Background and objectivesPrevious reports on the outbreak of coronavirus disease 2019 were on the basis of data from the general population. Our study aimed to investigate the clinical features of patients on maintenance hemodialysis.Design, setting, participants, & measurements In this retrospective, single-center study, we included 49 hospitalized patients on maintenance hemodialysis and 52 hospitalized patients without kidney failure (controls) with confirmed coronavirus disease 2019 at Tongren Hospital of Wuhan University from January 30, 2020 to March 10, 2020. Demographic, clinical, laboratory, and radiologic characteristics and treatment and outcomes data were analyzed. The final date of follow-up was March 19, 2020.ResultsThe median age of 101 patients was 62 years (interquartile range, 49–72). All patients were local residents of Wuhan. In terms of common symptoms, there were differences between patients on hemodialysis and controls (fatigue [59% versus 83%], dry cough [49% versus 71%], and fever [47% versus 90%]). Lymphocyte counts were decreased (0.8×109/L [patients on hemodialysis] versus 0.9×109/L [controls], P=0.02). Comparing patients on hemodialysis with controls, creatine kinase–muscle and brain type, myoglobin, hypersensitive troponin I, B-type natriuretic peptide, and procalcitonin were increased, and the percentage of abnormalities in bilateral lung was higher in computed tomographic scan (82% versus 69%, P=0.15) and unilateral lung was lower (10% versus 27%, P=0.03). Common complications including shock, acute respiratory distress syndrome, arrhythmia, and acute cardiac injury in patients on hemodialysis were significantly higher. Compared with controls, more patients on hemodialysis received noninvasive ventilation (25% versus 6%, P=0.008). As of March 19, 2020, three patients on hemodialysis (6%) were transferred to the intensive care unit and received invasive ventilation. Seven patients on hemodialysis (14%) had died.ConclusionsThe main symptoms of coronavirus disease 2019 pneumonia, including fever and cough, were less common in patients on hemodialysis. Patients on hemodialysis with coronavirus disease 2019 were at higher risk of death.
Stimulator of IFN genes (STING) is an adaptor that functions downstream of retinoic acid–inducible gene I (RIG-I) in mammalian cells; however, RIG-I is absent in chickens. We identified chicken STING (chSTING) as a critical mediator of virus-triggered type I IFN signaling in RIG-I–null chicken cells. Overexpression of chSTING in DF-1 cells inhibited Newcastle disease virus and avian influenza virus (AIV) viral replication and activated IRF-7 and NF-κB to induce expression of type I IFNs. Knockdown of endogenous chSTING abolished virus-triggered activation of IRF-7 and IFN-β and increased viral yield. chSTING was a critical component in the virus-triggered IRF-7 activation pathway and the cellular antiviral response. chSTING predominantly localized to the outer membrane of the endoplasmic reticulum and was also found in the mitochondrial membrane. Furthermore, knockdown of chSTING blocked polyinosinic-polycytidylic acid–, poly(deoxyadenylic-deoxythymidylic) acid–, and melanoma differentiation–associated gene 5 (MDA5)-stimulated induction of IFN-β. Coimmunoprecipitation experiments indicated that chicken MDA5 could interact with chSTING, and this interaction was enhanced by ectopically expressed chicken mitochondrial antiviral-signaling protein. Together, these results indicated that chSTING is an important regulator of chicken innate immune signaling and might be involved in the MDA5 signaling pathway in chicken cells. These results help with understanding the biological role of STING in innate immunity during evolution.
Staphylococcus aureus (S. aureus) is a Gram-positive pathogen causing a variety of infections in humans and animals. Extensive use of antibiotics has led to the emergence of methicillin-resistant S. aureus (MRSA). As an alternative antibacterial agent against drug-resistant S. aureus, a lytic phage, designated SLPW, was isolated from fecal sewage in a pig farm. The SLPW was morphologically classified under Podoviridae and contains a double-stranded DNA genome. The genome of SLPW was 17,861 bp (29.35% G+C) containing 20 open reading frames and lacked regions encoding lysogeny-related integrase gene and cI repressor gene. Phage SLPW showed a broad host range and high efficiency of plating against various types of S. aureus. One-step growth curve showed a short latency period (10 min) and a long lytic period (120 min). Phage SLPW remained stable under a wide range of temperatures or pH and was almost unaffected in chloroform or ultraviolet light. Further, it efficiently lysed MRSA strains in vitro and in vivo. Intraperitoneal phage administration at 1 h post-infection cured the mice and reduced the bacterial expression of inflammatory cytokines in mice. Specifically, the phage SLPW displayed a wide antibacterial spectrum. It was therapeutically effective against intra-abdominal infection in mice harboring different multilocus sequence typing (MLST) types of S. aureus strains. Therefore, phage SLPW is a potential therapeutic agent against MRSA infections.
Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that causes serious diseases in pigs and humans. GdpP protein is a recently discovered specific phosphodiesterase that degrades cyclic diadenosine monophosphate (c-di-AMP). It is widely distributed among the firmicutes phylum and altered expression of GdpP is associated with several phenotypes in various bacterial strains. We investigated the role of GdpP in physiology and virulence in SS2. An in-frame mutant of gdpP was constructed using homologous recombination and bacterial growth, biofilm formation, hemolytic activity, cell adherence and invasion, expression of virulence factors, and virulence were evaluated. Disruption of gdpP increased intracellular c-di-AMP level and affected growth and increased biofilm formation of SS2. Simultaneously, the gdpP mutant strain exhibited a significant decrease in hemolytic activity and adherence to and invasion of HEp-2 cells compared with the parental strain. Quantitative reverse transcriptase polymerase chain reaction indicated significantly reduced expression of the known virulence genes cps2, sly, fpbs, mrp, ef and gdh in the gdpP mutant. In murine infection models, the gdpP mutant strain was attenuated, and impaired bacterial growth was observed in specific organs. All these findings revealed a significant contribution of gdpP and its substrate (c-di-AMP) to the biology and virulence of SS2.
Bacterial biofilms are crucial to the pathogenesis of many important infections and are difficult to eradicate. Streptococcus suis is an important pathogen of pigs, and here the biofilm-forming ability of 32 strains of this species was determined. Significant biofilms were completely formed by 10 of the strains after 60 h of incubation, with exopolysaccharide production in the biofilm significantly higher than that in the corresponding planktonic cultures. S. suis strain SS2-4 formed a dense biofilm, as revealed by scanning electron microscopy, and in this state exhibited increased resistance to a number of antibiotics (ampicillin, amoxicillin, ciprofloxacin, kanamycin, and rifampin) compared to that of planktonic cultures. A bacteriophage lysin, designated LySMP, was used to attack biofilms alone and in combination with antibiotics and bacteriophage. The results demonstrated that the biofilms formed by S. suis, especially strains SS2-4 and SS2-H, could be dispersed by LySMP and with >80% removal compared to a biofilm reduction by treatment with either antibiotics or bacteriophage alone of less than 20%; in addition to disruption of the biofilm structure, the S. suis cells themselves were inactivated by LySMP. The efficacy of LySMP was not dose dependent, and in combination with antibiotics, it acted synergistically to maximize dispersal of the S. suis biofilm and inactivate the released cells. These data suggest that bacteriophage lysin could form part of an effective strategy to treat S. suis infections and represents a new class of antibiofilm agents.
Bacteriophage lysin has attracted considerable attentions as possible antimicrobial agents for solution of antibiotic resistance. SMP was a Streptococcus suis serotype 2 bacteriophage isolated from nasal swabs of healthy Bama minipigs. The putative SMP bacteriophage lysin, designated LySMP, was recombinantly expressed in Escherichia coli BL21, and chromatographically purified. Treated with 0.8% of beta-mercaptoethanol, LySMP exhibited an extensive lysin spectrum than those of whole phage against bacteria investigated. S. suis serotype 2, S. suis serotype 7 and S. suis serotype 9 strains were recovered from diseased pigs between 1998 and 2005 in China. Fifteen of seventeen strains of S. suis serotype 2 could be lysed, as well as S. suis serotype 7 and 9, Streptococcus equi ssp. zooepidemicus and Staphylococcus aureus. But E. coli and Salmonella enterica were not affected. Purified LySMP showed high degrading efficiency against PMSF or lysozyme treated cells comparing to PBS washed cells. Optimum pH and temperature conditions for the lysin were investigated by turbidity reduction assay. The lysin exerted efficient lysis activity at 37 degrees C, pH 5.2. The turbidity of bacterium investigated was observed to decrease by 1.2-68% in 30 min. Result indicated that putative LySMP could be a candidate antimicrobial agent in controlling S. suis infection.
IFN regulatory factor (IRF) 3 has been identified as the most critical regulator of both RNA and DNA virus–induced IFN production in mammals. However, ambiguity exists in research on chicken IRFs; in particular IRF3 seems to be missing in chickens, making IFN regulation in chickens unclear. In this study, we comprehensively investigated the potential IFN-related IRFs in chickens and showed that IRF7 is the most critical IFN-β regulator in chickens. With a chicken IRF7 (chIRF7) knockout DF-1 cell line, we conducted a series of experiments to demonstrate that chIRF7 is involved in both chicken STING (chSTING)- and chicken MAVS (chMAVS)-mediated IFN-β regulation in response to DNA and RNA viral infections, respectively. We further examined the mechanisms of chIRF7 activation by chSTING. We found that chicken TBK1 (chTBK1) is indispensable for chIRF7 activation by chSTING as well as that chSTING interacts with both chIRF7 and chTBK1 to function as a scaffold in chIRF7 activation by chTBK1. More interestingly, we discovered that chSTING mediates the activation of chIRF7 through a conserved SLQxSyS motif. In short, we confirmed that although IRF3 is missing in chickens, they employ IRF7 to reconstitute corresponding IFN signaling to respond to both DNA and RNA viral infections. Additionally, we uncovered a mechanism of chIRF7 activation by chSTING. The results will enrich and deepen our understanding of the regulatory mechanisms of the chicken IFN system.
BackgroundLong noncoding RNAs (lncRNAs) have been identified as a novel class of regulators implicated in diverse biological processes in human cancers. Currently, evidence have shown that SNHG6, a cancer-associated lncRNA, exerts critical functions in gastric cancer and hepatocellular carcinoma; however, its role in colorectal cancer (CRC) remains unclear.MethodsThe expression of SNHG6 was determined by quantitative real-time PCR in CRC tissues and cells. SNHG6 was downregulated by using RNAi technology. Cell proliferation was examined by MTT and clone formation assays. Cell migration and invasion were determined by wound healing and transwell assays. Fluorescence in situ hybridization assays were performed to examine subcellular localization of SNHG6 in CRC cells. Fluorescence reporter and Western blot assays were used to explore the potential mechanisms of SNHG6 in CRC progression.ResultsIn this study, we found that SNHG6 was significantly upregulated in CRC tissues and cell lines, compared with normal tissues and normal colorectal epithelial cell line NCM460, respectively. High expression of SNHG6 was positively correlated with tumor size, advanced TNM stage, and distant metastasis. Survival analyses revealed that SHNG6 was significantly associated with poor clinical outcomes and could serve as an independent prognostic factor. Loss-of-function studies demonstrated that SNHG6 knockdown inhibited CRC cell proliferation, induced G0/G1 arrest, promoted apoptosis, suppressed CRC cell migration and invasion, and restrained tumor growth. Mechanistic investigations showed that SNHG6 acted as a competing endogenous RNA for miR-181a-5p and attenuated the inhibitory effect of miR-181a-5p on E2F5.ConclusionTaken together, these results demonstrated that SNHG6 plays a crucial role in CRC progression via miR-181a-5p/E2F5 axis. Therefore, SNHG6 may serve as a prognostic and therapeutic biomarker in CRC.
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