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PubMed1994

Identification of three chitin synthase genes in the dimorphic fungal pathogen Sporothrix schenckii.

Degenerate PCR primers were used to amplify a 600-bp conserved gene region for chitin synthases from genomic DNA of Sporothrix schenckii, a dimorphic fungal pathogen of humans and animals. Three chitin synthase gene homologs were amplified as shown by DNA sequence analysis and by Southern blotting experiments. Based on differences among the predicted amino acid sequences of these homologs, each was placed within one of three different chitin synthase classes. Phylogenies constructed with the sequences and the PAUP 3.1.1 program showed that S. schenckii consistently clustered most closely with Neurospora crassa in each of the three chitin synthase classes. These findings are significant because the phylogenies support by a new method the grouping of the imperfect fungus S. schenckii with the Pyrenomycetes of the Ascomycota.

Base Sequence↗

PubMed2001

Molecular determinants of virulence, cell tropism, and pathogenic phenotype of infectious bursal disease virus.

Infectious bursal disease viruses (IBDVs), belonging to the family Birnaviridae, exhibit a wide range of immunosuppressive potential, pathogenicity, and virulence for chickens. The genomic segment A encodes all the structural (VP2, VP4, and VP3) and nonstructural proteins, whereas segment B encodes the viral RNA-dependent RNA polymerase (VP1). To identify the molecular determinants for the virulence, pathogenic phenotype, and cell tropism of IBDV, we prepared full-length cDNA clones of a virulent strain, Irwin Moulthrop (IM), and constructed several chimeric cDNA clones of segments A and B between the attenuated vaccine strain (D78) and the virulent IM or GLS variant strain. Using the cRNA-based reverse-genetics system developed for IBDV, we generated five chimeric viruses after transfection by electroporation procedures in Vero or chicken embryo fibroblast (CEF) cells, one of which was recovered after propagation in embryonated eggs. To evaluate the characteristics of the recovered viruses in vivo, we inoculated 3-week-old chickens with D78, IM, GLS, or chimeric viruses and analyzed their bursae for pathological lesions 3 days postinfection. Viruses in which VP4, VP4-VP3, and VP1 coding sequences of the virulent strain IM were substituted for the corresponding region in the vaccine strain failed to induce hemorrhagic lesions in the bursa. In contrast, viruses in which the VP2 coding region of the vaccine strain was replaced with the variant GLS or virulent IM strain caused rapid bursal atrophy or hemorrhagic lesions in the bursa, as seen with the variant or classical virulent strain, respectively. These results show that the virulence and pathogenic-phenotype markers of IBDV reside in VP2. Moreover, one of the chimeric viruses containing VP2 sequences of the virulent strain could not be recovered in Vero or CEF cells but was recovered in embryonated eggs, suggesting that VP2 contains the determinants for cell tropism. Similarly, one of the chimeric viruses containing the VP1 segment of the virulent strain could not be recovered in Vero cells but was recovered in CEF cells, suggesting that VP1 contains the determinants for cell-specific replication in Vero cells. By comparing the deduced amino acid sequences of the D78 and IM strains and their reactivities with monoclonal antibody 21, which binds specifically to virulent IBDV, the putative amino acids involved in virulence and cell tropism were identified. Our results indicate that residues Gln at position 253 (Gln253), Asp279, and Ala284 of VP2 are involved in the virulence, cell tropism, and pathogenic phenotype of virulent IBDV.

Amino Acid Sequence↗

PubMed2005

Identification of a universal Group B streptococcus vaccine by multiple genome screen.

Group B Streptococcus (GBS) is a multiserotype bacterial pathogen representing a major cause of life-threatening infections in newborns. To develop a broadly protective vaccine, we analyzed the genome sequences of eight GBS isolates and cloned and tested 312 surface proteins as vaccines. Four proteins elicited protection in mice, and their combination proved highly protective against a large panel of strains, including all circulating serotypes. Protection also correlated with antigen accessibility on the bacterial surface and with the induction of opsonophagocytic antibodies. Multigenome analysis and screening described here represent a powerful strategy for identifying potential vaccine candidates against highly variable pathogens.

Animals↗

PubMed2026

Genomic and phenotypic diversification of Pseudomonas aeruginosa during sustained exposure to a ciliate predator.

UNLABELLED: Predator-mediated selection is an important ecological force shaping bacterial evolution, but its effects on genomic adaptation and virulence in opportunistic pathogens are not fully understood. Here, we used experimental evolution to study how exposure to the ciliate predator Tetrahymena thermophila affects Pseudomonas aeruginosa. Replicate populations were evolved for 60 days with or without the predator, followed by whole-genome shotgun metagenomic sequencing and phenotypic analyses. Both treatments showed strong selection and evidence of parallel evolution at gene and nucleotide levels, indicating constrained adaptation. However, predator exposure altered evolutionary dynamics. Predator-evolved populations showed a wider distribution of mutation frequencies, with many mutations persisting at intermediate frequencies, consistent with increased clonal interference and ongoing competition among lineages. In contrast, populations evolved without predators showed more high-frequency mutations, consistent with selective sweeps, although some low-frequency variants remained. Despite substantial genomic change, phenotypic outcomes were variable. Virulence in an invertebrate host model did not consistently increase. Instead, evolved isolates showed context-dependent changes, including modest decreases or occasional increases. Competition assays also showed no consistent fitness advantage for predator-evolved isolates, suggesting trade-offs between predator resistance and growth in other environments. Overall, predator-mediated selection reshaped evolutionary dynamics by maintaining diversity and altering the balance of lineages rather than producing uniform increases in virulence. These results highlight how ecological complexity influences adaptive evolution and the context-dependent nature of pathogen traits. IMPORTANCE: Opportunistic pathogens such as Pseudomonas aeruginosa often evolve in environmental settings before infecting hosts, raising questions about how ecological interactions influence virulence. Predator-mediated selection has been suggested to increase virulence via coincidental evolution, but evidence is inconsistent. Here, we show that exposure to a eukaryotic predator does not consistently elevate virulence but does reshape evolutionary dynamics by altering how mutations spread in populations. Predator-exposed populations retained more intermediate-frequency mutations, consistent with increased clonal interference and ongoing competition among lineages, whereas non-predator populations were dominated by selective sweeps. These differences were also reflected in functional targets of adaptation, with predator exposure favoring mutations in genes involved in environmental sensing and interaction. Together, these findings suggest that ecological complexity shapes the dynamics of adaptation rather than driving a single evolutionary outcome, highlighting that virulence is an emergent property influenced by underlying evolutionary processes.

Pseudomonas aeruginosa↗

PubMed2026

Genomic characterization and therapeutic potential of five broad-spectrum lytic bacteriophages against multidrug-resistant avian pathogenic Escherichia coli (APEC).

UNLABELLED: Colibacillosis, caused by avian pathogenic Escherichia coli (APEC), results in substantial economic losses in global poultry production. The emergence of multidrug-resistant (MDR) APEC poses zoonotic risks through horizontal transfer of antimicrobial resistance (AMR) genes. Bacteriophage therapy emerges as a safe alternative to antibiotherapy; however, comprehensive characterization of phages targeting MDR-APEC from diverse geographical regions remains limited. We isolated five lytic bacteriophages from poultry fecal samples collected from five Indian states and characterized them through morphological analysis, physiological stability testing, whole-genome sequencing, and in vivo efficacy assessment. Host range was determined against APEC isolates, and therapeutic potential was validated in the Galleria mellonella infection model. All phages showed Myovirus-like morphology and stability across physiologically relevant temperatures (up to 55°C-70°C) and pH conditions (3-11). Phages were classified as Escherichia phage vB_EcoM_fRPOT1, vB_EcoM_fDMYT1, vB_EcoM_fBSZT1, vB_EcoM_fUAMT1, and vB_EcoM_fPKPT2. Their genome size ranges from 170 to 356 kb, belonging to three distinct genera: Dhakavirus, Gaprivervirus, and Asteriusvirus. Genomic analysis confirmed the absence of antimicrobial resistance, virulence, toxin, or lysogeny genes. Fifty-one APEC strains were isolated, of which 23 (45.1%) were MDR. Individual phages lysed 37%-51% of tested APEC and 17%-39% of MDR strains. Three phages (fBSZT1, fUAMT1, and fPKPT2) significantly improved larval survival to 60%-80% at an MOI of 10 in G. mellonella infection models compared to the untreated control. This study establishes a well-characterized phage bank targeting MDR-APEC strains, providing a foundation for developing phage-based interventions to reduce antibiotic dependency and mitigate AMR transmission risks under the One Health framework. IMPORTANCE: The overuse of antibiotics in poultry farming has created a crisis. The multidrug-resistant (MDR) bacteria threaten both animal health and human safety through the food chain. When antibiotics fail, farmers face devastating losses, and resistant bacteria can transfer to humans through consumption or environmental contamination. Bacteriophages offer a practical solution as they kill target bacteria without harming beneficial microbes or leaving chemical residues. Our comprehensive characterization confirms that these five phages are safe and effective as they lack any resistance or toxin genes and rescue 60%-80% of infected larvae. This represents a characterized phage bank targeting the specific resistant strains in Indian poultry. By providing a validated alternative to antibiotics, this work supports sustainable food production while reducing the spread of antimicrobial resistance from farms to humans.

Animals↗

PubMed2006

Genome size and ploidy of Paracoccidioides brasiliensis reveals a haploid DNA content: flow cytometry and GP43 sequence analysis.

The aim of this study was to evaluate genome size and ploidy of the dimorphic pathogenic fungus Paracoccidioides brasiliensis. The cell cycle analysis of 10 P. brasiliensis isolates by flow cytometry (FCM) revealed a genome size ranging from 26.3+/-0.1Mb (26.9+/-0.1fg) to 35.5+/-0.2Mb (36.3+/-0.2fg) per uninucleated yeast cell. The DNA content of conidia from P. brasiliensis ATCC 60855-30.2+/-0.8Mb (30.9+/-0.8fg) -showed no significant differences with the yeast form, possibly excluding the occurrence of ploidy shift during morphogenesis. The ploidy of several P. brasiliensis isolates was assessed by comparing genome sizing by FCM with the previously described average haploid size obtained from electrophoretic karyotyping. The analysis of intra-individual variability of a highly polymorphic P. brasiliensis gene, GP43, indicated that only one allele seems to be present. Overall, the results showed that all analysed isolates presented a haploid, or at least aneuploid, DNA content and no association was detected between genome size/ploidy and the clinical-epidemiological features of the studied isolates. This work provides new knowledge on P. brasiliensis genetics/genomics, important for future research in basic cellular/molecular mechanisms and for the development/design of molecular techniques in this fungus.

Antigens, Fungal↗

PubMed1998

PCR-Based detection of the causal agent of watermark disease in willows (Salix spp.)

The watermark disease, caused by Brenneria salicis (formerly Erwinia salicis), is of significant concern wherever tree-forming willows are grown or occur naturally. The movement of infected, asymptomatic cuttings is a major cause of pathogen dispersal. A reliable and sensitive diagnostic procedure is necessary for the safe movement of willow planting material. We derived primers from the nucleotide sequence of the 16S rRNA gene of B. salicis for the development of a PCR to detect this pathogen. One set of primers, Es1a-Es4b, directed the amplification of a 553-bp fragment from B. salicis genomic DNA as well as B. salicis cells. PCR products were not observed when genomic DNA was tested for 27 strains of other, related plant-associated bacteria. Genomic fingerprinting by amplification fragment length polymorphism of B. salicis strains, originating from four different countries, and related Brenneria, Pectobacterium, and Erwinia strains revealed a very high similarity among the B. salicis genomes, indicating that the spread of the pathogen is mainly due to the transportation of infected cuttings. The PCR had to be preceded by a DNA extraction in order to detect the pathogen in the vascular fluid of willows. The minimum number of cells that could be detected from vascular fluid was 20 CFU/ml. The PCR assays proved to be very sensitive and reliable in detecting B. salicis in willow plant material.

Journal Article↗

PubMed2006

Marek's disease virus encodes MicroRNAs that map to meq and the latency-associated transcript.

MicroRNAs (miRNAs) are a class of small (approximately 22-nucleotide) regulatory molecules that block translation or induce degradation of target mRNAs. These have been identified in a wide range of organisms, including viruses. In particular, the oncogenic gammaherpesviruses Kaposi's sarcoma herpesvirus and Epstein-Barr virus encode miRNAs that could potentially regulate either viral or host genes. To determine if Marek's disease virus (MDV), an oncogenic alphaherpesvirus of chickens, encodes miRNAs, we isolated small RNAs from MDV-infected chicken embryo fibroblasts (CEF) and used the 454 Life Sciences sequencing technology to obtain the sequences of 13,679 candidate host and viral small RNAs. Eight miRNAs were found, five of which flank the meq oncogene and three that map to the latency-associated transcript (LAT) region of the genome. The meq gene is unique to pathogenic serotypes of MDV and is transcriptionally active during latency and transformation, and the LAT region of the MDV genome is antisense to the immediate-early gene ICP4. Secondary structure analysis predicted that the regions flanking the miRNAs could form hairpin precursors. Northern blot analysis confirmed expression of all miRNAs in MDV-infected CEF, MDV-induced tumors, and MDV lymphoblastoid cell lines. We propose that the MDV miRNAs function to enable MDV pathogenesis and contribute to MDV-induced transformation of chicken T cells.

Amino Acid Sequence↗

PubMed1997

[Unconventional transmissible agents or prions].

UNLABELLED: NEUROGENERATIVE DISEASES: Unconventional transmissible agents or prions cause subacute transmissible spongiform encephalopathies (TSE) in man and animals. These rare neurological diseases have a long incubation period. The only clinical manifestations are signs of central nervous system deficits. HISTOPATHOLOGY: There are three characteristics features vacuolization of the cerebral cortex, neuronal loss and astrogliosis. A host protein, the PrP (prion protein) accumulates in the central nervous system of infected individuals in quantities proportional to the titer of the infectious agent. The gene coding for the PrP is the main factor determining genetic susceptibility to unconventional transmissible agents. THE TRANSMISSIBLE AGENT: The exact nature of these unconventional transmissible agents remains a question of debate. For certain authors, prions are proteins totally devoid of nucleic genomes, being composed entirely by a particular pathogenic form of the protease-resistant PrP protein. For others, the structure is more conventional, containing an independent genome, the PrP being the recepto and virulence factor.

Animals↗

PubMed1994

Construction of an ordered genomic library of Mycoplasma genitalium.

As a first step towards sequencing the chromosome of the suspected human pathogen Mycoplasma genitalium, we attempted to clone its entire genome in a set of ordered cosmids. Cosmid libraries were established by partial digestion of M. genitalium genomic DNA with Sau3AI or EcoRI. A chromosome-walking strategy was used to identify 20 overlapping cosmid clones which contained over 99% of the genome. The final 5.1 kb could not be cloned in cosmids, and was eventually obtained from a genomic library established in a lambda vector. Correspondence of cloned and genomic EcoRI fragments indicated no detectable major deletions or rearrangements in the library. The library was oriented on established XhoI and SmaI physical maps of the chromosome with restriction sites present at the expected locations in the library. The genome contained 74 EcoRI fragments which added up to a total genome size of 578 kb. These were arranged in a partial EcoRI physical map, and those containing the MgPa major attachment protein-encoding operon and its repeat sequences were identified. The existence of this ordered genomic library, which accurately and completely encompasses the entire M. genitalium genome, should serve as a valuable tool for many future studies of this organism and facilitate our long-term goal of sequencing its genome.

Bacterial Proteins↗

PubMed2004

Gene synteny and evolution of genome architecture in trypanosomatids.

The trypanosomatid protozoa Trypanosoma brucei, Trypanosoma cruzi and Leishmania major are related human pathogens that cause markedly distinct diseases. Using information from genome sequencing projects currently underway, we have compared the sequences of large chromosomal fragments from each species. Despite high levels of divergence at the sequence level, these three species exhibit a striking conservation of gene order, suggesting that selection has maintained gene order among the trypanosomatids over hundreds of millions of years of evolution. The few sites of genome rearrangement between these species are marked by the presence of retrotransposon-like elements, suggesting that retrotransposons may have played an important role in shaping trypanosomatid genome organization. A degenerate retroelement was identified in L. major by examining the regions near breakage points of the synteny. This is the first such element found in L. major suggesting that retroelements were found in the common ancestor of all three species.

Animals↗

PubMed2006

Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome.

BACKGROUND: Burkholderia cenocepacia is recognized as opportunistic pathogen that can cause lung infections in cystic fibrosis patients. A hallmark of B. cenocepacia infections is the inability to eradicate the organism because of multiple intrinsic antibiotic resistance. As Resistance-Nodulation-Division (RND) efflux systems are responsible for much of the intrinsic multidrug resistance in Gram-negative bacteria, this study aims to identify RND genes in the B. cenocepacia genome and start to investigate their involvement into antimicrobial resistance. RESULTS: Genome analysis and homology searches revealed 14 open reading frames encoding putative drug efflux pumps belonging to RND family in B. cenocepacia J2315 strain. By reverse transcription (RT)-PCR analysis, it was found that orf3, orf9, orf11, and orf13 were expressed at detectable levels, while orf10 appeared to be weakly expressed in B. cenocepacia. Futhermore, orf3 was strongly induced by chloramphenicol. The orf2 conferred resistance to fluoroquinolones, tetraphenylphosphonium, streptomycin, and ethidium bromide when cloned and expressed in Escherichia coli KAM3, a strain lacking the multidrug efflux pump AcrAB. The orf2-overexpressing E. coli also accumulate low concentrations of ethidium bromide, which was restored to wild type level in the presence of CCCP, an energy uncoupler altering the energy of the drug efflux pump. CONCLUSION: The 14 RND pumps gene we have identified in the genome of B. cenocepacia suggest that active efflux could be a major mechanism underlying antimicrobial resistance in this microorganism. We have characterized the ORF2 pump, one of these 14 potential RND efflux systems. Its overexpression in E. coli conferred resistance to several antibiotics and to ethidium bromide but it remains to be determined if this pump play a significant role in the antimicrobial intrinsic resistance of B. cenocepacia. The characterization of antibiotic efflux pumps in B. cenocepacia is an obligatory step prior to the design of specific, potent bacterial inhibitors for the improved control of infectious diseases. Consequently, the topic deserves to be further investigated and future studies will involve systematic investigation on the function and expression of each of the RND efflux pump homologs.

Amino Acid Motifs↗

PubMed2005

In silico genome-scale reconstruction and validation of the Staphylococcus aureus metabolic network.

A genome-scale metabolic model of the Gram-positive, facultative anaerobic opportunistic pathogen Staphylococcus aureus N315 was constructed based on current genomic data, literature, and physiological information. The model comprises 774 metabolic processes representing approximately 23% of all protein-coding regions. The model was extensively validated against experimental observations and it correctly predicted main physiological properties of the wild-type strain, such as aerobic and anaerobic respiration and fermentation. Due to the frequent involvement of S. aureus in hospital-acquired bacterial infections combined with its increasing antibiotic resistance, we also investigated the clinically relevant phenotype of small colony variants and found that the model predictions agreed with recent findings of proteome analyses. This indicates that the model is useful in assisting future experiments to elucidate the interrelationship of bacterial metabolism and resistance. To help directing future studies for novel chemotherapeutic targets, we conducted a large-scale in silico gene deletion study that identified 158 essential intracellular reactions. A more detailed analysis showed that the biosynthesis of glycans and lipids is rather rigid with respect to circumventing gene deletions, which should make these areas particularly interesting for antibiotic development. The combination of this stoichiometric model with transcriptomic and proteomic data should allow a new quality in the analysis of clinically relevant organisms and a more rationalized system-level search for novel drug targets.

Computational Biology↗

PubMed1996

A homologue of the cysteine proteinase gene (ACP1 or Eh-CPp3) of pathogenic Entamoeba histolytica is present in non-pathogenic E. dispar strains.

One of the three cysteine proteinase genes, ACP1 (or CP 3), has been reported to be missing in non-pathogenic strains of Entamoeba histolytica (or Entamoeba dispar as recently labeled). Unexpectedly, a gene fragment very similar in its sequence (95% homology) to ACP1 of pathogenic strains was obtained by use of the polymerase chain reaction from genomic DNA and cDNA of various cloned non-pathogenic strains as well as in 23 clinical isolates from asymptomatic carriers. The finding of the ACP1 homologue in non-pathogenic or E. dispar strains rules out the proposed use of its absence for diagnostic purposes.

Amino Acid Sequence↗

PubMed2026

Fatty Acid Biosynthesis Inhibitors─Fabimycin and Triclosan─Trigger Distinct Resistance Mutations in FabI and Potently Kill Gram-Negative Pathogens.

In an effort to develop efficacious antibacterials that engage targets for which there is no preexisting resistance, inhibition of the enoyl-acyl carrier protein reductase FabI has shown promise, with triclosan and fabimycin as representative members of the two major drug classes that show activity against important bacterial pathogens. Here, we use a morbidostat and whole-genome sequencing approach to comprehensively evaluate the resistance profiles that arise in pathogenic bacteria in response to these FabI inhibitors. When assessed against E. coli, fabimycin and triclosan were found to induce primarily nonoverlapping resistance profiles, leading to minimal cross-resistance between the two compounds. Furthermore, in vivo evaluation of the prominent resistant mutants indicates poor fitness, with the fittest mutant still susceptible to fabimycin. Collectively, these results suggest the combination use of two antibiotics that engage different positions on the same target as a means to kill pathogenic bacteria and limit resistance.

Triclosan↗

PubMed2026

Predicting genome-wide functional constraints with GPN-Star.

Genomic language models have emerged as a powerful approach for learning genome-wide functional constraints directly from DNA sequences1. However, standard genomic language models adapted from natural language processing often require large model sizes and computational resources, yet still fall short of classical evolutionary models in predictive tasks2-4. Here we introduce a genomic pretrained network with species tree and alignment representations (GPN-Star), which is a biologically grounded genomic language model featuring a phylogeny-aware architecture that leverages whole-genome alignments and species trees to model evolutionary relationships explicitly. Trained on alignments spanning vertebrate, mammal and primate evolutionary timescales, GPN-Star achieves state-of-the-art performance across a wide range of variant effect prediction tasks in both coding and non-coding regions of the human genome. Analyses across timescales show task-dependent advantages of modelling more recent versus deeper evolution. To demonstrate its potential to advance human genetics, we show that GPN-Star substantially outperforms previous methods in prioritizing pathogenic and fine-mapped genome-wide association study variants, yields strong enrichments of complex trait heritability and improves power in rare variant association testing5. Extending beyond humans, we train GPN-Star for five model organisms-Mus musculus, Gallus gallus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana-demonstrating the robustness and generalizability of the framework. Taken together, these results position GPN-Star as a scalable, powerful and flexible tool for genome interpretation, well suited to leverage the growing abundance of comparative genomics data.

Journal Article↗

PubMed2003

Prokaryotic chromosomes and disease.

Recent insights into bacterial genome organization and function have improved our understanding of the nature of pathogenic bacteria and their ability to cause disease. It is becoming increasingly clear that the bacterial chromosome constantly undergoes structural changes due to gene acquisition and loss, recombination, and mutational events that have an impact on the pathogenic potential of the bacterium. Even though the bacterial genome includes additional genetic elements, the chromosome represents the most important entity in this context. Here, we will show that various processes of genomic instability have an influence on the many manifestations of infectious disease.

Adaptation, Physiological↗

PubMed2006

Genomic changes during chronic Helicobacter pylori infection.

The gastric pathogen Helicobacter pylori shows tremendous genetic variability within human populations, both in gene content and at the sequence level. We investigated how this variability arises by comparing the genome content of 21 closely related pairs of isolates taken from the same patient at different time points. The comparisons were performed by hybridization with whole-genome DNA microarrays. All loci where microarrays indicated a genomic change were sequenced to confirm the events. The number of genomic changes was compared to the number of homologous replacement events without loss or gain of genes that we had previously determined by multilocus sequence analysis and mathematical modeling based on the sequence data. Our analysis showed that the great majority of genetic changes were due to homologous recombination, with 1/650 events leading to a net gain or loss of genes. These results suggest that adaptation of H. pylori to the host individual may principally occur through sequence changes rather than loss or gain of genes.

Adult↗