Gene/Protein Disease Symptom Drug Enzyme Compound
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After several years of controversy, antibodies (Abs) are now believed to play an important role in the protection against fungal infections. Among them, recent data are strongly supporting the relevance of protective yeast killer toxin-like Abs ("antibiobodies", KT-Abs), which are able to exert a direct microbicidal activity by mimicking a killer toxin (PaKT) and its interaction with cell wall receptors on susceptible cells essentially constituted by beta-glucans. This review will focus on the implications of the yeast killer phenomenon, and, particularly, the occurrence and antimicrobial activity of protective antifungal KT-Abs, such as those produced during the course of experimental and natural infections caused by PaKT-sensitive microorganisms or produced by idiotypic vaccination with a PaKT-neutralizing mAb. The strong therapeutic activity exerted against different experimental mucosal and systemic mycoses by monoclonal and recombinant microbicidal KT-Abs (either in their soluble forms or expressed on human commensal bacteria) as well as by a synthetic killer peptide (KP, an antibody fragment engineered from the sequence of a recombinant KT-Ab) will be discussed. The surprisingly wide antimicrobial spectrum of activity against eukaryotic and prokaryotic pathogenic agents, such as fungi, bacteria and protozoa, of these Abs and Ab-derived molecules suggests new potential strategies for transdisease anti-infective prevention and therapy.
Curr Mol Med 2005 Jun
PMID:Protective antifungal yeast killer toxin-like antibodies. 1597

We present the case of a 6-year-old male who received an allogeneic bone marrow transplant as part of treatment for acute lymphoblastic leukemia. The patient relapsed 5 months after transplantation and received additional chemotherapy. He acquired an angioinvasive fungal infection that required transfusion of granulocytes. Approximately 5 weeks after relapsing (181 days after transplant), a bone marrow specimen was taken for molecular engraftment analysis and flow cytometry to assess graft loss as well as residual disease. The engraftment results generated by the multiple short tandem repeat loci tested were inconsistent, and alleles were present at several loci that were of neither patient nor donor origin. An error in specimen identification was initially considered. Further investigation into the circumstances surrounding procurement of the patient's bone marrow aspirate revealed that the patient had received a granulocyte transfusion approximately 10 hours before the bone marrow specimen was taken. In addition, morphological and flow cytometric analyses of the same bone marrow aspirate demonstrated a significant degree of peripheral blood contamination. We determined that the unknown alleles in the bone marrow engraftment specimen were derived from the donor of the transfused granulocytes. This case illustrates that white cell transfusion can lead to erroneous bone marrow engraftment results, particularly if only one microsatellite locus is used to monitor engraftment.
J Mol Diagn 2005 Aug
PMID:Bone marrow engraftment analysis after granulocyte transfusion. 1604 15

Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, an endemic mycosis of Latin America. This fungus presents a dimorphic character; it grows as a mycelium at room temperature, but it is isolated as yeast from infected individuals. It is believed that the transition from mycelium to yeast is important for the infective process. The Functional and Differential Genome of Paracoccidioides brasiliensis Project--PbGenome Project was developed to study the infection process by analyzing expressed sequence tags--ESTs, isolated from both mycelial and yeast forms. The PbGenome Project was executed by a consortium that included 70 researchers (professors and students) from two sequencing laboratories of the midwest region of Brazil; this project produced 25,741 ESTs, 19,718 of which with sufficient quality to be analyzed. We describe the computational procedures used to receive process, analyze these ESTs, and help with their functional annotations; we also detail the services that were used for sequence data exploration. Various programs were compared for filtering and grouping the sequences, and they were adapted to a user-friendly interface. This system made the analysis of the differential transcriptome of P. brasiliensis possible.
Genet Mol Res 2005 Jun 30
PMID:Bioinformatics of the Paracoccidioides brasiliensis EST Project. 1611 Apr 42

Proteases perform a wide variety of functions inside and outside cells, regulating many biological processes. Infectious microorganisms use proteases, either secreted or attached to their cell surface to weaken and invade their hosts. Therefore, proteases are targets for drugs against a diverse set of diseases. Paracoccidioides brasiliensis is the most prevalent fungal pathogen causing systemic mycosis in Latin America. The development of paracoccidioidomycosis depends on interactions between fungal and host components and proteases have been described as important factors implicated in the mechanism of host colonization by fungi. The primary goal for this study is to present an overview of the transcriptome sequences--identified cDNAs that encode proteases. We obtained a total of 53 cDNAs encoding proteases; 15 were classified as ATP-independent, 12 as ATP-dependent, 22 as proteasome subunits, and 4 as deubiquitinating proteases. The mechanisms and biological activity of these proteases differ in substrate specificity and in catalytic mechanisms.
Genet Mol Res 2005 Jun 30
PMID:Transcriptome overview of Paracoccidioides brasiliensis proteases. 1611 Apr 51

Rice blast, caused by Magnaporthe grisea, is the most important fungal disease of cultivated rice worldwide. We have developed a strategy for creating disease resistance to M. grisea whereby pathogen-induced expression of the afp (antifungal protein) gene from Aspergillus giganteus occurs in transgenic rice plants. Here, we evaluated the activity of the promoters from three maize pathogenesis-related (PR) genes, ZmPR4, mpi, and PRms, in transgenic rice. Chimeric gene fusions were prepared between the maize promoters and the beta-glucuronidase reporter gene (gus A). Histochemical assays of GUS activity in transgenic rice revealed that the ZmPR4 promoter is strongly induced in response to fungal infection, treatment with fungal elicitors, and mechanical wounding. The ZmPR4 promoter is not active in the seed endosperm. The mpi promoter also proved responsiveness to fungal infection and wounding but not to treatment with elicitors. In contrast, no activity of the PRms promoter in leaves of transgenic rice was observed. Transgenic plants expressing the afp gene under the control of the ZmPR4 promoter were generated. Transformants showed resistance to M. grisea at various levels. Our results suggest that pathogen-inducible expression of the afp gene in rice plants may be a practical way for protection against the blast fungus. Most agricultural crop species suffer from a vast array of fungal diseases that cause severe yield losses all over the world. Rice blast, caused by the fungus Magnaporthe grisea (Herbert) Barr (anamorph Pyricularia grisea), is the most devastating disease of cultivated rice (Oryza sativa L.), due to its
Mol Plant Microbe Interact 2005 Sep
PMID:Pathogen-induced production of the antifungal AFP protein from Aspergillus giganteus confers resistance to the blast fungus Magnaporthe grisea in transgenic rice. 1616 66

The complex relationship between the local inflammatory response and the spread of airway mycosis during prolonged glucocorticoid therapy in bronchial asthma patients remains unclear. We assessed the ability of airway leukocytes to produce nitric oxide (NO) in relation to differential inflammatory cell counts, levels of asthma severity, and coexisting airway mycotic infections. The study was carried out on leukocytes from the induced sputa (IS) of 14 patients with asthma complicated by mycotic airway infections undergoing prolonged glucocorticoid therapy (group FcA). Three groups of subjects without airway fungal infections were also studied: 18 glucocorticoid-treated asthmatics (group cA), 11 steroid-free asthmatics (group A), and 13 healthy control subjects (group H). In group FcA, both the level of spontaneous production of NO and the percentages of neutrophils in the IS were significantly higher than in all the remaining groups. Additionally, a significant positive correlation was noticed between the NO levels and both the percentages of neutrophils in the IS and the symptom intensity scores. The results suggest a possible predominant role of neutrophils in the overproduction of NO related to asthma severity and coexisting fungal infections in glucocorticoid-treated patients.
Cell Mol Biol Lett 2005
PMID:The overproduction of nitric oxide associated with neutrophilic predominance is relevant to airway mycotic infections in asthmatics undergoing prolonged glucocorticoid treatment. 1634 Dec 76

Infection imaging is complicated due to multitude of factors interfering with the design of radiopharmaceuticals. More than 3 decades ago, labeled leukocytes have been introduced for infection imaging and new radiopharmaceuticals have been emerging on regular basis. However, labeled leukocytes by in vivo and in vitro methods are very effective for diagnosing various lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease and in distinguishing prosthetic infection from loosening of prosthesis. But in vitro labeling method using (111)In-oxine, (99m)Tc-HMPAO or (99m)Tc-stannous colloid have the inherent limitation of personnel safety risks of infection and cross contamination. To overcome these problems, attempts have been made to directly target leukocytes by in vivo labeling techniques. There are several receptors present on the leukocytes and the granulocytes, which can be targeted with suitable ligands. These will include anti-NCA90-Fab, murine MoAb IgG(1) that is cross-reactive to antigen 95 on neutrophils, anti-CD15 antigen and DPC-11870 that targets the leukotriene B4 receptors of granulocytes. In a new approach, (99m)Tc-labeled ciprofloxacin has been developed to directly target ''live bacteria'' to detect infection by in vivo method. This approach showed considerable promise in the preliminary studies but clinical trials showed limitations. Analogs of a natural mammalian antimicrobial agents, such as Ubiquicidin were successful in animal studies and have now entered clinical trials. (99m)Tc-labeled fluconazole (a fungal antibiotic) and labeled Chitinase ((123)I-ChiB_E144Q), have been developed to detect fungal infection. The ability to distinguish between fungal and bacterial infection is considered important, as patients undergoing chemotherapy are prone to fungal infection. Undoubtedly, the new trends and new radiopharmaceuticals developed for infection and inflammation imaging have contributed towards a better understanding of the underlying processes.
Q J Nucl Med Mol Imaging 2005 Dec
PMID:Radiolabeled white blood cells and direct targeting of micro-organisms for infection imaging. 1640 16

7-Methylguanosine (m7G) modification of tRNA occurs widely in prokaryotes and eukaryotes, although information about its biological roles is limited. Here, we report that a gene involved in m7G modification of tRNA is required for infection by the phytopathogenic fungus Colletotrichum lagenarium. Analysis of the infection-deficient mutant of C. lagenarium, produced by plasmid insertional mutagenesis, identified a tagged gene that is designated APH1. The aph1 mutants, generated by targeted gene disruption, exhibit significant reduction in pathogenicity on the host plants. We conclude that APH1 is required for fungal infection in C. lagenarium. Aph1 showed a strong similarity to Saccharomyces cerevisiae Trm8 involved in m7G modification of tRNA. The m7G content of tRNA from the aph1 deletion mutant was severely reduced compared with that from the wild type, indicating that APH1 is required for m7G methyltransferase activity. Appressoria formed by the aph1 mutants developed penetration hyphae into cellophane, suggesting that appressoria of the mutants retain basic function for penetration. However, the aph1 mutants failed to develop intracellular penetration hyphae into epidermis of the host plants, suggesting a specific requirement of APH1 for appressorium-mediated host invasion. The mutants also had increased sensitivity to salinity and H2O2 stresses. Interestingly, a heat shock treatment on the host plants enabled the aph1 mutant to penetrate them. These data suggest that the APH1 is required for the plant invasion, probably to overcome environmental stresses derived from basal preinvasion (penetration) defence of the host plants.
Mol Microbiol 2006 Apr
PMID:A gene involved in modifying transfer RNA is required for fungal pathogenicity and stress tolerance of Colletotrichum lagenarium. 1655 22

Candida glabrata emerged in the last decade as a common cause of mucosal and invasive fungal infection, in large part due to its intrinsic or acquired resistance to azole antifungals such as fluconazole. In C. glabrata clinical isolates, the predominant mechanism behind azole resistance is upregulated expression of multidrug transporter genes CDR1 and PDH1. We previously reported that azole-resistant mutants (MIC >or= 64 microg ml(-1)) of strain 66032 (MIC = 16 microg ml(-1)) similarly show coordinate CDR1-PDH1 upregulation, and in one of these (F15) a putative gain-of-function mutation was identified in the single homologue of Saccharomyces cerevisiae transcription factors Pdr1-Pdr3. Here we show that disruption of C. glabrata PDR1 conferred equivalent fluconazole hypersensitivity (MIC = 2 microg ml(-1)) to both F15 and 66032 and eliminated both constitutive and fluconazole-induced CDR1-PDH1 expression. Reintroduction of wild-type or F15 PDR1 fully reversed these effects; together these results demonstrate a role for this gene in both acquired and intrinsic azole resistance. CDR1 disruption had a partial effect, reducing fluconazole trailing in both strains while restoring wild-type susceptibility (MIC = 16 microg ml(-1)) to F15. In an azole-resistant clinical isolate, PDR1 disruption reduced azole MICs eight- to 64-fold with no effect on sensitivity to other antifungals. To extend this analysis, C. glabrata microarrays were generated and used to analyse genome-wide expression in F15 relative to its parent. Homologues of 10 S. cerevisiae genes previously shown to be Pdr1-Pdr3 targets were upregulated (YOR1, RTA1, RSB1, RPN4, YLR346c and YMR102c along with CDR1, PDH1 and PDR1 itself) or downregulated (PDR12); roles for these genes include small molecule transport and transcriptional regulation. However, expression of 99 additional genes was specifically altered in C. glabrata F15; their roles include transport (e.g. QDR2, YBT1), lipid metabolism (ATF2, ARE1), cell stress (HSP12, CTA1), DNA repair (YIM1, MEC3) and cell wall function (MKC7, MNT3). These azole resistance-associated changes could affect C. glabrata tissue-specific virulence; in support of this, we detected differences in F15 oxidant, alcohol and weak acid sensitivities. C. glabrata provides a promising model for studying the genetic basis of multidrug resistance and its impact on virulence.
Mol Microbiol 2006 Aug
PMID:Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. 1680 98

The field of infectious diseases is in urgent need of new approaches to antimicrobial therapy. Radio-immunotherapy (RIT) has evolved into successful therapy for certain malignancies. Published preclinical and clinical investigations have demonstrated that radiolabeled microorganism-specific antibodies localize to tissue sites of bacterial and fungal infection. The potential of RIT as an antimicrobial treatment strategy has not been developed clinically, which could reflect lack of awareness of the difficult problems in clinical infectious diseases by the nuclear medicine community and of RIT by the infectious diseases physicians. We have recently demonstrated the feasibility of using RIT for treating murine cryptococcosis using a monoclonal antibody to Crypto-coccus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 or Rhenium-188. Subsequently, we showed the applicability of RIT to bacterial (Streptococcus pneumonia) and viral (HIV-1) infections. Treatment did not cause acute hematologic toxicity in treated animals. The mechanisms of RIT of infection include killing of microbial cells by ''direct hit'' and ''cross-fire'' effects, promotion of apoptosis-like death, cooperation with macrophages and modulation of the inflammatory response. RIT for infection is theoretically useful for any microbe susceptible to radiation, including bacteria, fungi, viruses and parasites. The promise of this technique is based on the fact that the technology is largely in place and that the only requirements are availability of microbe-specific monoclonal antibodies and suitable radionuclides. In fact, one could anticipate that targeting microbes will be easier than targeting neoplastic cells when the enormous antigenic differences between host and microbes are taken into consideration. However, considerable basic work remains to be done to ascertain the optimal conditions for the efficacy of RIT for infection.
Q J Nucl Med Mol Imaging 2006 Sep
PMID:Treatment of infection with radiolabeled antibodies. 1686 33


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