Project description:Myeloid progenitors derived from antibiotic-treated mice have cell-intrinsic functional defects. In this microarray dataset, the transcriptomes of bone marrow myeloid progenitors from antibiotic-treated and control mice are compared. Myeloid progenitors from antibiotic-treated mice have a reduced interferon gene expression signature. These data suggest that tonic interferon signaling is sensed by myeloid progenitors and such signals are reduced in antibiotic-treated mice.
Project description:Tan2012 - Antibiotic Treatment, Inoculum Effect
The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies.
This model is described in the article:
The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.
Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L.
Mol Syst Biol. 2012 Oct 9; 8:617
Abstract:
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.
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Project description:STAT1 plays a cental role in the induction of interferon-stimulated genes, but interferon alpha can activate a STAT1-independent pathway that leads to gene expression. We performed microarray analysis to examine whether like interferon alpha, interferon lambda, a newly discovered interferon, can induce the expression of interferon-stimulated genes in the absence of STAT1. Control and STAT1 knockout Huh-7.5 hepatoma cells were left untreated or treated with 1000 U/ml of human interferon alpha 2a or interferon lambda 1 (PBL) for 24 h, and total RNA was extracted. Sense-strand DNA was generated from 200 ng of total RNA, fragmented, and labeled using a GeneChip WT Plus Reagent Kit (Affymetrix). Six samples were obtained and each sample was anlyzed using one GeneChip.
Project description:Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Using a mouse model mimicking pediatric antibiotic use, we found that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide altered both host and microbiota development. Early-life PAT accelerated total mass and bone growth, and resulted in progressive changes in gut microbiome diversity, population structure, and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. While control microbiota rapidly adapted to a change in diet, PAT slowed the ecological progression, with delays lasting several months in response to the macrolide. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.
Project description:Interferons (IFNs) induced early after SARS-CoV-2 infection are crucial for shaping immunity and preventing severe COVID-19. We previously demonstrated that injection of pegylated interferon-lambda1 (PEG-IFN-λ) accelerated viral clearance in COVID-19 patients. To determine if the viral decline was mediated by enhanced immunity, we assessed in vivo responses to PEG-IFN-λ by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-λ-treated patients. PEG-IFN-λ treatment induced interferon stimulated genes in peripheral immune cells expressing IFNLR1, including plasmacytoid dendritic cells and B cells. PEG-IFN-λ did not affect SARS-CoV-2-specific antibody levels or the magnitude of virus-specific T cells. However, we identified delayed T cell responses in older adults, suggesting that PEG-IFN-λ can overcome delays in adaptive immunity to accelerate viral clearance in high-risk patients. Altogether, PEG-IFN-λ offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral adaptive immunity.
Project description:Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Using a mouse model mimicking pediatric antibiotic use, we found that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide altered both host and microbiota development. Early-life PAT accelerated total mass and bone growth, and resulted in progressive changes in gut microbiome diversity, population structure, and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. While control microbiota rapidly adapted to a change in diet, PAT slowed the ecological progression, with delays lasting several months in response to the macrolide. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. C57BL/6J mice received three antibiotic courses: at days 10-15, 28-31, and 37-40 of life, amoxicillin or tylosin.Livers were collected at age 22 weeks, RNA was extracted, and transcriptional differences were measured by microarray analysis.
Project description:The maternal microbiota plays an important role in shaping and priming infant immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure caused significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s caused by diminished production of microbiota-derived metabolite butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (GPR41-/-) or type 1 interferon receptor (Ifnar1-/-) recapitulated the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induced persistent epigenetic changes in ILC2s and had a long-lasting deteriorative effect on allergic airway inflammation in adulthood. Prenatal supplementation with butyrate ameliorated airway inflammation in adult offspring born to antibiotic-exposed dams. These observations demonstrate an essential role for the maternal microbiota in the control of type 2 innate immunity at the neonatal stage, which provides a therapeutic window for treating asthma in early life.