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Formaldehyde Stress Responses in Bacterial Pathogens.

ABSTRACT: Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol-dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR, and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed.

SUBMITTER: Chen NH

PROVIDER: S-EPMC4776306 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Formaldehyde Stress Responses in Bacterial Pathogens.

Chen Nathan H NH Djoko Karrera Y KY Veyrier Frédéric J FJ McEwan Alastair G AG

Frontiers in microbiology 20160303

Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent ...[more]

PMID: 26973631

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Project description:Transcriptomics provides valuable data for functional annotations of genes, the discovery of biomarkers, and quantitative assessment of responses to challenges. Meta-analysis of Nofima's Atlantic salmon microarray database was performed for the selection of genes that have shown strong and reproducible expression changes. Using data from 127 experiments including 6440 microarrays, four transcription modules (TM) were identified with a total of 902 annotated genes: 161 virus responsive genes - VRG (activated with five viruses and poly I:C), genes that responded to three pathogenic bacteria (523 up and 33 down-regulated genes), inflammation not caused by infections - wounds, melanized foci in skeletal muscle and exposure to PAMP (180 up and 72 down-regulated genes), and stress by exercise, crowding and cortisol implants (33 genes). To assist the selection of gene markers, genes in each TM were ranked according to the scale of expression changes. In terms of functional annotations, association with diseases and stress was unknown or not reflected in public databases for a large part of genes, including several genes with the highest ranks. A set of multifunctional genes was discovered. Cholesterol 25-hydroxylase was present in all TM and 22 genes, including most differentially expressed matrix metalloproteinases 9 and 13 were assigned to three TMs. The meta-analysis has improved understanding of the defense strategies in Atlantic salmon. VRG have demonstrated equal or similar responses to RNA (SAV, IPNV, PRV, and ISAV), and DNA (gill pox) viruses, injection of bacterial DNA (plasmid) and exposure of cells to PAMP (CpG and gardiquimod) and relatively low sensitivity to inflammation and bacteria. Genes of the highest rank show preferential expression in erythrocytes. This group includes multigene families (gig and several trim families) and many paralogs. Of pathogen recognition receptors, only RNA helicases have shown strong expression changes. Most VRG (82%) are effectors with a preponderance of ubiquitin-related genes, GTPases, and genes of nucleotide metabolism. Many VRG have unknown roles. The identification of TMs makes possible quantification of responses and assessment of their interactions. Based on this, we are able to separate pathogen-specific responses from general inflammation and stress.

Project description:Bacterial infections can induce exuberant immune responses that can damage host tissues. Previously, we demonstrated that systemic Escherichia coli infection in mice causes tissue damage in the liver. This liver necrosis is associated with the expression of endogenous retroviruses, chromosomally integrated retroviruses that encode a reverse transcriptase. Furthermore, nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) completely prevent tissue damage and subsequent bacterial growth within necrotic lesions. Since liver necrosis is linked to heightened systemic inflammatory responses, we hypothesized that NRTIs diminish inflammation caused by E. coli infection and may also have broad impacts on the systemic immune response to bacterial pathogens. Here, we tested this hypothesis by characterizing the effects of NRTIs on the innate immune response to bacteria. In the liver, NRTI administration following E. coli inoculation reduced the expression of a large repertoire of proinflammatory transcripts. NRTIs also had systemic anti-inflammatory effects, including reducing proinflammatory cytokine levels in serum in response to E. coli in different mouse strains. The anti-inflammatory effects of NRTIs were also apparent in response to lipopolysaccharide (LPS) and Staphylococcus aureus, suggesting that the molecular mechanisms underlying the immunomodulatory functions of NRTIs are likely conserved across distinct immune signaling pathways. Moreover, in a model of lethal LPS shock, NRTI administration prevented hypothermia and death. Together, our observations reveal that NRTIs can potently impede systemic inflammatory responses during Gram-positive and Gram-negative bacterial infections. Our findings lay the groundwork for further investigation of the therapeutic scope of NRTIs and the mechanisms underlying their anti-inflammatory effects across non-retroviral infectious diseases.IMPORTANCEInflammatory responses are critical for host control of bacterial infection, but excessive inflammation can damage host tissues and lead to sepsis. Understanding how innate immune responses are controlled during infection is important for developing new approaches to dampen excessive inflammation. In previous work, we found that tissue damage caused by excessive inflammatory responses may be driven by endogenous reverse transcriptases. Here we demonstrate that treatment of mice with reverse transcriptase inhibitors leads to broad reductions in systemic proinflammatory responses during bacterial infections and can protect mice from acute death in a lethal model of sepsis. Our findings indicate that uncovering the mechanisms underlying the anti-inflammatory functions of reverse transcriptase inhibitors may lead to new therapeutics for bacterial infectious diseases.

Dataset Information

Formaldehyde Stress Responses in Bacterial Pathogens.

Publications

Formaldehyde Stress Responses in Bacterial Pathogens.

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