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PubMed1990

Generation of hybrid genes and proteins by vaccinia virus-mediated recombination: application to human immunodeficiency virus type 1 env.

The ability of poxviruses to undergo intramolecular recombination within tandemly arranged homologous sequences can be used to generate chimeric genes and proteins. Genes containing regions of nucleotide homology will recombine to yield a single sequence composed of portions of both original genes. A recombinant virus containing two genes with a number of conserved regions will yield a population of recombinant viruses containing a spectrum of hybrid sequences derived by recombination between the original genes. This scheme has been used to generate hybrid human immunodeficiency virus type 1 env genes. Recombinant vaccinia viruses that contain two divergent env genes in tandem array have been constructed. In the absence of selective pressure to maintain both genes, recombination between conserved homologous regions in these genes generated a wide range of progeny, each of which expressed a novel variant polypeptide encoded by the newly created hybrid env gene. Poxvirus-mediated recombination may be applied to map type-specific epitopes, to create novel pharmaceuticals such as hybrid interferons, to study receptor-binding or enzyme substrate specificities, or to mimic the antigenic diversity found in numerous pathogens.

Animals↗

PubMed2025

Emergence of carbapenem-resistant Serratia marcescens co-harboring blaNDM-1, blaKPC-2, and blaSRT-2 in bloodstream infection.

Serratia marcescens is an emerging opportunistic pathogen with high genetic diversity. The emergence and prevalence of carbapenem-resistant S. marcescens poses a major health threat due to its intrinsic resistance to multiple antibiotics, which severely restricts the selection and treatment of antibiotics for S. marcescens infection. This study presents the first documented case in China of a bloodstream infection caused by Staphylococcus epidermidis and S. marcescens strain (designated S96) co-producing blaNDM-1, blaKPC-2, and blaSRT-2. Strain S96 exhibited resistance to nearly all categories of β-lactam antimicrobials, β-lactam/inhibitor combinations, aminoglycosides, quinolones, and other clinical antibacterial agents, with the exception of tigecycline. Our main objective was to characterize the genetic mechanisms underlying its carbapenem resistance and plasmid transfer potential. Whole-genome sequencing revealed blaKPC-2 on a 44,047 bp "IncX6-like" plasmid and blaNDM-1 on a 100,081 bp IncFII(Yp)-type plasmid, alongside chromosomal blaSRT-2 and aac(6')-Ic. "IncX6-like" and IncFII(Yp)-type plasmids are widely distributed among carbapenem-resistant Enterobacteriaceae strains globally. Conjugation experiments demonstrated that the blaNDM-1-carrying plasmid could be successfully transferred to recipient Escherichia coli 600, with no significant fitness cost observed (P > 0.05). The experimental results demonstrate that carbapenem-resistant genes can disseminate among Enterobacteriaceae via plasmid-mediated horizontal transfer between bacterial cells. Comparative genomic analysis revealed plasmid structural homology with global counterparts, demonstrating IS-mediated recombination and horizontal gene transfer. The low adaptive cost of plasmid carriage and multidrug resistance phenotype pose significant challenges for clinical management. This study highlights the need for enhanced clinical surveillance and antibiotic stewardship to curb the spread of such multidrug-resistant pathogens.IMPORTANCECarbapenem resistance in Serratia marcescens is primarily mediated by Klebsiella pneumoniae carbapenemase (KPC), with New Delhi metallo-β-lactamase (NDM) being a relatively uncommon alternative resistance mechanism. KPC-2 and NDM-1 coexisting in S. marcescens is extremely rare clinically. This study reports the first clinical isolate of S. marcescens in China co-harboring blaNDM-1, blaKPC-2, and blaSRT-2. The isolate exhibits multidrug resistance to nearly all β-lactam antibiotics and β-lactam/inhibitor combinations, with low adaptive costs and high dissemination potential. The potential spread of resistance genes through mobile genetic elements poses a serious public health risk. The study underscores the need for enhanced surveillance, rational antibiotic use, and novel strategies to combat resistance. It also provides insights into the evolutionary mechanisms of bacterial resistance, emphasizing the urgent need for interventions to address the growing threat of antimicrobial resistance.

Humans↗

PubMed2005

Toward an understanding of NKT cell biology: progress and paradoxes.

Natural killer T (NKT) cells constitute a conserved T cell sublineage with unique properties, including reactivity for a synthetic glycolipid presented by CD1d, expression of an invariant T cell antigen receptor (TCR) alpha chain, and unusual requirements for thymic selection. They rapidly produce many cytokines after stimulation and thus influence diverse immune responses and pathogenic processes. Because of intensive research effort, we have learned much about factors promoting the development and survival of NKT cells, regulation of their cytokine production, and the means by which they influence dendritic cells and other cell types. Despite this progress, knowledge of the natural antigen(s) they recognize and their physiologic role remain incomplete. The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and we cannot predict which will occur. Despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.

Animals↗

PubMed2026

De Novo TRIO Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus.

Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architecture remains incompletely defined. We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in TRIO (c.3232C > T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of TRIO variation in our CV/CH cohort (2,697 patient-parent trios) using exome sequencing. We identified five additional unrelated probands with de novo TRIO variants, including two novel substitutions affecting the same residue within the Ras-GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene-level enrichment for protein-damaging de novo variants (adjusted p = 6.12 × 10-5). All affected individuals exhibited CV, frequently accompanied by developmental delay and additional structural brain abnormalities. In silico structural modeling predicted that associated variants destabilize critical TRIO Ras-GEF domains required for Rho GTPase activation. Analysis of single-nucleus transcriptomic data from the developing human neocortex revealed enrichment of TRIO expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with TRIO de novo variants and reported CV or CH, including an unrelated patient with the same p.(Arg1078Trp) substitution. Together, these findings expand the phenotypic spectrum associated with pathogenic TRIO variation to include CV/CH and support TRIO as a clinically relevant gene in the genetic evaluation of syndromic CV/CH patients.

Humans↗

PubMed2005

Role of protein phosphorylation on serine/threonine and tyrosine in the virulence of bacterial pathogens.

Bacterial pathogens have developed a diversity of strategies to interact with host cells, manipulate their behaviors, and thus to survive and propagate. During the process of pathogenesis, phosphorylation of proteins on hydroxyl amino acids (serine, threonine, tyrosine) occurs at different stages, including cell-cell interaction and adherence, translocation of bacterial effectors into host cells, and changes in host cellular structure and function induced by infection. The phosphorylation reactions are catalyzed in a reversible fashion by specific protein kinases and phosphatases that belong to either the invading bacterial cells or the infected eukaryotic host cells. Among the various virulence factors involved in bacterial pathogenesis, special attention has been paid recently to the cell wall components, exopolysaccharides. A major breakthrough has been made by showing the existence of a biological link between the activity of certain protein-tyrosine kinases/phosphatases and the production and/or transport of surface polysaccharides. In addition, genetic studies have revealed a key role played by some serine/threonine kinases in pathogenesis. Considering the structural organization and membrane topology of these different kinases, it can be envisaged that they operate as one-component systems in signal transduction pathways, in the form of single proteins containing input and output domains on the same polypeptide chain. From a general standpoint, the demonstration of a direct relationship between protein phosphorylation on serine/threonine/tyrosine and bacterial virulence represents a novel concept of great importance in deciphering the molecular and cellular mechanisms that underlie pathogenesis.

Adaptation, Physiological↗

PubMed1999

Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease.

Gaucher disease is an autosomal recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal hydrolase, acid beta-glucosidase. Three phenotypically distinct subtypes result from different acid beta-glucosidase mutations encoding enzymes with absent or low activity. A severe neonatal type 2 variant who presented with collodion skin, ichthyosis, and a rapid neurodegenerative course had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K+L444P, and a paternally inherited nonsense mutation, E233X. Because the only other non-pseudogene-derived complex allele, D140H+E326K, also had the E326K lesion and was reported in a mild type 1 patient with a D140H+E326K/K157Q genotype, these complex alleles and their individual mutations were expressed and characterized. Because the E233X mutation expressed no activity and the K157Q allele had approximately 1% normal specific activity based on cross-reacting immunologic material (CRIM SA) in the baculovirus system, the residual activity in both patients was primarily from their complex alleles. In the type 1 patient, the D140H+E326K allele was neuroprotective, encoding an enzyme with a catalytic efficiency similar to that of the N370S enzyme. In contrast, the E326K+L444P allele did not have sufficient activity to protect against the neurologic manifestations and, in combination with the inactive E233X lesion, resulted in the severe neonatal type 2 variant. Thus, characterization of these novel genotypes with non-pseudogene-derived complex mutations provided the pathogenic basis for their diverse phenotypes.

Alleles↗

PubMed2000

Antiviral therapy for enteroviruses and rhinoviruses.

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens--the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.

3C Viral Proteases↗

PubMed2003

Selection assisted by a BoLA-DR/DQ haplotype against susceptibility to bovine dermatophilosis.

Bovine dermatophilosis is a severe skin infection of tropical ruminants inducing a severe loss in productivity and a 15% mortality rate. This disease is caused by the actinomycete bacterium Dermatophilus congolensis associated with the tick Amblyomma variegatum. Currently there are no prospects for a vaccine, and acaricide or antibiotic control is hampered by the development of chemoresistance. Animal breeders have observed that dermatophilosis susceptibility seems to be determined genetically, and we previously identified a BoLA-DRB3-DQB class II haplotype marker for high (R2= 0.96) susceptibility to the disease. With this marker, we developed a successful eugenic selection procedure for zebu Brahman cattle in Martinique (FWI). Over a period of five years, a marked reduction in disease prevalence, from 0.76 to 0.02 was achieved, and this low level has been maintained over the last two years. The selection procedure, based on a genetic marker system targeting the highly polymorphic BoLA locus, eliminates only those individuals which are at the highest risk of contracting the disease. In the present work, we discuss the properties of this system, including the "heterozygote advantage" and the "frequency dependence" theories, and examine their involvement in the biological mechanisms at the host/pathogen interface. We speculate on the exact role of the MHC molecules in the control of the disease, how the natural selection pressure imposed by the pathogens selectively maintains MHC diversity, and how our results can be practically applied for integrated control of dermatophilosis in developing countries.

Actinomycetales Infections↗

PubMed2005

Genotyping of Mycobacterium tuberculosis clinical isolates in two cities of Turkey: description of a new family of genotypes that is phylogeographically specific for Asia Minor.

BACKGROUND: Population-based bacterial genetics using repeated DNA loci is an efficient approach to study the biodiversity and phylogeographical structure of human pathogens, such as Mycobacterium tuberculosis, the agent of tuberculosis. Indeed large genetic diversity databases are available for this pathogen and are regularly updated. No population-based polymorphism data were yet available for M. tuberculosis in Turkey, at the crossroads of Eurasia. RESULTS: A total of 245 DNAs from Mycobacterium tuberculosis clinical isolates from tuberculosis patients residing in Turkey (Malatya n = 147 or Ankara n = 98) were genotyped by spoligotyping, a high-throughput genotyping method based on the polymorphism of the Direct Repeat locus. Thirty-three spoligotyping-defined clusters including 206 patients and 39 unique patterns were found. The ST41 cluster, as designated according to the international SpolDB3 database project, represented one fourth and when gathered to three genotypes, ST53, ST50 and ST284, one half of all the isolates. Out of 34 clinical isolates harboring ST41 which were further genotyped by IS6110 and by MIRU-VNTR typing, a typical 2-copy IS6110-RFLP pattern and a "215125113322" MIRU-VNTR pattern were observed among 21 clinical isolates. Further search in various databases confirms the likely Turkish-phylogeographical specificity of this clonal complex. CONCLUSION: We described a new phylogeographically-specific clone of M. tuberculosis, designated LAM7-TUR. Further investigations to assess its frequency within all regions of Turkey and its phylogeographical origin and phylogenetic position within the global M. tuberculosis phylogenetic tree will shed new light on its endemicity in Asia Minor.

DNA, Bacterial↗

PubMed2006

Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.

Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease, yet rarely present in the neonatal period. Here we report the clinical, biochemical, and molecular genetic findings of an infant who died at the age of 1 mo with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis due to a previously described but unusual mtDNA mutation, a 7-bp intragenic inversion within the mitochondrial gene encoding ND1 protein of complex I (MTND1). In direct contrast to the previous case, an adult with exercise intolerance who only harbored the mutation in muscle, the MTND1 inversion in our patient was present at high levels in several tissues including the heart, muscle, liver, and cultured skin fibroblasts. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Transmitochondrial cytoplasmic hybrids (cybrids) containing high mutant loads of the inversion expressed the biochemical defect but apparently normal levels of the assembled complex. Our report highlights the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasizes the need for appropriate genetic counseling for families affected by mtDNA disease.

Acidosis, Lactic↗

PubMed2003

Transmission and immunopathogenesis of FIV in cats as a model for HIV.

The feline immunodeficiency virus (FIV) model provides a system to study lentivirus transmission, virus kinetics, pathogenesis, host responses, and immune dysfunction in a natural, out-bred host, under controlled conditions with specific-pathogen-free animals. The diversity of primary FIV strains can be exploited to mirror the range of disease manifestations associated with HIV infection. FIV is infectious via intravenous, intraperitoneal, intradermal, or subcutaneous injection as well as by atraumatic instillation onto the oral, vaginal, or rectal mucosa. Together, these features allow investigators to model specific aspects of HIV infection in a highly relevant and relatively inexpensive animal model. Well-developed areas of the FIV model include: (1) transmission of cell-associated as well as cell-free virus; (2) mucosal infectivity and immunopathogenesis; (3) vertical transmission; (4) acquired immunodeficiency including defects of the innate immune system; (5) thymic dysfunction; (6) neurotropism and neuropathogenesis; (7) host-virus interactions and the role of specific gene products; (8) efficacy of antiviral therapy; and (9) efficacy and immune correlates of experimental vaccines. This review will encompass areas specific to transmission and immunopathogenesis.

Animals↗

PubMed1994

B cell development in the chicken.

A central feature of the vertebrate humoral immune system is that an organism must have a vast repertoire of antibodies to protect it against foreign pathogens. Chickens create a diverse immunological repertoire by intrachromosomal gene conversion of the single variable gene segments of the Ig heavy and light chain genes. This diversification process has been shown to require the bursa of Fabricius. Immature cells commit to the B cell lineage by rearranging their Ig genes prior to migration to the bursa. Recent work has suggested that the ability of a developing B cell to migrate to the bursa may depend on the expression of the carbohydrate structure sialyl Lewis x. Developing B cells in the spleen with the ability to migrate to the bursa have been shown to express sialyl Lewis x. Cells expressing sialyl Lewis x begin appearing in the bursa anlage between embryonic Days 10 and 12. These sialyl Lewis x-positive cells appear to form the nascent bursal follicles and are induced to proliferate. Coincident with the time that B cells initiate the gene conversion process, cells cease expressing sialyl Lewis x and begin expressing the related surface epitope Lewis x. As cells mature further, they undergo another phenotypic change and switch from expressing high levels of Lewis x to become Lewis x-low. At the same time that Lewis x-low cells accumulate in the bursa, cells with this phenotype begin to appear in the spleen. These phenotypic markers may be useful in identifying chicken B cells at different developmental stages.

Animals↗

PubMed2003

Experimental murine cryptococcal infection results in contamination of bedding with Cryptococcus neoformans.

Cryptococcus neoformans is a fungal pathogen that survives in diverse environments. To determine whether cages of mice infected with C. neoformans posed an infection risk to animal caregivers, we investigated whether the fungus could be isolated from the bedding or stool of mice infected by intratracheal (i.t.), intravenous (i.v.), or intraperitoneal (i.p.) routes. The bedding of mice infected i.t. was contaminated with C. neoformans. In contrast, no contamination of bedding with C. neoformans was detected in cages of mice infected i.v. or i.p. C. neoformans was not isolated from murine feces. The C. neoformans strain recovered from bedding material was indistinguishable from the infecting strain by biochemical and molecular techniques. This result suggests that precautions may be warranted when disposing bedding from cages that housed mice with pulmonary C. neoformans infection.

Animals↗

PubMed2003

Integrating B cell homeostasis and selection with BLyS.

The mechanisms that maintain a pool of B cells that is adequately diverse yet devoid of pathogenic autoreactivity remain poorly understood. B cells complete maturation after migrating to the periphery, where they transit several intermediate developmental stages prior to recruitment into the long-lived primary pool. Since B lineage commitment is not coupled to peripheral B cell numbers and most mature peripheral B cells are quiescent, the sizes of mature peripheral compartments are primarily determined by the proportion of immature B cells that survive transit through later developmental stages, coupled with the longevity of mature B cells themselves. Compelling evidence indicates that the B cell antigen receptor (BcR) plays an essential role in all of these processes, but further findings indicate a similar role for the recently described tumor necrosis factor family member B lymphocyte stimulator (BLyS). Signaling through the BLyS receptor, Bcmd/BR3, controls B cell numbers in two ways: by varying the proportion of cells that complete transitional B cell development, and by serving as the primary determinant of mature B cell longevity. The striking congruence of BcR- and BLyS-mediated effects on B cell selection and survival suggests these pathways may be related. The recent discovery that BcR signaling is selectively coupled to Bcmd/BR3 expression links BcR- and BLyS-mediated activities in transitional and mature B cells, suggesting specificity-based selection and survival may be mechanistically similar processes.

Animals↗

PubMed1981

[Inhabitual sites for Neisseria and Branhamella].

The authors bring together a bibliographical study and their own personal results concerning inhabitual sites for Neisseria and Branhamella. Among various species, gonococci (N. gonorrhoeae) and meningococci (N. meningitidis) may either be manifest pathogenic agents or exist in asymptomatic carrier states and they are found in normal microflora. Other species of Neisseria and Branhamella may be opportunistic pathogenic bacteria isolated in diverse infections. The utility of complete bacteriological diagnosis is emphasized for all of these cases.

Cardiovascular System↗

PubMed1995

Characterization of clinical isolates of Streptococcus agalactiae by random amplified polymorphic DNA using degenerate oligonucleotides.

Epidemiological studies of Streptococcus agalactiae strains have been limited by the lack of sensitive and discriminatory methods for comparing clinical isolates. Serotyping, albeit a widely used methodology, has been shown to possess low capability to distinguish between epidemiologically related and unrelated isolates. We have employed here a random amplification of polymorphic DNA (RAPD) assay, using degenerate oligonucleotides as primers, to characterize S. agalactiae isolates from related or unrelated clinical samples. Epidemiologically-related isolates (mother-infant pairs) showed identical profiles by this methodology. On the contrary, 12 epidemiologically-unrelated isolates (classified into 5 different serotypes) resulted in 11 distinct RAPD patterns. This suggests that the proposed modified RAPD assay provides a highly discriminatory tool for the analysis of genomic diversity among isolates from pathogenic organisms.

DNA Primers↗

PubMed2003

Inhibition of human pathogenic fungi by ethnobotanically selected plant extracts.

In this study, 36 extracts derived from 29 plant species selected using an ethnobotanical approach were tested for antifungal activity against a taxonomically diverse group of 13 human pathogenic fungi. We compared the inhibitory characteristics of these plant extracts with those of the commonly used antifungals, amphotericin B and ketoconazole, and the plant-derived antifungal, berberine. Several plant extracts, notably those from Zingiber officinale (ginger) and Juglans cinerea (butternut), had pronounced antifungal activity against a wide variety of fungi, including strains that were highly resistant to amphotericin B and ketoconazole. Further exploration of Z. officinale as an antifungal is warranted as this species is generally regarded as safe for human consumption.

Amphotericin B↗

PubMed2006

Molecular analysis of microbial communities identified in different developmental stages of Ixodes scapularis ticks from Westchester and Dutchess Counties, New York.

Ixodes scapularis ticks play an important role in the transmission of a wide variety of pathogens between various mammalian species, including humans. Pathogens transmitted by ticks include Borrelia, Anaplasma and Babesia. Although ticks may harbour both pathogenic and non-pathogenic microflora, little is known about how the diversity of the microflora within ticks may influence the transmission of pathogens. To begin addressing this question, we examined the composition of bacterial communities present in Ixodes scapularis collected from Westchester and Dutchess Counties, New York State, at different developmental and nutritional stages. Genetic fingerprints of bacterial populations were generated by temporal temperature gradient gel electrophoresis (TTGE) separation of individual polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments, followed by DNA sequence analysis for bacterial identification. The fingerprints of the TTGE bands were grouped into five clusters. The most abundant DNA sequence found in all the samples was Rickettsia, followed by Pseudomonas and Borrelia. Ralstonia, Anaplasma, Enterobacterias, Moraxella, Rhodococcus and uncultured proteobacterium were present as well. We also determined the prevalence of Anaplasma phagocytophilum and Borrelia burgdorferi by PCR and DNA sequence analysis. Statistical analyses indicated significant variations in the bacterial communities depending on tick developmental stage and degree of engorgement. We suggest that these two elements affect microbial diversity within the tick and may in turn influence pathogen transmission to humans and animals after tick bite.

Animals↗