High levels of plasma S100A9 at admission indicate an increased risk of death in severe tuberculosis patients

Liu, Qiuyue; Li, Ru; Li, Qi; Luo, Bin; Lin, Jun; Lyu, Lingna

doi:10.1016/j.jctube.2021.100270

Cited by 7 publications

(4 citation statements)

References 28 publications

(27 reference statements)

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“…At present, it relies mainly on antibiotics and vaccines, but new methods of molecular resistance to the disease need to be explored. It has been previously reported that S100A9 affected the innate immune response ( Liu et al, 2021 ). This study revealed that knockdown of S100A9 reduced injury due to cellular inflammatory injury suggesting that S100A9 regulates the progression of diarrheal disease.…”

Section: Discussionmentioning

confidence: 99%

Decreased S100A9 expression alleviates Clostridium perfringens beta2 toxin-induced inflammatory injury in IPEC-J2 cells

Huang

Xie

et al. 2023

PeerJ

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Background S100 calcium-binding protein A9 (S100A9) is a commonly known pro-inflammatory factor involved in various inflammatory responses. Clostridium perfringens (C. perfringens ) type C is known to cause diarrhea in piglets. However, the role of S100A9 in C. perfringens type C-induced infectious diarrhea is unclear. Methods Here, the S100A9 gene was overexpressed and knocked down in the IPEC-J2 cells, which were treated with C. perfringens beta2 (CPB2) toxin. The role of S100A9 in CPB2 toxin-induced injury in IPEC-J2 cells was assessed by measuring the levels of inflammatory cytokines, reactive oxygen species (ROS), lactate dehydrogenase (LDH), cell proliferation, and tight junction-related proteins. Results The results showed elevated expression of S100A9 in diarrhea-affected piglet tissues, and the elevation of S100A9 expression after CPB2 toxin treatment of IPEC-J2 was time-dependent. In CPB2 toxin-induced IPEC-J2 cells, overexpression of S100A9 had the following effects: the relative expression of inflammatory factors IL-6, IL8, TNF-α, and IL-1β was increased; the ROS levels and LDH viability were significantly increased; cell viability and proliferation were inhibited; the G0/G1 phase cell ratio was significantly increased. Furthermore, overexpression of S100A9 reduced the expression of tight junction proteins in CPB2-induced IPEC-J2 cells. The knockdown of S100A9 had an inverse effect. In conclusion, our results confirmed that S100A9 exacerbated inflammatory injury in CPB2 toxin-induced IPEC-J2 cells, inhibited cell viability and cell proliferation, and disrupted the tight junctions between cells. Thus, decreased S100A9 expression alleviates CPB2 toxin-induced inflammatory injury in IPEC-J2 cells.

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Section: Discussionmentioning

confidence: 99%

Decreased S100A9 expression alleviates Clostridium perfringens beta2 toxin-induced inflammatory injury in IPEC-J2 cells

Huang

Xie

et al. 2023

PeerJ

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“…Some forms activate Toll-Like receptor 4 signaling; some activate the receptor for advanced glycation end-products; and some sequester calcium, zinc, and manganese metal ions [99,103,104]. In pulmonary TB, S100A9 contributes to neutrophil localization to granulomas, and both S100A8 and S100A9 are protein biomarkers of TBrelated lung damage [38,39,[104][105][106][107]. Interestingly, 4 polymorphisms in S100a8 were predicted to have deleterious effects on function but the lack of S100a8 did not change the ability of C57BL/6 inbred mice to restrict M. tuberculosis growth.…”

Section: Discussionmentioning

confidence: 99%

Systems genetics uncover new loci containing functional gene candidates inMycobacterium tuberculosis-infected Diversity Outbred mice

Gatti,

Tyler,

Mahoney

et al. 2023

Preprint

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Mycobacterium tuberculosis,the bacillus that causes tuberculosis (TB), infects 2 billion people across the globe, and results in 8-9 million new TB cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. We investigated the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected withM. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using clinical indicators of disease, granuloma histopathological features, and immune response traits identified five new loci on mouse chromosomes 1, 2, 4, 16 and three previously identified loci on chromosomes 3 and 17. Quantitative trait loci (QTLs) on chromosomes 1, 16, and 17, associated with multiple correlated traits and had similar patterns of allele effects, suggesting these QTLs contain important genetic regulators of responses toM. tuberculosis. To narrow the list of candidate genes in QTLs, we used a machine learning strategy that integrated gene expression signatures from lungs ofM. tuberculosis-infected Diversity Outbred mice with gene interaction networks, generating functional scores. The scores were then used to rank candidates for each mapped trait in each locus, resulting in 11 candidates:Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa,andZfp318. Importantly, all 11 candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling. Further, all candidates contain single nucleotide polymorphisms (SNPs), and some but not all SNPs were predicted to have deleterious consequences on protein functions. Multiple methods were used for validation including (i) a statistical method that showed Diversity Outbred mice carrying PWH/PhJ alleles on chromosome 17 QTL have shorter survival; (ii) quantification of S100A8 protein levels, confirming predicted allele effects; and (iii) infection of C57BL/6 mice deficient for theS100a8gene. Overall, this work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and new functionally relevant gene candidates that may be major regulators of granuloma necrosis and acute inflammation in pulmonary TB.

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“…expression of plasma S100A9 was also found to be associated with the death risk of severe TB patients (Liu et al, 2021). S100A9 could also play a key role in granuloma formation (Yoshioka et al, 2016).…”

Section: Figure 3 |mentioning

confidence: 96%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

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High levels of plasma S100A9 at admission indicate an increased risk of death in severe tuberculosis patients

Cited by 7 publications

References 28 publications

Decreased S100A9 expression alleviates Clostridium perfringens beta2 toxin-induced inflammatory injury in IPEC-J2 cells

Decreased S100A9 expression alleviates Clostridium perfringens beta2 toxin-induced inflammatory injury in IPEC-J2 cells

Systems genetics uncover new loci containing functional gene candidates inMycobacterium tuberculosis-infected Diversity Outbred mice

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

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