Hepatocytic transcriptional signatures predict comparative drug interaction potential of rifamycin antibiotics

Dyavar, Shetty Ravi; Mykris, Timothy M; Winchester, Lee C.; Scarsi, Kimberly K; Fletcher, Courtney V.; Podany, Anthony T.

doi:10.1038/s41598-020-69228-z

Cited by 16 publications

(16 citation statements)

References 48 publications

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“…Ingenuity Pathway Analysis (IPA) software (Qiagen) was used to perform pathway enrichment, gene network, and upstream regulator analyses (URA) according to the standard protocols as previously described (39,40). A list of differentially expressed genes in a dataset with a minimum of 1.5-fold change and p value of <0.05 significance were compared between the two groups and uploaded into IPA.…”

Section: Rna Isolation and Gene Expression Analysismentioning

confidence: 99%

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

Hall

Smith

Dyavar

et al. 2021

The Journal of Immunology

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Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.

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Section: Rna Isolation and Gene Expression Analysismentioning

confidence: 99%

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

Hall

Smith

Dyavar

et al. 2021

The Journal of Immunology

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“…We considered the possibility that our observations could reflect differences in drug metabolism. Rifampicin induces gene expression changes in hepatocytes [ 29 , 30 ], but after reviewing this literature and publicly available RNASeq data (Gene Expression Omnibus, Series GEO139896) [ 29 ] we found no evidence for this (data not shown). This could also be attributed to the fact that our study focused on peripheral blood-associated gene expression changes as compared to the liver-derived hepatocytes described in these previously reported studies.…”

Section: Discussionmentioning

confidence: 96%

Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals

et al. 2021

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We hypothesised that individuals with immunological sensitisation to Mycobacterium tuberculosis ( Mtb ), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy (PT), reflecting the differential immunological consequences of the sterilisation of viable infection in those with active Mtb infection versus no Mtb killing in those who did not harbour viable bacilli. We investigated longitudinal whole blood transcriptional profile responses to PT of Interferon gamma release assay (IGRA)-positive tuberculosis contacts and IGRA-negative, tuberculosis-unexposed controls. Longitudinal unsupervised clustering analysis with a subset of 474 most variable genes in antigen-stimulated blood separated the IGRA-positive participants into two distinct subgroups, one of which clustered with the IGRA-negative controls. 117 probes were differentially expressed over time between the two cluster groups, many of them associated with immunological pathways important in mycobacterial control. We contend that the differential host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA-negative unexposed controls, and Mtb viability in the group (1/3 of IGRA-positives) that clustered away. Gene expression patterns in the blood of IGRA-positive individuals emerging during the course of PT, which reflect Mtb viability, could have major implications in the identification of risk of progression, treatment stratification and biomarker development.

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“…A similar trend was observed when mice with low n-3 PUFA status were supplemented with EPA/DHA, suggesting that the coadministration of EPA/DHA together with the currently used TB antibiotics has no observable adverse effects. Multidrug combination therapy approaches for TB treatment make it a candidate for possible drug-drug interactions (DDIs) or drugnutrient interactions (DNIs) (67), which subsequently may result in poor TB treatment outcomes and the emergence of drugresistant TB (68,69). Considering the recent interest and the prospects associated with the use of repurposed drugs and pharmaconutrients as an adjunct therapy in TB (35,(70)(71)(72), this study further reinforces the prospect for the use of n-3 LCPUFA # Data are reported as means ± SEM percentage of total fatty acids of n = 6 mice/group and representative of two independent experiments.…”

Section: Discussionmentioning

confidence: 99%

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status

et al. 2021

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Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n-3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Post-infection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group (p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Pro-inflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1α (p = 0.039), MCP1 (p = 0.003), MIP1- α (p = 0.043), and RANTES (p = 0.034); were lower, and the anti-inflammatory cytokine IL-4 (p = 0.002) and growth factor GMCSF (p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators.

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Hepatocytic transcriptional signatures predict comparative drug interaction potential of rifamycin antibiotics

Cited by 16 publications

References 48 publications

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status

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