Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human pathogen Streptococcus pneumoniae contains genes for a putative polyamine ABC transporter which are organized in an operon and designated potABCD. Polyamine transport protein D (PotD) is an extracellular protein which binds polyamines and possibly other structurally related molecules. PotD has been shown to contribute to virulence in both a murine sepsis model and a pneumonia model with capsular type 3 pneumococci. The protective efficacy of recombinant PotD was evaluated by active immunization and intravenous challenge with capsular type 3 pneumococci in CBA/N mice. Immunized mice had 91.7% survival following lethal pneumococcal challenge, compared with 100% mortality in the control group. Immunized animals had high-titer anti-PotD antibodies following three immunizations with alum. Protection in a sepsis model was also seen after passive administration of rabbit antiserum raised against PotD (P < 0.004). These results suggest that antibodies to PotD confer protection against invasive pneumococcal disease and that this protein should be studied further as a potential vaccine candidate for protection against invasive pneumococcal infections.
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PMID:Immunization with polyamine transport protein PotD protects mice against systemic infection with Streptococcus pneumoniae. 1698 68

Protein-based vaccines are considered to be the next-generation of pneumococcal vaccines. Here we evaluated the protection elicited by immunization with recombinant glutamyl tRNA synthetase (Gts), polyamine transport protein D (PotD) and sortase A (SrtA) antigens in preclinical mouse models. In mucosal immunization studies, intranasal immunization with either Gts, PotD or SrtA could significantly reduce pneumococcal nasopharyngeal and lung colonization and significantly increase mice survival times following invasive pneumococcal challenge, and combinations of these antigens could enhance this protection. In systemic immunization studies, intraperitoneal immunization with multiple protein antigens also provided better protection against pneumococcal sepsis caused by different pneumococcal strains. Finally, passive immunization studies showed an additive effect by using multiple anti-sera when compared to single anti-sera. Therefore, a multicomponent protein-based pneumococcal vaccine composed of Gts, PotD or SrtA could confer protection against pneumococcal colonization as well as invasive infections in terms of efficacy of protection and serotype coverage.
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PMID:Protection against pneumococcal infection elicited by immunization with glutamyl tRNA synthetase, polyamine transport protein D and sortase A. 2246 66

Polyhistidine triad protein D (PhtD) has been described as a promising vaccine candidate for use against Streptococcus pneumoniae, but there has been a lack of examination of its structure and of which region(s) of the protein are targeted by protective immune responses. In this study, we purified recombinant truncated derivatives of PhtD and examined their secondary structural composition, as well as their capacity to bind antibodies from polyclonal murine serum generated against the full length protein. This allowed the identification of a particularly immunogenic fragment of PhtD, which was also purified and characterised. The truncated derivatives were tested as vaccine antigens in mouse models of pneumococcal sepsis and colonisation, using alum and E. coli heat labile toxin B subunit respectively as adjuvants. These experiments revealed that whilst the immunogenic region identified may be a promising candidate to protect against sepsis, the full length PhtD was ineffective at conferring significant protective immunity. These results are significant for the potential for PhtD to be used in novel vaccines, which are currently being tested in clinical trials.
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PMID:Vaccination against Streptococcus pneumoniae using truncated derivatives of polyhistidine triad protein D. 2420 51

Haemophilus parasuis is a commensal bacterium of the upper respiratory tract of healthy pigs. However, in conjunction with viral infections in immunocompromised animals H. parasuis can transform into a pathogen that is responsible for causing Glasser's disease which is typically characterized by fibrinous polyserositis, polyarthritis, meningitis and sometimes acute pneumonia and septicemia in pigs. Haemophilus parasuis serovar 5 is highly virulent and more frequently isolated from respiratory and systemic infection in pigs. Recently a highly virulent H. parasuis serovar 4 was isolated from the tissues of diseased pigs. To understand the differences in virulence and virulence-associated genes between H. parasuis serovar 5 and highly virulent H. parasuis serovar 4 strains, a genomic library was generated by TruSeq preparation and sequenced on Illumina HiSeq 2000 obtaining 50 bp PE reads. A three-way comparative genomic analysis was conducted between two highly virulent H. parasuis serovar 4 strains and H. parasuis serovar 5. Haemophilus parasuis serovar 5 GenBank isolate SH0165 (GenBank accession number CP001321.1) was used as reference strain for assembly. Results of these analysis revealed the highly virulent H. parasuis serovar 4 lacks genes encoding for, glycosyl transferases, polysaccharide biosynthesis protein capD, spore coat polysaccharide biosynthesis protein C, polysaccharide export protein and sialyltransferase which can modify the lipopolysaccharide forming a short-chain LPS lacking O-specific polysaccharide chains often referred to as lipooligosaccharide (LOS). In addition, it can modify the outer membrane protein (OMP) structure. The lack of sialyltransferase significantly reduced the amount of sialic acid incorporated into LOS, a major and essential component of the cell wall and an important virulence determinant. These molecules may be involved in various stages of pathogenesis through molecular mimicry and by causing host cell cytotoxicity, reduced inflammatory and immunological response to infection with this organism. The mechanism by which sialyation of LPS contributes to virulence is a key to understanding the pathogenesis of this highly virulent H. parasuis serovar 4. This analysis also revealed the presence of virulence associated genes similar to the MerR family transcriptional regulators, macrophage infectivity potentiator protein, hemolysin, opacity associated protein, toxin antitoxin system, and virulence associated protein D and colicins. Haemophilus parasuis serovar 4 variants also possess extensive metal ion uptake and regulation mechanism which controls various virulence and virulence associated genes. A combination of virulence associated factors and/or genes and proteins with overlapping functions may be responsible for the apparent enhanced virulence of this organism. The extensive structural modification of LOS and OMP of variant H. parasuis serovar 4 strains appear to aid in nasal colonization, are associated with the organisms' ability to evade the host immune response and provide serum-resistance. In addition, the combination of capsule modification and phase variation due to LOS substitutions could help variant H. parasuis serovar 4 transform into a highly virulent pathogen. Based on these results, the variant H. parasuis serovar 4 strains harbor a diverse repertoire of virulence associated genes which have not been previously reported.
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PMID:Map-based comparative genomic analysis of virulent haemophilus parasuis serovars 4 and 5. 2587 16

Currently marketed Streptococcus pneumoniae (Spn) vaccines, which contain polysaccharide capsular antigens from the most common Spn serotypes, have substantially reduced pneumococcal disease rates but have limited coverage. A trivalent pneumococcal protein vaccine containing pneumococcal choline-binding protein A (PcpA), pneumococcal histidine triad protein D (PhtD), and detoxified pneumolysin is being developed to provide broader, cross-serotype protection. Antibodies against detoxified pneumolysin protect against bacterial pneumonia by neutralizing Spn-produced pneumolysin, but how anti-PhtD and anti-PcpA antibodies protect against Spn has not been established. Here, we used a murine passive protection sepsis model to investigate the mechanism of protection by anti-PhtD and anti-PcpA antibodies. Depleting complement using cobra venom factor eliminated protection by anti-PhtD and anti-PcpA monoclonal antibodies (mAbs). Consistent with a requirement for complement, complement C3 deposition on Spn in vitro was enhanced by anti-PhtD and anti-PcpA mAbs and by sera from PhtD- and PcpA-immunized rabbits and humans. Moreover, in the presence of complement, anti-PhtD and anti-PcpA mAbs increased uptake of Spn by human granulocytes. Depleting neutrophils using anti-Ly6G mAbs, splenectomy, or a combination of both did not affect passive protection against Spn, whereas depleting macrophages using clodronate liposomes eliminated protection. These results suggest anti-PhtD and anti-PcpA antibodies induced by pneumococcal protein vaccines protect against Spn by a complement- and macrophage-dependent opsonophagocytosis.
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PMID:Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism. 2913 32

Introduction: Pneumococcal diseases (including pneumonia, meningitis and sepsis) are among the leading vaccine-preventable causes of death in under-5-year-olds. Pneumococci are also one of the main bacterial pathogens associated with acute otitis media (AOM). Infant immunization programs with pneumococcal conjugate vaccines (PCVs) have led to stark reductions in pneumococcal disease rates.Areas covered: We summarized the development of the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and evidence of its protective effect in children, since its licensure one decade ago. We highlighted the most recent data from post-licensure studies on invasive pneumococcal disease (IPD), pneumonia and AOM and from health economic evaluations. We present results from a model estimating PHiD-CV's impact on pneumococcal-related deaths.Expert opinion: Recent data from post-licensure studies confirm the previously demonstrated positive impact of PHiD-CV on IPD, pneumonia, AOM and AOM-related interventions (e.g., antibiotic use). Despite the success of infant PHiD-CV (and other PCV) programs, pneumococcal diseases still pose a substantial public health burden. Further reducing this burden will require improving access to currently available PCVs, increasing vaccination coverage and addressing the remaining burden due to non-vaccine serotypes. Future availability of lower-cost PCVs, PCVs with a broader serotype coverage and serotype-independent vaccines may contribute to this.
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PMID:Ten years of experience with the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (Synflorix) in children. 3219 2