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PubMed2004

Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes.

Glutathione peroxidases are widespread among eukaryotic organisms and function as a major defense against hydrogen peroxide and organic peroxides. However, glutathione peroxidases are not well studied among prokaryotic organisms and have not previously been shown to promote bacterial virulence. Recently, a gene with homology to glutathione peroxidase was shown to contribute to the antioxidant defenses of Streptococcus pyogenes (group A streptococcus). Since this bacterium causes numerous suppurative diseases that require it to thrive in highly inflamed tissue, it was of interest to determine if glutathione peroxidase is important for virulence. In this study, we report that GpoA glutathione peroxidase is the major glutathione peroxidase in S. pyogenes and is essential for S. pyogenes pathogenesis in several murine models that mimic different aspects of streptococcal suppurative disease. In contrast, glutathione peroxidase is not essential for virulence in a zebrafish model of streptococcal myositis, a disease characterized by the absence of an inflammatory cell infiltrate. Taken together, these data suggest that S. pyogenes requires glutathione peroxidase to adapt to oxidative stress that accompanies an inflammatory response, and the data provide the first demonstration of a role for glutathione peroxidase in bacterial virulence. The fact that genes encoding putative glutathione peroxidases are found in the genomes of many pathogenic bacterial species suggests that glutathione peroxidase may have a general role in bacterial pathogenesis.

Animals↗
PubMed2005

Selective capture of Salmonella enterica serovar typhi genes expressed in macrophages that are absent from the Salmonella enterica serovar Typhimurium genome.

Thirty-six Salmonella enterica serovar Typhi-specific genes, absent from the Salmonella enterica serovar Typhimurium genome, that were expressed in human macrophages were identified by selective capture of transcribed sequences. These genes are located on 15 unique loci of the serovar Typhi genome, including Salmonella pathogenicity islands (SPI-7, SPI-8, and SPI-10) and bacteriophages (ST15, ST18, and ST35).

Fimbriae Proteins↗
PubMed2006

Acquisition and evolution of the exoU locus in Pseudomonas aeruginosa.

ExoU is a potent Pseudomonas aeruginosa cytotoxin translocated into host cells by the type III secretion system. A comparison of genomes of various P. aeruginosa strains showed that that the ExoU determinant is found in the same polymorphic region of the chromosome near a tRNA(Lys) gene, suggesting that exoU is a horizontally acquired virulence determinant. We used yeast recombinational cloning to characterize four distinct ExoU-encoding DNA segments. We then sequenced and annotated three of these four genomic regions. The sequence of the largest DNA segment, named ExoU island A, revealed many plasmid- and genomic island-associated genes, most of which have been conserved across a broad set of beta- and gamma-Proteobacteria. Comparison of the sequenced ExoU-encoding genomic islands to the corresponding PAO1 tRNA(Lys)-linked genomic island, the pathogenicity islands of strain PA14, and pKLC102 of clone C strains allowed us to propose a mechanism for the origin and transmission of the ExoU determinant. The evolutionary history very likely involved transposition of the ExoU determinant onto a transmissible plasmid, followed by transfer of the plasmid into different P. aeruginosa strains. The plasmid subsequently integrated into a tRNA(Lys) gene in the chromosome of each recipient, where it acquired insertion sequences and underwent deletions and rearrangements. We have also applied yeast recombinational cloning to facilitate a targeted mutagenesis of ExoU island A, further demonstrating the utility of the specific features of the yeast capture vector for functional analyses of genes on large horizontally acquired genetic elements.

Bacterial Proteins↗
PubMed2001

The SHI-3 iron transport island of Shigella boydii 0-1392 carries the genes for aerobactin synthesis and transport.

In Shigella boydii 0-1392, genes encoding the synthesis and transport of the hydroxamate siderophore aerobactin are located within a 21-kb iron transport island between lysU and the pheU tRNA gene. DNA sequence analysis of the S. boydii 0-1392 island, designated SHI-3 for Shigella island 3, revealed a conserved aerobactin operon associated with a P4 prophage-like integrase gene and numerous insertion sequences (IS). SHI-3 is present at the pheU tRNA locus in some S. boydii isolates but not in others. The map locations of the aerobactin genes vary among closely related species. The association of the aerobactin operon with phage genes and mobile elements and its presence at different locations within the genomes of enteric pathogens suggest that these virulence-enhancing genes may have been acquired by bacteriophage integration or IS element-mediated transposition. An S. boydii aerobactin synthesis mutant, 0-1392 iucB, was constructed and was similar to the wild type in tissue culture assays of invasion and intercellular spread.

Bacterial Proteins↗
PubMed2004

Sortase B, a new class of sortase in Listeria monocytogenes.

Sortases are transamidases that covalently link proteins to the peptidoglycan of gram-positive bacteria. The genome of the pathogenic bacterium Listeria monocytogenes encodes two sortases genes, srtA and srtB. The srtA gene product anchors internalin and some other LPXTG-containing proteins to the listerial surface. Here, we focus on the role of the second sortase, SrtB. Whereas SrtA acts on most of the proteins in the peptidoglycan fraction, SrtB appears to target minor amounts of surface polypeptides. We identified one of the SrtB-anchored proteins as the virulence factor SvpA, a surface-exposed protein which does not contain the LPXTG motif. Therefore, as in Staphylococcus aureus, the listerial SrtB represents a second class of sortase in L. monocytogenes, involved in the attachment of a subset of proteins to the cell wall, most likely by recognizing an NXZTN sorting motif. The DeltasrtB mutant strain does not have defects in bacterial entry, growth, or motility in tissue-cultured cells and does not show attenuated virulence in mice. SrtB-mediated anchoring could therefore be required to anchor surface proteins involved in the adaptation of this microorganism to different environmental conditions.

Amino Acid Sequence↗
PubMed1992

Presence of transplantable T-lymphoid cells in C57BL/6 mice infected with murine AIDS virus.

The Duplan strain of murine leukemia virus induces murine AIDS in C57BL/6 mice. When spleen cells from C57BL/6 mice infected with the virus were transplanted into nude mice, subcutaneous solid tumors at the transplanted sites were formed and splenomegaly and lymphadenopathy were induced. These transplantable cells were Thy-1- CD4+ alpha-beta T-cell receptor-positive T cells and integrated with the pathogenic defective viral genome. These results indicate that neoplastic cells of T-cell lineage were induced by infecting C57BL/6 mice with murine AIDS virus.

Animals↗
PubMed2004

Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity.

Nitric oxide (NO) may affect the genomes of various pathogens, and this mutagenesis is of particular interest for viral pathogenesis and evolution. Here, we investigated the effect of NO on viral replication and mutation. Exogenous or endogenous NO had no apparent antiviral effect on influenza A virus and Sendai virus. The mutagenic potential of NO was analyzed with Sendai virus fused to a green fluorescent protein (GFP) gene (GFP-SeV). GFP-SeV was cultured in SW480 cells transfected with a vector expressing inducible NO synthase (iNOS). The mutation frequency of GFP-SeV was examined by measuring loss of GFP fluorescence of the viral plaques. GFP-SeV mutation frequency in iNOS-SW480 cells was much higher than that in parent SW480 cells and was reduced to the level of mutation frequency in the parent cells by treatment with an NO synthase (NOS) inhibitor. Immunocytochemistry showed generation of more 8-nitroguanosine in iNOS-SW480 cells than in SW480 cells without iNOS transfection. Authentic 8-nitroguanosine added exogenously to GFP-SeV-infected CV-1 cells increased the viral mutation frequency. Profiles of the GFP gene mutations induced by 8-nitroguanosine appeared to resemble those of mutations occurring in mouse lungs in vivo. A base substitution that was characteristic of both mutants (those induced by 8-nitroguanosine and those occurring in vivo) was a C-to-U transition. NO-dependent oxidative stress in iNOS-SW480 cells was also evident. Together, the results indicate unambiguously that NO has mutagenic potential for RNA viruses such as Sendai virus without affecting viral replication, possibly via 8-nitroguanosine formation and cellular oxidative stress.

Animals↗
PubMed2000

Nonsuppurative meningoencephalitis associated with Aleutian mink disease parvovirus infection in ranch mink.

Severe nonsuppurative meningoencephalitis associated with Aleutian mink disease parvovirus (ADV) infection was observed in adult ranch mink. Brain lesions included severe, locally extensive to coalescing lymphoplasmacytic meningoencephalitis with accompanying gliosis, satellitosis, and mild extension of inflammation into the leptomeninges. ADV was identified in mesenteric lymph node, spleen, brain, and liver of affected mink by polymerase chain reaction techniques. Sequences of the ADV isolate (TH5) revealed 2 unique residues in the region of the viral genome that determines pathogenicity. These findings suggest that certain strains of ADV may preferentially cause disease in the nervous system. ADV infection should be considered in the differential diagnosis of neurologic disorders in mink.

Aleutian Mink Disease↗
PubMed2003

Treatment of canine cyclic neutropenia by lentivirus-mediated G-CSF delivery.

Cyclic neutropenia is a rare disease that occurs both in humans and gray collie dogs and is characterized by recurrent severe neutropenia leading to bacterial infections and shortened life expectancy. Daily injections of recombinant granulocyte colony-stimulating factor (rG-CSF) are effective in shortening the period of severe neutropenia and reducing infections. After demonstrating that rG-CSF induced elevated neutrophil production in an affected dog, cytokine administration was stopped and 109 infectious units (IUs) of a lentivirus pseudotyped with vesicular stomatitis virus G protein (VSV-G) encoding canine G-CSF cDNA was administered intramuscularly. Serial blood cell counts showed elevated neutrophil production for longer than 17 months. Although neutrophil counts continued to cycle, the range at nadirs was from 3710 to 5300 cells/microL, well above the nadirs before lentivirus administration. After the injection of lentivirus, mean neutrophil counts +/- SD were 12 460 +/- 4240 cells/microL, significantly increased over both pretreatment values of 3040 +/- 2540 cells/microL(P <.0001) and neutrophil counts during G-CSF administration of 10 290 +/- 4860 cells/microL(P <.007). The changes in blood counts from lentivirus injection were associated with absence of clinical signs of infection and fever. The gray collie continued to gain weight and was no longer housed in a pathogen-free environment. Genomic DNA from muscle at injection sites was positive for provirus, whereas gonad, lung, spleen, heart, liver, kidney, leukocytes, and noninjected muscle samples were all negative for provirus. Thus, intramuscular administration of lentivirus encoding G-CSF provided sustained therapeutic levels of neutrophils, suggesting this approach may be applied for long-term treatment of patients with cyclic and other neutropenias.

Animals↗
PubMed2001

The genome of Mycobacterium leprae: a minimal mycobacterial gene set.

Comparison of the recently sequenced genome of the leprosy-causing pathogen Mycobacterium leprae with other mycobacterial genomes reveals a drastic gene reduction and decay in M. leprae affecting many metabolic areas, exemplified by the retention of a minimal set of genes required for cell-wall biosynthesis.

Cell Membrane↗
PubMed2002

Small Molecule Inhibitors of Herpes Simplex Virus Type 1 Immediate Early Gene Expression.

The only therapeutic agents that are currently available for the treatment of herpes simplex virus type 1 (HSV-1) infections are a small number of nucleoside analogues, each of which acts by inhibiting the replication of the DNA genome of this pathogen. The observations that these drugs fail to modulate the frequency of latent virus reactivation and that their effectiveness can be significantly weakened through the acquisition of viral resistance mutations argue that efforts to identify additional classes of HSV-1 inhibitors should continue. One stage in the viral life cycle that would seem to be an excellent target for the development of novel therapeutic agents is the expression of HSV-1 immediate early genes, as this represents a key regulatory checkpoint utilized not only during lytic infections but also reactivation from latent infections. Full activation of HSV-1 immediate early gene promoters requires two viral-encoded polypeptides, VP16 and ICP0, each of which stimulates transcription by effecting multiple interactions with host cell proteins. Although to date no small molecule inhibitors of the VP16 and ICP0 proteins themselves have been discovered, a number of compounds that interfere with host cell functions critical for immediate early gene expression have been described. Several of the latter molecules target previously identified proteins that are known to be critical for cell viability, such as the proteasome, cyclin-dependent kinases and nuclear transcription factors. Unfortunately, these compounds typically reveal narrow therapeutic margins and poor selectivity when their antiviral and cytotoxic properties are compared. However, a number of other small molecule inhibitors have recently been described that exhibit remarkable levels of selective inhibition of HSV-1 immediate early gene expression. Although the development of each of these compound series has been discontinued because of pharmacokinetic or toxicological concerns, further studies with these promising leads could lead to the identification of one or more novel cellular targets against which a new generation of antiherpesviral drugs may be discovered. (c) 2002 Prous Science. All rights reserved.

Journal Article↗
PubMed2025

Establishment of reverse genetics systems for Colorado tick fever virus.

The Colorado tick fever virus (CTFV), which has 12-segmented double-stranded RNA genomes, is a pathogenic arbovirus that causes severe diseases in humans. However, little progress has been made in the analysis of replication mechanisms and pathogenicity. This virological constraint is due to the absence of a reverse genetics system for CTFV; therefore, we aimed to establish the system. Initially, the efficacy of CTFV replication was investigated in various cell lines. CTFV was found to grow in many cell types derived from different hosts and organs. Subsequently, BHK-T7 cells stably expressing T7 RNA polymerase were transfected with plasmids encoding each of the 12 CTFV gene segments, expression plasmids encoding all CTFV proteins, and a vaccinia virus RNA-capping enzyme. Following transfection, the cells were co-cultured with Vero or HeLa cells. Using this system, we rescued monoreassortants and recombinant viruses harboring peptide-tagged viral proteins. Furthermore, an improved system using Expi293F cells expressing T7 RNA polymerase was established, which enabled the generation of recombinant reporter CTFVs. In conclusion, these reverse genetics systems for CTFV will greatly contribute to the understanding of viral replication mechanisms, pathogenesis, and transmission, ultimately facilitating the development of rational treatments and candidate vaccines.

Animals↗
PubMed2001

Cloning and sequence determination of a gene encoding an osmotin-like protein from strawberry (Fragaria X ananassa Duch.).

Osmotin and osmotin-like proteins (OLPs) are pathogenesis-related (PR) proteins, whose synthesis is normally stimulated upon infection of plants by pathogens. A strawberry genomic clone containing an osmotin-like protein (OLP) gene was isolated and sequenced. This clone contains an open reading frame of 681 nucleotides without any intron. The predicted amino acid sequence of the protein shares high degrees of homology with a number of other OLPs and related proteins, of which several are known to have antifungal activities. Southern hybridization analysis of strawberry genomic DNA suggested that the OLP is coded by a multi-gene family. Results from reverse transcriptase-polymerase chain reaction indicated that this OLP gene is expressed in uninfected strawberry plants.

Amino Acid Sequence↗
PubMed2003

Immunoresponse of Coho salmon immunized with a gene expression library from Piscirickettsia salmonis.

We have used the expression library immunization technology to study the protection of Coho salmon Oncorhynchus kisutch to the infection with Piscirickettsia salmonis. Purified DNA from this bacterium was sonicated and the fragments were cloned in the expression vector pCMV-Bios. Two libraries were obtained containing 22,000 and 28,000 colonies and corresponding to approximately 8 and 10 times the genome of the pathogen, respectively. On average, the size of the inserts ranged between 300 and 1,000 bp. The plasmid DNA isolated from one of these libraries was purified and 20 micrograms were injected intramuscularly into 60 fish followed by a second dose of 10 micrograms applied 40 days later. As control, fish were injected with the same amount of DNA of the vector pCMV-Bios without insert. The titer of IgM anti-P. salmonis of vaccinated fish, evaluated 60 days post-injection, was significantly higher than that of the control group injected with the vector alone. Moreover, this response was specific against P. salmonis antigens, since no cross reaction was detected with Renibacterium salmoninarum and Yersinia ruckeri. The vaccinated and control fish were challenged 60 days after the second dose of DNA with 2.5 x 10(7) P. salmonis corresponding to 7.5 times the LD50. At 30 days post-challenge, 100% mortality was obtained with the control fish while 20% of the vaccinated animals survived. All surviving fish exhibited a lower bacterial load in the kidney than control fish. The expression library was also tested in Balb/c mice and it was found that the humoral immune response was specific to P. salmonis and it was dependent on the amount of DNA injected.

Animals↗
PubMed2006

Arabidopsis thaliana: a model host plant to study plant-pathogen interaction using Chilean field isolates of Botrytis cinerea.

One of the fungal pathogens that causes more agriculture damage is Botrytis cinerea. Botrytis is a constant threat to crops because the fungus infects a wide range of host species, both native and cultivated. Furthermore, Botrytis persists on plant debris in and on the soil. Some of the most serious diseases caused by Botrytis include gray mold on vegetables and fruits, such as grapes and strawberries. Botrytis also causes secondary soft rot of fruits and vegetables during storage, transit and at the market. In many plant-pathogen interactions, resistance often is associated with the deposition of callose, accumulation of autofluorescent compounds, the synthesis and accumulation of salicylic acid as well as pathogenesis-related proteins. Arabidopsis thaliana has been used as a plant model to study plant-pathogen interaction. The genome of Arabidopsis has been completely sequenced and this plant serves as a good genetic and molecular model. In this study, we demonstrate that Chilean field isolates infect Arabidopsis thaliana and that Arabidopsis subsequently activates several defense response mechanisms associated with a hypersensitive response. Furthermore, we propose that Arabidopsis may be used as a model host species to analyze the diversity associated with infectivity among populations of Botrytis cinerea field isolates.

Arabidopsis↗
PubMed2000

[Molecular biology characteristics of Helicobacter pylori].

Attention has been recently adverted to the Helicobacter pylori (H. pylori) by the fact, that its association with occurrence of gastroduodenal ulcer and gastric carcinoma had been justified. Our current understanding about metabolism and physiology of it is still not full, however, great strides have been made as for the methods of investigation during the last 16 years. Complete genome sequence of pathogenic strain of the bacteria have recently became identified, by which certain fundamental aspects of biology of H. pylori have been highlighted. Based on data, infection may presumably act as a cofactor to the development of peptic ulcer disease and carcinogenesis, however, details of pathomechanism are still unclear. Variability and genotype of bacteria, immune reactions and genetic patterns of host organism and mechanisms sustaining the balance of mucosal integrity may have additional influence. This study provides an overview on the current understanding about molecular biology of H. pylori.

Adenocarcinoma↗
PubMed2003

[Hansen's disease in the laboratory].

A physical doctor with a PhD in Pathology, Euzenir Nunes Sarno studies the immunology factors of Hansen's disease, one of the oldest chronic infections and that is an exclusively human disease. Staff member of an ambulatory that has become a reference on the disease in Brazil with 220 to 250 new patients per year, Euzenir emphasizes that the fact one cannot cultivate Mycobacterium leprae brings about some everlasting questions in relation to the transmission of and the sensitivity to the disease. There are also many epidemiology questions that remain unanswered. Estimates show that, among those who have contact with multi-bacilli patients, 90% are infected but only about 8% get sick. The high infection rate of those who live with multi-bacilli patients but never fall sick shows that just a small number of individuals are sensitive to Mycobacterium leprae. This is one of the questions immunology has not been able to answer. Why do some people resist to it and some don't? The figures are even lower when compared to those who are in contact with patients that are paucibacillus-infected, i.e. a manifestation of the disease with few bacilli. Hansen's disease is known as a skin malady. But, according to the specialist, its first damage is to the nerve, when the area becomes insensitive. Besides damaging the sensitive skin nerves, the disease can lead to motor disability and irreversible deformities, which sometimes lead to the amputation of limbs and protruded parts of the body. Mycobacterium leprae was one of the first pathogenic bacteria whose genome sequence has been entirely mapped. Only now we have the capacity to have more precise assessments. The disease is not inherited, and only in 1986 health services in Brazil began to take the responsibility for both the disease and its patients. During the twenty-year military dictatorship the country underwent, the health system was dismantled. In 1991, the one-year treatment with three drugs - Dapsone, Rifanpicine and Clofazimine- was introduced in our country. Just 30% of the cases get to negative results after the treatment. according to the interviewee, whereas tuberculosis is a highly virulent multi-bacilli disease, leprosy bacillus is not virulent, is a 'lazy' germ at the end of its evolutional process. One third of its genome does not work.

Autobiographies as Topic↗
PubMed2003

Immunogenomics: towards a digital immune system.

One of the major differences that set apart vertebrates from non-vertebrates is the presence of a complex immune system. Over the past 400-500 million years, many novel immune genes and gene families have emerged and their products form sophisticated pathways providing protection against most pathogens. The Human Genome Project has laid the foundation to study these genes and pathways in unprecedented detail. Members of the immunoglobulin (Ig) superfamily alone were found to make up over 2% of human genes possibly constituting the largest gene family in the human genome. A subgroup of these human immune genes, those (among others) involved in antigen processing and presentation, are encoded in a single region, the major histocompatibility complex (MHC) on the short arm of chromosome 6. My laboratory has a long-standing interest in understanding the molecular organization and evolution of the MHC. To this end, we have been generating a range of MHC genomic resources that we make available in the form of maps and databases. Much of the complex data of the immune system can be reduced to binary (on/off) information that can easily be made available and analysed by bioinformatics approaches, thus contributing to better understand immune function via a 'digital immune system'.

Animals↗