Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recently identified human metapneumovirus (HMPV) is a worldwide respiratory virus affecting all age groups and causing pneumonia and bronchiolitis in severe cases. Despite its clinical significance, no specific antiviral agents have been approved for treatment of HMPV infection. Unlike the case for most paramyxoviruses, the fusion proteins (F) of a number of strains, including the clinical isolate CAN97-83, can be triggered by low pH. We recently reported that residue H435 in the HRB linker domain acts as a pH sensor for HMPV CAN97-83 F, likely through electrostatic repulsion forces between a protonated H435 and its surrounding basic residues, K295, R396, and K438, at low pH. Through site-directed mutagenesis, we demonstrated that a positive charge at position 435 is required but not sufficient for F-mediated membrane fusion. Arginine or lysine substitution at position 435 resulted in a hyperfusogenic F protein, while replacement with aspartate or glutamate abolished fusion activity. Studies with recombinant viruses carrying mutations in this region confirmed its importance. Furthermore, a second region within the F(2) domain identified as being rich in charged residues was found to modulate fusion activity of HMPV F. Loss of charge at residues E51, D54, and E56 altered local folding and overall stability of the F protein, with dramatic consequences for fusion activity. As a whole, these studies implicate charged residues and potential electrostatic interactions in function, pH sensing, and overall stability of HMPV F.
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PMID:Potential electrostatic interactions in multiple regions affect human metapneumovirus F-mediated membrane fusion. 2276 66

Streptococcus pneumoniae is a causative agent of nosocomial infections such as pneumonia, meningitis, and septicemia. Penicillin resistance in S. pneumoniae depends in part upon MurM, an aminoacyl-tRNA ligase that attaches L-serine or L-alanine to the stem peptide lysine of Lipid II in cell wall peptidoglycan. To investigate the exact substrates the translation machinery provides MurM, quality control by alanyl-tRNA synthetase (AlaRS) was investigated. AlaRS mischarged serine and glycine to tRNA(Ala), as observed in other bacteria, and also transferred alanine, serine, and glycine to tRNA(Phe). S. pneumoniae tRNA(Phe) has an unusual U4:C69 mismatch in its acceptor stem that prevents editing by phenylalanyl-tRNA synthetase (PheRS), leading to the accumulation of misaminoacylated tRNAs that could serve as substrates for translation or for MurM. Although the peptidoglycan layer of S. pneumoniae tolerates a combination of both branched and linear muropeptides, deletion of MurM results in a reversion to penicillin sensitivity in strains that were previously resistant. However, because MurM is not required for cell viability, the reason for its functional conservation across all strains of S. pneumoniae has remained elusive. We now show that MurM can directly function in translation quality control by acting as a broad specificity lipid-independent trans editing factor that deacylates tRNA. This activity of MurM does not require the presence of its second substrate, Lipid II, and can functionally substitute for the activity of widely conserved editing domain homologues of AlaRS, termed AlaXPs proteins, which are themselves absent from S. pneumoniae.
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PMID:Lipid II-independent trans editing of mischarged tRNAs by the penicillin resistance factor MurM. 2386 53

Small ruminant lentivirus (SRLV), also called ovine progressive pneumonia virus or maedi-visna, is present in 24% of US sheep. Like human immunodeficiency virus, SRLV is a macrophage-tropic lentivirus that causes lifelong infection. The production impacts from SRLV are due to a range of disease symptoms, including pneumonia, arthritis, mastitis, body condition wasting and encephalitis. There is no cure and no effective vaccine for preventing SRLV infection. However, breed differences in prevalence and proviral concentration indicate a genetic basis for susceptibility to SRLV. Animals with high blood proviral concentration show increased tissue lesion severity, so proviral concentration represents a live animal test for control post-infection in terms of proviral replication and disease severity. Recently, it was found that sheep with two copies of TMEM154 haplotype 1 (encoding lysine at position 35) had lower odds of SRLV infection. In this study, we examined the relationship between SRLV control post-infection and variants in two genes, TMEM154 and CCR5, in four flocks containing 1403 SRLV-positive sheep. We found two copies of TMEM154 haplotype 1 were associated with lower SRLV proviral concentration in one flock (P < 0.02). This identified the same favorable diplotype for SRLV control post-infection as for odds of infection. However, frequencies of haplotypes 2 and 3 were too low in the other three flocks to test. The CCR5 promoter deletion did not have consistent association with SRLV proviral concentration. Future work in flocks with more balanced allele frequencies is needed to confirm or refute TMEM154 association with control of SRLV post-infection.
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PMID:Mutations in Ovis aries TMEM154 are associated with lower small ruminant lentivirus proviral concentration in one sheep flock. 2493 28

Shuang-huang-lian injection (SHLI) is a famous Chinese patent medicine, which has been wildly used in clinic for the treatment of acute respiratory tract infection, pneumonia, influenza, etc. The existing randomized controlled trial (RCT) studies suggested that SHLI could afford a certain anti-febrile action. However, seldom does research concern the pharmacological mechanisms of SHLI. In the current study, we explored plasma metabolomic profiling technique and selected potential metabolic markers to reveal the antipyretic mechanism of SHLI on yeast-induced pyrexia rat model using UPLC-Q-TOF/MS coupled with multivariate statistical analysis and pattern recognition techniques. We discovered a significant perturbance of metabolic profile in the plasma of fever rats and obvious reversion in SHLI-administered rats. Eight potential biomarkers, i.e. 1) 3-hydeoxybutyric acid, 2) leucine, 3) 16:0 LPC, 4) allocholic acid, 5) vitamin B2, 6) Cys-Lys-His, 7) 18:2 LPC, and 8) 3-hydroxychola-7, 22-dien-24-oic acid, were screened out by OPLS-DA approach. Five potential perturbed metabolic pathways, i.e. 1) valine, leucine, and isoleucine biosynthesis, 2) glycerophospholipid metabolism, 3) ketone bodies synthesis and degradation, 4) bile acid biosynthesis, and 5) riboflavin metabolism, were revealed to relate to the antipyretic mechanisms of SHLI. Overall, we investigated antipyretic mechanisms of SHLI at metabolomic level for the first time, and the obtained results highlights the necessity of adopting metabolomics as a reliable tool for understanding the holism and synergism of Chinese patent drug.
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PMID:Plasma metabolomic profiling to reveal antipyretic mechanism of Shuang-huang-lian injection on yeast-induced pyrexia rats. 2494 May 99

Mannheimia haemolytica causes pneumonia in domestic and wild ruminants. Leukotoxin (Lkt) is the most important virulence factor of the bacterium. It is encoded within the four-gene lktCABD operon: lktA encodes the structural protoxin, and lktC encodes a trans-acylase that adds fatty acid chains to internal lysine residues in the protoxin, which is then secreted from the cell by a type 1 secretion system apparatus encoded by lktB and lktD. It has been reported that LktC-mediated acylation is necessary for the biological effects of the toxin. However, an LktC mutant that we developed previously was only partially attenuated in its virulence for cattle. The objective of this study was to elucidate the role of LktC-mediated acylation in Lkt-induced cytotoxicity. We performed this study in bighorn sheep (Ovis canadensis) (BHS), since they are highly susceptible to M. haemolytica infection. The LktC mutant caused fatal pneumonia in 40% of inoculated BHS. On necropsy, a large number of necrotic polymorphonuclear leukocytes (PMNs) were observed in the lungs. Lkt from the mutant was cytotoxic to BHS PMNs in an in vitro cytotoxicity assay. Flow cytometric analysis of mutant Lkt-treated PMNs revealed the induction of necrosis. Scanning electron microscopic analysis revealed the presence of pores and blebs on mutant-Lkt-treated PMNs. Mass spectrometric analysis confirmed that the mutant secreted an unacylated Lkt. Taken together, these results suggest that acylation is not necessary for the cytotoxic activity of M. haemolytica Lkt but that it enhances the potency of the toxin.
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PMID:Acylation Enhances, but Is Not Required for, the Cytotoxic Activity of Mannheimia haemolytica Leukotoxin in Bighorn Sheep. 2621 18

Acinetobacter baumannii is an important nosocomial pathogen, causing a variety of opportunistic infections of the skin, soft tissues and wounds, urinary tract infections, secondary meningitis, pneumonia and bacteremia. Over 63% of A. baumannii infections occurring in the United States are caused by multidrug resistant isolates, and pan-resistant isolates have begun to emerge that are resistant to all clinically relevant antibiotics. The complement system represents the first line of defense against invading pathogens. However, many A. baumannii isolates, especially those causing severe bacteremia are resistant to complement-mediated killing, though the underlying mechanisms remain poorly understood. Here we show for the first time that A. baumannii binds host-derived plasminogen and we identify the translation elongation factor Tuf as a moonlighting plasminogen-binding protein that is exposed on the outer surface of A. baumannii. Binding of plasminogen to Tuf is at least partly dependent on lysine residues and ionic interactions. Plasminogen, once bound to Tuf can be converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component C3b. Thus, Tuf acts as a multifunctional protein that may contribute to virulence of A. baumannii by aiding in dissemination and evasion of the complement system.
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PMID:Translation Elongation Factor Tuf of Acinetobacter baumannii Is a Plasminogen-Binding Protein. 2636 40

The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.
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PMID:PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS. 2697 18

Selection for residual feed intake (RFI), which is used to select animals for feed efficiency, also influences nutrient partitioning between growth and maintenance functions. This study was designed to investigate if selection for reduced RFI can alter the trade-off between growth and immunity and contributes to differences in metabolic responses to an inflammatory challenge. Piglets from 2 lines divergently selected on RFI (low: RFI, = 10, and high: RFI, = 11) were challenged at 55 d of age (on d 0) with complete Freund's adjuvant (CFA) to induce a noninfectious pneumonia. Plasma haptoglobin and nutrient concentrations (in fasted state and 2 h after feeding) were determined from d -1 to d 7, and tissue protein metabolism was determined on d 8. Haptoglobin concentrations were greater from d 1 to d 7 relative to d -1 ( < 0.01). Feed intake was less on d 1 than on the other days ( < 0.001), as was total AA plasma concentrations at fasted state ( < 0.05). Fasted concentrations of His ( = 0.06) and Trp ( = 0.05) tended to be less, those of Val were less ( < 0.05), and fed concentrations of Lys were increased ( < 0.05) on d 7 compared to d -1. Uremia was less on d 7 than on d -1 at fasted state ( < 0.05), whereas it did not vary at fed state ( 0.1). Fasted glucose and insulin plasma concentrations were stable across days ( 0.1). In the fed state and in only RFI pigs, glucose concentration was greater on d 1 than on d 3, 5, and 7 ( < 0.05). Total AA, Gln, Ile, Leu, Pro ( < 0.05), and hydroxyproline ( = 0.07) were less in RFI than RFI pigs at fed state, whereas Ala and Gly were less in RFI pigs at fasted and fed states ( < 0.05). Citrulline ( < 0.05) and Met ( < 0.01) concentrations were greater in RFI than RFI pigs in the fasted state, whereas Asp was greater in RFI pigs in both fasted and fed states ( < 0.05). On d 8, liver and LM protein synthesis tended to be lower ( = 0.07 and 0.09, respectively) and liver calpain activity was greater ( = 0.07) in RFI than RFI pigs. Liver and LM proteasome did not differ between lines ( 0.1). The metabolic differences between lines were not associated with differences in feed intake, ADG between d -1 and d 8, and haptoglobin concentration ( 0.1). Thus, it seems that that, using different metabolic strategies, both lines coped similarly with the CFA challenge. Contrary to our hypothesis, this experiment showed, in young pigs, no advantage of RFI animals in response to an inflammatory challenge.
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PMID:Metabolic response to an inflammatory challenge in pigs divergently selected for residual feed intake. 2706 26

Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. The infection process involves bacterial cell surface receptors, which interact with host extracellular matrix components to facilitate colonization and dissemination of bacteria. Here, we investigated the role of host-derived extracellular RNA (eRNA) in the process of pneumococcal alveolar epithelial cell infection. Our study demonstrates that eRNA dose-dependently increased S. pneumoniae invasion of alveolar epithelial cells. Extracellular enolase (Eno), a plasminogen (Plg) receptor, was identified as a novel eRNA-binding protein on S. pneumoniae surface, and six Eno eRNA-binding sites including a C-terminal 15 amino acid motif containing lysine residue 434 were characterized. Although the substitution of lysine 434 for glycine (K434G) markedly diminished the binding of eRNA to Eno, the adherence to and internalization into alveolar epithelial cells of S. pneumoniae strain carrying the C-terminal lysine deletion and the mutation of internal Plg-binding motif were only marginally impaired. Accordingly, using a mass spectrometric approach, we identified seven novel eRNA-binding proteins in pneumococcal cell wall. Given the high number of eRNA-interacting proteins on pneumococci, treatment with RNase1 completely inhibited eRNA-mediated pneumococcal alveolar epithelial cell infection. Our data support further efforts to employ RNAse1 as an antimicrobial agent to combat pneumococcal infectious diseases.
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PMID:Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells. 2789 61

Salmonella infections can be seen in four clinical types, namely gastroenteritis, bacteremia/sepsis, enteric fever and carriage. These infections can result in uncomplicated diarrhea in most cases, but can lead to invasive disease requiring antimicrobial therapy and can be life-threatening in elderly or immunocomprimised patients. Broad-spectrum cephalosporins and fluoroquinolones are crucial options in the treatment of the invasive infections. Ciprofloxacin resistance is rarely seen in non-typhoid Salmonella enterica isolates, and only in S. Typhimurium, S. Choleraesuis and S. Schwarzengrund. In this report, we aimed to discuss a patient infected with ciprofloxacin-resistant Salmonella Kentucky under the light of data from our country and the world. A 52-year-old male patient wih acute myocardial infarction was hospitalized in intensive care unit of cardiovasculer surgery for left ventricular assist device (LVAD) implantation for the treatment of left ventricular disfunction. On the seventh day of LVAD and coronary artery bypass grafting (CABG), the patient presented high fever and productive cough. His physical examination revealed hyperemia around the insertion point of right jugular central venous catheter (CVC) and a serous discharge from the insertion point of LVAD located just below the inferior edge of sternum. Empiric IV cefoperazone/sulbactam (SCF) therapy was started with the prediagnosis of pneumonia and bloodstream infection. The blood samples taken from peripheral veins and CVC, and swabs taken from LVAD insertion point for culture when the patient was febrile, revealed the growth of bacteria with S type and lactose-negative colonies on EMB and SS media. Biochemical characteristics of the isolate were as follows: lactose fermentation negative, H2S positive, IMVIC (-,+,-,+), urease negative, lysine/ornithine decarboxylase positive and motile. The bacteria was then identified as Salmonella enterica serotype Kentucky (8,20;i;z6) by agglutination tests. Antibiotic susceptibility tests were conducted according to CLSI guidelines and it was found as ampicillin- and ciprofloxacin-resistant. Ciprofloxacin resistance of the isolate was confirmed with E-test. Stool culture was performed to investigate the source of infection, and S. Kentucky was isolated. On the 15th day of SCF treatment, LVAD was taken out, and tissue cultures taken from the fibrillar tissues between pericardial layers during surgery, also yielded S. Kentucky growth. On the second day of SCF therapy the patient's fever returned normal and on the seventh day, CBC and CRP values were normalized. Nevertheless, the clinical situation of the patient worsened gradually and on the 40th day he was intubated due to low oxygen saturation and pleural effusion. His antibiotherapy was stopped on 42nd day as the blood cultures were negative and his clinical situation was attributed to cardiac failure. The patient died four days after the antibiotherapy has stopped due to cardiac reasons. To our knowledge, this is the first reported case infected with ciprofloxacin-resistant Salmonella Kentucky in our country.
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PMID:[Bacteremia caused by ciprofloxacin-resistant Salmonella serotype Kentucky: a case report and the review of literature]. 2812 65


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