Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections

被引：460

作者：

Tobin, David M. ^{[1
,2
]}

Roca, Francisco J. ^{[1
]}

Oh, Sungwhan F. ^{[3
]}

McFarland, Ross ^{[1
]}

Vickery, Thad W. ^{[3
]}

Ray, John P. ^{[1
]}

Ko, Dennis C. ^{[1
]}

Zou, Yuxia ^{[2
]}

Bang, Nguyen D. ^{[4
]}

Chau, Tran T. H.

Vary, Jay C. ^{[5
]}

Hawn, Thomas R. ^{[5
]}

Dunstan, Sarah J. ^{[6
,7
]}

Farrar, Jeremy J. ^{[6
,7
]}

Thwaites, Guy E. ^{[8
]}

King, Mary-Claire ^{[5
,9
]}

Serhan, Charles N. ^{[3
]}

Ramakrishnan, Lalita ^{[1
,5
,10
]}

机构：

[1] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA

[2] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA

[3] Harvard Univ, Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med,Sch Med, Boston, MA 02115 USA

[4] Pham Ngoc Thach Hosp TB & Lung Dis, Ho Chi Minh City, Vietnam

[5] Univ Washington, Dept Med, Seattle, WA 98195 USA

[6] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam

[7] Univ Oxford, Ctr Trop Med, Nuffield Dept Clin Med, Oxford OX3 7LJ, England

[8] Kings Coll London, Ctr Clin Infect & Diagnost Res, St Thomas Hosp, London SE1 9RT, England

[9] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[10] Univ Washington, Dept Immunol, Seattle, WA 98195 USA

来源：

CELL | 2012年 / 148卷 / 03期

基金：

英国惠康基金;

关键词：

LIPID MEDIATORS; TNF-ALPHA; TUBERCULOSIS; ASPIRIN; CELLS; HIV; MANAGEMENT; INDUCTION; IMMUNITY; A(4);

D O I：

10.1016/j.cell.2011.12.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation causedby excess lipoxins and hyperinflammation driven by excess leukotriene B-4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

引用

页码：434 / 446

页数：13

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