Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion.
Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion.
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差异表达的转录本同工型与对结核蛋白皮肤测试的抗性和干扰素伽马释放测定转换相关。
DOI：
10.1371/journal.pone.0284498
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
Hawn, Thomas R.
中科院分区：
文献类型：
--
作者：
Simmons, Jason D.;Segnitz, R. Max;Dill-McFarland, Kimberly A.;Stein, Catherine M.;Peterson, Glenna J.;Mayanja-Kizza, Harriet;Boom, W. Henry;Hawn, Thomas R.
对不常见的免疫结果（如对感染的抵抗力）的机械理解导致了新疗法的开发。使用基因水平的分析方法，我们以前发现不同的单核细胞转录反应与结核分枝杆菌（Mtb）感染的耐药性定义为持续阴性结核菌素皮肤试验（TST）和干扰素γ释放试验（IGRA）反应之间的高度暴露接触（RSTR表型）。使用转录异构体分析，我们的目的是确定新的RSTR相关基因假设，以前的基因水平的差异表达分析掩盖异构体特异性差异，有助于表型。49例RSTR和52例潜伏性结核分枝杆菌感染（LTBI）受试者的单核细胞感染M。结核病（H37 Rv）或在RNA分离和测序之前保持未刺激（培养基）。RSTR相关基因的表达，然后确定使用差异转录异构体分析。我们在70个基因中鉴定了81个差异表达转录物（DET）（FDR <0.05），将RSTR和LTBI表型与Mtb刺激条件下鉴定的大多数（n = 79个DET）进行比较。这些基因中的17个先前通过基因水平批量RNAseq分析鉴定，包括在LTBI受试者中表达增加的IFNγ应答中的基因，发现与基于IGRA反应性的临床表型一致。在结核分枝杆菌感染的RSTR单核细胞中具有阳性差异表达的23个基因的子集中，13个先前未被鉴定。这些新的DET基因包括PDE 4A和ZEB 2，它们各自具有多个DET，在RSTR受试者中表达更高，以及ACSL 4和GAPDH，它们各自具有与RSTR相关的单个转录物同种型。转录异构体特异性分析确定转录协会，如与TST/IGRA转换，这是模糊的，当使用基因水平的方法。这些发现应该用额外的RSTR群组来验证，并且新鉴定的候选耐药基因是否直接影响单核细胞Mtb反应需要功能研究。
A mechanistic understanding of uncommon immune outcomes such as resistance to infection has led to the development of novel therapies. Using gene level analytic methods, we previously found distinct monocyte transcriptional responses associated with resistance to Mycobacterium tuberculosis (Mtb) infection defined as persistently negative tuberculin skin test (TST) and interferon gamma release assay (IGRA) reactivity among highly exposed contacts (RSTR phenotype). Using transcript isoform analyses, we aimed to identify novel RSTR-associated genes hypothesizing that previous gene-level differential expression analysis obscures isoform-specific differences that contribute to phenotype. Monocytes from 49 RSTR versus 52 subjects with latent Mtb infection (LTBI) were infected with M. tuberculosis (H37Rv) or left unstimulated (media) prior to RNA isolation and sequencing. RSTR-associated gene expression was then identified using differential transcript isoform analysis. We identified 81 differentially expressed transcripts (DETs) in 70 genes (FDR <0.05) comparing RSTR and LTBI phenotypes with the majority (n = 79 DETs) identified under Mtb-stimulated conditions. Seventeen of these genes were previously identified with gene-level bulk RNAseq analyses including genes in the IFNγ response that had increased expression among LTBI subjects, findings consistent with a clinical phenotype based on IGRA reactivity. Among the subset of 23 genes with positive differential expression among Mtb-infected RSTR monocytes, 13 were not previously identified. These novel DET genes included PDE4A and ZEB2, which each had multiple DETs with higher expression among RSTR subjects, and ACSL4 and GAPDH that each had a single transcript isoform associated with RSTR. Transcript isoform-specific analyses identify transcriptional associations, such as those associated with resistance to TST/IGRA conversion, that are obscured when using gene-level approaches. These findings should be validated with additional RSTR cohorts and whether the newly identified candidate resistance genes directly influence the monocyte Mtb response requires functional study.
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DOI：
10.1084/jem.20150194
发表时间：
2015-11-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Omilusik KD;Best JA;Yu B;Goossens S;Weidemann A;Nguyen JV;Seuntjens E;Stryjewska A;Zweier C;Roychoudhuri R;Gattinoni L;Bird LM;Higashi Y;Kondoh H;Huylebroeck D;Haigh J;Goldrath AW
通讯作者：
Goldrath AW
影响因子：
6
作者：
Subbian, Selyakumar;Tsenova, Liana;Kaplan, Gilla
通讯作者：
Kaplan, Gilla
DOI：
10.1016/s2213-2600(17)30060-7
发表时间：
2017-04
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Andrews JR;Nemes E;Tameris M;Landry BS;Mahomed H;McClain JB;Fletcher HA;Hanekom WA;Wood R;McShane H;Scriba TJ;Hatherill M
通讯作者：
Hatherill M
影响因子：
5.3
作者：
Shinoda, Tomoyasu;Taya, Shinichiro;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
影响因子：
5.6
作者：
Li H;Zuo J;Tang W
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Tang W