Concordant and discordant gene expression patterns in mouse strains identify best-fit animal model for human tuberculosis

Domaszewska, Teresa; Scheuermann, Lisa; Hahnke, Karin; Mollenkopf, Hans; Dorhoi, Anca; Kaufmann, Stefan H. E.; Weiner, January

doi:10.1038/s41598-017-11812-x

Cited by 40 publications

(44 citation statements)

References 41 publications

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“…The experimental design for murine array analysis compared two factors: pregnancy status (pregnant/non-pregnant control) and vaccination status (Boostrix-IPV/placebo [PBS]). To further investigate whether pregnancy altered the global transcriptomic response to vaccination, we conducted discordance/concordance analysis using the disco R package 13 . The idea is that a heuristic score combines the effect size estimates (log 2 fold changes) and the p values between two comparisons, thus providing a measure that corresponds to concordance (when two genes are regulated in the same direction) or discordance (when the two genes are regulated in opposing directions).…”

Section: Resultsmentioning

confidence: 99%

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Pregnancy has a minimal impact on the acute transcriptional signature to vaccination

et al. 2020

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Vaccination in pregnancy is an effective tool to protect both the mother and infant; vaccines against influenza, pertussis and tetanus are currently recommended. A number of vaccines with a specific indication for use in pregnancy are in development, with the specific aim of providing passive humoral immunity to the newborn child against pathogens responsible for morbidity and mortality in young infants. However, the current understanding about the immune response to vaccination in pregnancy is incomplete. We analysed the effect of pregnancy on early transcriptional responses to vaccination. This type of systems vaccinology approach identifies genes and pathways that are altered in response to vaccination and can be used to understand both the acute inflammation in response to the vaccine and to predict immunogenicity. Pregnant women and mice were immunised with Boostrix-IPV, a multivalent vaccine, which contains three pertussis antigens. Blood was collected from women before and after vaccination and RNA extracted for analysis by microarray. While there were baseline differences between pregnant and nonpregnant women, vaccination induced characteristic patterns of gene expression, with upregulation in interferon response and innate immunity gene modules, independent of pregnancy. We saw similar patterns of responses in both women and mice, supporting the use of mice for preclinical screening of novel maternal vaccines. Using a systems vaccinology approach in pregnancy demonstrated that pregnancy does not affect the initial response to vaccination and that studies in non-pregnant women can provide information about vaccine immunogenicity and potentially safety.npj Vaccines (2020) 5:29 ; https://doi.

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Section: Resultsmentioning

confidence: 99%

“…To this end, we have used two approaches. First, we used the disco metric 13 , which allows to compare two comparisons ( Fig. 1b).…”

Section: Resultsmentioning

confidence: 99%

Pregnancy has a minimal impact on the acute transcriptional signature to vaccination

et al. 2020

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“…The IPA canonical pathway P values were calculated by a one-sided Fisher's Exact Test, with P < 0.01 considered as significant. The transcriptional module P values were calculated using the CERNO statistical test, with P < 0.05 considered as significant after Benjamini-Hochberg correction (42). For all other statistical tests, P < 0.05 was considered as significant.…”

Section: Resultsmentioning

confidence: 99%

“…To compare transcriptional modules altered in humans to those altered in mice and macaques, we used the recently defined disco score to identify concordantly and discordantly altered modules between these species (42). Several modules related to T cells, NK cells and monocytes were enriched (adjusted P < 0.05) in each pairwise comparison between two species (human vs. mouse, human vs. monkey, and monkey vs. mouse) ( Figure 4F).…”

Section: Time Since Tb Exposure In Humans Is Associated With Alteratimentioning

confidence: 99%

“…Genes used in this analysis included all detected probes (mice and macaques) and genes (humans). Differential expression and ortholog assignment were performed as previously described (42). The 6-month time point in the GC6-74 cohort was taken as the early time point in humans based on the results in Figures 5 and S3, as this time point had the highest 6-gene score (data not shown).…”

Section: Cell Type Deconvolution Pathway and Transcriptional Modulementioning

confidence: 99%

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Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Ault

Headley

Hare

et al. 2019

Preprint

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Tuberculosis (TB) is the leading cause of death due to a single infectious disease.Knowing when a person was infected with Mycobacterium tuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure.First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

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Mechanisms of ag85a/b DNA vaccine conferred immunotherapy and recovery from Mycobacterium tuberculosis‐induced injury

Wang,

Liang,

et al. 2023

Immunity Inflam & Disease

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Our previous research developed a novel tuberculosis (TB) DNA vaccine ag85a/b that showed a significant therapeutic effect on the mouse tuberculosis model by intramuscular injection (IM) and electroporation (EP). However, the action mechanisms between these two vaccine immunization methods remain unclear. In a previous study, 96 Mycobacterium tuberculosis (MTB) H37Rv‐infected BALB/c mice were treated with phosphate‐buffered saline, 10, 50, 100, and 200 μg ag85a/b DNA vaccine delivered by IM and EP three times at 2‐week intervals, respectively. In this study, peripheral blood mononuclear cells (PBMCs) from three mice in each group were isolated to extract total RNA. The gene expression profiles were analyzed using gene microarray technology to obtain differentially expressed (DE) genes. Finally, DE genes were validated by real‐time reverse transcription‐quantitive polymerase chain reaction and the GEO database. After MTB infection, most of the upregulated DE genes were related to the digestion and absorption of nutrients or neuroendocrine (such as Iapp, Scg2, Chga, Amy2a5), and most of the downregulated DE genes were related to cellular structural and functional proteins, especially the structure and function proteins of the alveolar epithelial cell (such as Sftpc, Sftpd, Pdpn). Most of the abnormally upregulated or downregulated DE genes in the TB model group were recovered in the 100 and 200 μg ag85a/b DNA IM groups and four DNA EP groups. The pancreatic secretion pathway downregulated and the Rap1 signal pathway upregulated had particularly significant changes during the immunotherapy of the ag85a/b DNA vaccine on the mouse TB model. The action targets and mechanisms of IM and EP are highly consistent. Tuberculosis infection causes rapid catabolism and slow anabolism in mice. For the first time, we found that the effective dose of the ag85a/b DNA vaccine immunized whether by IM or EP could significantly up‐regulate immune‐related pathways and recover the metabolic disorder and the injury caused by MTB.

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Concordant and discordant gene expression patterns in mouse strains identify best-fit animal model for human tuberculosis

Cited by 40 publications

References 41 publications

Pregnancy has a minimal impact on the acute transcriptional signature to vaccination

Pregnancy has a minimal impact on the acute transcriptional signature to vaccination

Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Mechanisms of ag85a/b DNA vaccine conferred immunotherapy and recovery from Mycobacterium tuberculosis‐induced injury

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