebral malaria [J].

Brown, H ;

Turner, G ;

Rogerson, S ;

Tembo, M ;

Mwenechanya, J ;

Molyneux, M ;

Taylor, T .

JOURNAL OF INFECTIOUS DISEASES, 1999, 180 (05) :1742-1746

[8] Murine cerebral malaria: how far from human cerebral malaria? [J].

Carvalho, Leonardo J. M. .

TRENDS IN PARASITOLOGY, 2010, 26 (06) :271-272

[9] High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria [J].

Casals-Pascual, Climent ;

Idro, Richard ;

Gicheru, Nimmo ;

Gwer, Samson ;

Kitsao, Barnes ;

Gitau, Evelyn ;

Mwakesi, Robert ;

Roberts, David J. ;

Newton, Charles R. J. C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (07) :2634-2639

[10]

Clark I A, 1992, Immunol Ser, V56, P365

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