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Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2.

ABSTRACT: Important for both host and pathogen survivals, iron is a key factor in determining the outcome of an infectious process. Iron with-holding, including sequestration inside tissue macrophages, is considered an important strategy to fight infection. However, for intra-macrophagic pathogens, such as Mycobacterium avium, host defence may depend on intracellular iron sequestration mechanisms. Ferritin, the major intracellular iron storage protein, plays a critical role in this process. In the current study, we studied ferritin expression in mouse bone marrow-derived macrophages upon infection with M. avium. We found that H-ferritin is selectively increased in infected macrophages, through an up-regulation of gene transcription. This increase was mediated by the engagement of Toll like receptor-2, and was independent of TNF-alpha or nitric oxide production. The formation of H-rich ferritin proteins and the consequent iron sequestration may be an important part of the panoply of antimicrobial mechanisms of macrophages.

SUBMITTER: Silva-Gomes S

PROVIDER: S-EPMC3857292 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2.

Silva-Gomes Sandro S Bouton Cécile C Silva Tânia T Santambrogio Paolo P Rodrigues Pedro P Appelberg Rui R Gomes Maria Salomé MS

PloS one 20131209 12

Important for both host and pathogen survivals, iron is a key factor in determining the outcome of an infectious process. Iron with-holding, including sequestration inside tissue macrophages, is considered an important strategy to fight infection. However, for intra-macrophagic pathogens, such as Mycobacterium avium, host defence may depend on intracellular iron sequestration mechanisms. Ferritin, the major intracellular iron storage protein, plays a critical role in this process. In the current ...[more]

PMID: 24349383

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Project description:BackgroundMycobacterium avium subsp. paratuberculosis (MAP) persistently infects intestines and mesenteric lymph nodes leading to a prolonged subclinical disease. The MAP genome sequence was published in 2005, yet its transcriptional organization in natural infection is unknown. While prior research analyzed regulated gene sets utilizing defined, in vitro stress related or advanced surgical methods with various animal species, we investigated the intracellular lifestyle of MAP in the intestines and lymph nodes to understand the MAP pathways that function to govern this persistence.ResultsOur transcriptional analysis shows that 21%, 8% and 3% of the entire MAP genome was represented either inside tissues, macrophages or both, respectively. Transcripts belonging to latency and cell envelope biogenesis were upregulated in the intestinal tissues whereas those belonging to intracellular trafficking and secretion were upregulated inside the macrophages. Transcriptomes of natural infection and in vitro macrophage infection shared genes involved in transcription and inorganic ion transport and metabolism. MAP specific genes within large sequence polymorphisms of ancestral M. avium complex were downregulated exclusively in natural infection.ConclusionsWe have unveiled common and unique MAP pathways associated with persistence, cell wall biogenesis and virulence in naturally infected cow intestines, lymph nodes and in vitro infected macrophages. This dichotomy also suggests that in vitro macrophage models may be insufficient in providing accurate information on the events that transpire during natural infection. This is the first report to examine the primary transcriptome of MAP at the local infection site (i.e. intestinal tissue). Regulatory pathways that govern the lifecycle of MAP appear to be specified by tissue and cell type. While tissues show a "shut-down" of major MAP metabolic genes, infected macrophages upregulate several MAP specific genes along with a putative pathogenicity island responsible for iron acquisition. Many of these regulatory pathways rely on the advanced interplay of host and pathogen and in order to decipher their message, an interactome must be established using a systems biology approach. Identified MAP pathways place current research into direct alignment in meeting the future challenge of creating a MAP-host interactome.

Project description:Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne’s disease (JD), which is also known as paratuberculosis, in ruminants. The mechanisms of JD pathogenesis are still unclear, but it is known that MAP subverts the host immune system for years by using macrophages as its primary reservoir. The effect of MAP infection on macrophages is often studied in healthy or experimentally infected cows, but reports on primary macrophages from naturally infected cows are lacking. In our study, the transcriptome of primary monocyte-derived macrophages challenged with live MAP was analyzed using next-generation sequencing (RNA‑seq). The gene expression signatures of macrophages from cows diagnosed as negative or positive for JD [JD(–) or JD(+), respectively] revealed differential host–pathogen interplay, highlighting long-term mechanisms established during mycobacterial disease. In JD(–) cows, a considerable number of genes (1,436) were differentially expressed at 8 h post-infection (hpi). Interestingly, while expected inflammatory immune response pathways were among the significant pathways, others related to Hepatic fibrosis/hepatic stellate cell activation, lipid homeostasis, such as the LXR/RXR [liver X receptor/retinoid X receptor] activation, and autoimmune diseases such as atherosclerosis and rheumatoid arthritis were consistently among the top significant pathways. Unexpectedly, the macrophages from JD(+) cows did not present a clear response pattern to ex vivo MAP infection, neither during the early period nor at 24 hpi. Analyzing of the transcriptomic profile of the uninfected macrophages, revealed 868 genes that were differentially expressed in JD(+) versus JD(–) cows. The down-regulated genes particularly modified the general cell metabolism by down-regulating amino acid synthesis, cholesterol biosynthesis, and other energy production pathways while introducing a pro-fibrotic pattern associated with foam cells. These modifications show the apparent importance of the metabolic pathways hijacked by MAP to subvert the immune cells. Our findings support the hypothesis that MAP could induce a tolerant-like state in circulating peripheral blood monocytes when they are differentiating into macrophages, which could further promote the persistence. Similar to other mycobacteria and pathogen-associated molecular patterns, MAP could influence macrophage behavior in the long term. This report contributes to a better understanding of MAP control of immune cells and its mechanisms of survival.

Project description:BackgroundMany efforts have been made to understand basal mechanisms of mycobacterial infections. Macrophages are the first line of host immune defence to encounter and eradicate mycobacteria. Pathogenic species have evolved different mechanisms to evade host response, e.g. by influencing macrophage apoptotic pathways. However, the underlying molecular regulation is not fully understood. A new layer of eukaryotic regulation of gene expression is constituted by microRNAs. Therefore, we present a comprehensive study for identification of these key regulators and their targets in the context of host macrophage response to mycobacterial infections.Methodology/principal findingsWe performed microRNA as well as mRNA expression analysis of human monocyte derived macrophages infected with several Mycobacterium avium hominissuis strains by means of microarrays as well as quantitative reverse transcription PCR (qRT-PCR). The data revealed the ability of all strains to inhibit apoptosis by transcriptional regulation of BCL2 family members. Accordingly, at 48 h after infection macrophages infected with all M. avium strains showed significantly decreased caspase 3 and 7 activities compared to the controls. Expression of let-7e, miR-29a and miR-886-5p were increased in response to mycobacterial infection at 48 h. The integrated analysis of microRNA and mRNA expression as well as target prediction pointed out regulative networks identifying caspase 3 and 7 as potential targets of let-7e and miR-29a, respectively. Consecutive reporter assays verified the regulation of caspase 3 and 7 by these microRNAs.Conclusions/significanceWe show for the first time that mycobacterial infection of human macrophages causes a specific microRNA response. We furthermore outlined a regulatory network of potential interactions between microRNAs and mRNAs. This study provides a theoretical concept for unveiling how distinct mycobacteria could manipulate host cell response. In addition, functional relevance was confirmed by uncovering the control of major caspases 3 and 7 by let-7e and miR-29a, respectively.

Dataset Information

Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2.

Publications

Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2.

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