Microbes and Infection最新文献

Genetics is central to the susceptibility or resistance to autoimmunity, and mounting evidence indicates that the intestinal microbiota also plays an essential role. In murine arthritis models, short-chain fat acid supplementation reduces disease severity by modulating tryptophan-metabolizing bacteria. Common microbiota transfer methods modulate arthritis severity, however, they are not practical for chronic models such as pristane-induced arthritis (PIA). PIA-resistant (HIII) and PIA-susceptible (LIII) mice harbor diverse intestinal microbiomes, which might be implicated in their divergent susceptibility. To investigate this hypothesis, we used cross-fostering to stably transfer the microbiota. In this study, we show that extreme susceptibility to arthritis can be modulated by early microbiota transfer, with long-lasting effects. HIII and LIII pups were cross-fostered and injected with pristane after weaning. PIA severity in cross-fostered LIII mice was significantly reduced in the chronic phase. Metagenomic analyses showed that HIII and LIII microbiomes were partly shifted by cross-fostering. Microbial groups whose abundance was associated with either HIII or LIII mice presented similar composition in cross-fostered mice of the opposite strains, suggesting a role in PIA susceptibility. Identification of bacterial groups that modulate chronic arthritis will contribute novel insights on the pathogenesis of human rheumatoid arthritis and targets for replication and functional studies.

Sterols perform essential structural and signalling functions in living organisms. Ergosterol contributes to the fluidity, permeability, microdomain formation and functionality of proteins in the yeast membrane. In our study, desmosterol was the most successful at compensating for the lack of ergosterol in Saccharomyces cerevisiae, besides stigmasterol and sitosterol. These three sterols supported cell growth without causing severe morphological defects, unlike cholesterol, 7-dehydrocholesterol, lathosterol, cholestanol or lanosterol. Together with ergosterol, they were also able to bring the plasma membrane potential of hem1Δ cells closer to the level of the wild type. In addition, desmosterol conferred even higher thermotolerance to yeast than ergosterol. Some sterols counteracted the antifungal toxicity of polyenes, azoles and terbinafine to hem1Δ cells. Plant sterols (stigmasterol, sitosterol) and desmosterol ensured the glucose-induced activation of H⁺-ATPase in hem1Δ cells analogously to ergosterol, whereas cholesterol and 7-dehydrocholesterol were less effective. Exogenous ergosterol, stigmasterol, sitosterol, desmosterol and cholesterol also improved the growth of Candida glabrata and Candida albicans in the presence of inhibitory concentration of fluconazole. The proper incorporation of exogenous sterols into the membrane with minimal adverse side effects on membrane functions was mainly influenced by the structure of the sterol acyl chain, and less by their ring structures.

CD4+ T cells are critical to control of Pneumocystis infection, and Cxcr6 has been shown to be upregulated in these cells during infection, but the roles of CD4 and Cxcr6 in this setting are undefined. To explore this, mice deficient in CD4 or Cxcr6 expression were utilized in a co-housing mouse model that mimics the natural route of Pneumocystis infection. Organism load and anti-Pneumocystis antibodies were assayed over time, and immunohistochemistry, flow cytometry, and quantitative PCR were used to characterize host immune responses during infection. CD4 was found to be necessary for clearance of Pneumocystis murina, though partial control was seen in it's absence; based on ThPOK expression, double negative T cells with T helper cell characteristics may be contributing to this control. Using a Cxcr6 deficient mouse expressing gfp, control of infection in the absence of Cxcr6 was similar to that in heterozygous control mice. It is noteworthy that gfp + cells were seen in the lungs with similar frequencies between the 2 strains. Interferon-ɣ and chemokine/ligands Cxcr3, Cxcl9, and Cxcl10 increased during P. murina infection in all models. Thus, CD4, but not Cxcr6, is needed for clearance of P. murina infection.

Tuberculosis (TB) is a high mortality infectious disease caused by Mycobacterium tuberculosis (Mtb), and often develops into latent infection. About 5～10% of latent infections turn into active tuberculosis when the host immune system becomes deficient. Therefore, exploring the latent infection mechanism of Mtb is pivotal for the prevention and treatment of tuberculosis. We first established the zebrafish latent infection model and the chronic infection model utilizing Mycobacterium marinum, which has the highly similar gene background to Mtb. Using the latent infection model, we characterized the gene expression profiles and found 462 genes expressed differentially in the latent period and chronic tuberculosis infection. These differentially expressed genes are involved in various biological processes including transcription, transcriptional regulation, organism development, and immune responses. Among them, nineteen immune-related genes were found to express differentially in the latent period. By analyzing immune related protein network, the genes in the center of the network, including Nos2b, TNFα, IL1, TNFβ, TLR1, TLR2, and TLR4b, displayed significant deferential expression in latent infection and chronic infection period of zebrafish, suggesting that these genes might play an important role in controlling latent infection of Mtb. Identifying immune biomarker related to the status of tuberculosis latent infection might lead to novel strategy for diagnosis and treatment.

Mycobacterium caprae is linked to regular outbreaks of tuberculosis (TB) in geographically distinct caprine populations across Europe, namely Iberia where this ecovar may represent up to 8% of total animal TB cases, circulating in multi-host communities encompassing domestic ruminants and wildlife, representing severe financial losses. It also causes zoonotic human disease. In this work, we undertake the first phylodynamic and phylogeographic analyses of M. caprae to reconstruct past demography and transmission chains. First, we examined the worldwide diversity of M. caprae based on 229 unpublished and publicly available whole genome sequences, depicting Asian, Central-East European, and Iberian clades. Phylodynamic analyses of the SB0157 Iberian clade (n = 81) positioned the most recent common ancestor in goats, around 100 years ago. Host transition events were common between goats, wild boars, and humans, possibly resulting from mixed farming, extensive management, and close human proximity, facilitating interspecific transmission. We show the spread of M. caprae on multiple scales due to local and transnational animal trade, supporting historical and sustained cross-species transmission in Iberia. We highlight the value of intersecting genomic epidemiology with molecular ecology to resolve epidemiological links and show that an EU-official eradication program in goats is utterly needed to control TB in a multi-host scenario.

Acute aortic dissection (AAD) is the most severe traumatic disease affecting the aorta. Pyroptosis-mediated vascular wall inflammation is a crucial trigger for AAD, and the exact mechanism requires further investigation. In this study, our proteomic analysis showed that Lipopolysaccharide (LPS)-binding protein (LBP) was significantly upregulated in the plasma and aortic tissue of patients with AAD. Further, 16S rRNA sequencing of stool samples suggested that patients with AAD exhibit gut dysbiosis, which may lead to an impaired intestinal barrier and LPS leakage. By comparing with control mice, we found that LBP, including Pyrin Domain Containing Protein3 (NLRP3), the CARD-containing adapter apoptosis-associated speck-like protein (ASC), and Cleaved caspase-1, were upregulated in the AAD aorta, whereas gut intestinal barrier-related proteins were downregulated. Moreover, treated with LBPK95A (an LBP inhibitor) attenuated the incidence of AAD, the expression levels of pyroptosis-related factors, and the extent of vascular pathological changes compared to those in AAD mice. In addition, LPS and LBP treatment of human umbilical vein endothelial cells (HUVECs) activated TLR4 signaling and intracellular reactive oxygen species (ROS) production, which stimulated NLRP3 inflammasome formation and mediated pyroptosis in endothelial cells. Our findings showed that gut dysbiosis mediates pyroptosis by the LPS-LBP complex, thus providing new insights into developing AAD.