cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.27178225.v1
title: The intricate pathogenicity of group a <i>Streptococcus</i>: A comprehensive update

description: Group A <i>Streptococcus</i> (GAS) is a versatile pathogen that targets human lymphoid, decidual, skin, and soft tissues. Recent advancements have shed light on its airborne transmission, lymphatic spread, and interactions with neuronal systems. GAS promotes severe inflammation through mechanisms involving inflammasomes, IL-1β, and T-cell hyperactivation. Additionally, it secretes factors that directly induce skin necrosis via Gasdermin activation and sustains survival and replication in human blood through sophisticated immune evasion strategies. These include lysis of erythrocytes, using red cell membranes for camouflage, resisting antimicrobial peptides, evading phagocytosis, escaping from neutrophil extracellular traps (NETs), inactivating chemokines, and cleaving targeted antibodies. GAS also employs molecular mimicry to traverse connective tissues undetected and exploits the host’s fibrinolytic system, which contributes to its stealth and potential for causing autoimmune conditions after repeated infections. Secreted toxins disrupt host cell membranes, enhancing intracellular survival and directly activating nociceptor neurons to induce pain. Remarkably, GAS possesses mechanisms for precise genome editing to defend against phages, and its fibrinolytic capabilities have found applications in medicine. Immune responses to GAS are paradoxical: robust responses to its virulence factors correlate with more severe disease, whereas recurrent infections often show diminished immune reactions. This review focuses on the multifaceted virulence of GAS and introduces novel concepts in understanding its pathogenicity.
DOI: 10.6084/m9.figshare.24796026
title: Synergistic effects of putative Ca<sup>2+</sup>-binding sites of calmodulin in fungal development, temperature stress and virulence of <i>Aspergillus fumigatus</i>

description: In pathogenic fungi, calcium-calmodulin-dependent serine-threonine-specific phosphatase calcineurin is involved in morphogenesis and virulence. Therefore, calcineurin and its tightly related protein complexes are attractive antifungal drug targets. However, there is limited knowledge available on the relationship between <i>in vivo</i> Ca<sup>2+</sup>-binding sites of calmodulin (CaM) and its functions in regulating stress responses, morphogenesis, and pathogenesis. In the current study, we demonstrated that calmodulin is required for hyphal growth, conidiation, and virulence in the human fungal pathogen, <i>Aspergillus fumigatus</i>. Site-directed mutations of calmodulin revealed that a single Ca<sup>2+</sup>-binding site mutation had no significant effect on <i>A. fumigatus</i> hyphal development, but multiple Ca<sup>2+</sup>-binding site mutations exhibited synergistic effects, especially when cultured at 42 °C, indicating that calmodulin function in response to temperature stress depends on its Ca<sup>2+</sup>-binding sites. Western blotting implied that mutations in Ca<sup>2+</sup>-binding sites caused highly degraded calmodulin fragments, suggesting that the loss of Ca<sup>2+</sup>-binding sites results in reduced protein stability. Moreover, normal intracellular calcium homeostasis and the nuclear translocation of the transcriptional factor CrzA are dependent on Ca<sup>2+</sup>-binding sites of <i>Af</i>CaM, demonstrating that Ca<sup>2+</sup>-binding sites of calmodulin are required for calcium signalling and its major transcription factor CrzA. Importantly, <i>in situ</i> mutations for four Ca<sup>2+</sup>-binding sites of calmodulin resulted in an almost complete loss of virulence in the <i>Galleria mellonella</i> wax moth model. This study shed more light on the functional characterization of putative calcium-binding sites of calmodulin in the morphogenesis and virulence of <i>A. fumigatus</i>, which enhances our understanding of calmodulin biological functions in cells of opportunistic fungal pathogens.
DOI: 10.6084/m9.figshare.26089792
title: NagZ modulates the virulence of <i>E. cloacae</i> by acting through the gene of unknown function, ECL_03795

description: β-N-acetylglucosaminidase (NagZ), a cytosolic glucosaminidase, plays a pivotal role in peptidoglycan recycling. Previous research demonstrated that NagZ knockout significantly eradicated AmpC-dependent β-lactam resistance in <i>Enterobacter cloacae</i>. However, NagZ’s role in the virulence of <i>E. cloacae</i> remains unclear. Our study, incorporating data on mouse and <i>Galleria mellonella</i> larval mortality rates, inflammation markers, and histopathological examinations, revealed a substantial reduction in the virulence of <i>E. cloacae</i> following NagZ knockout. Transcriptome sequencing uncovered differential gene expression between NagZ knockout and wild-type strains, particularly in nucleotide metabolism pathways. Further investigation demonstrated that NagZ deletion led to a significant increase in cyclic diguanosine monophosphate (c-di-GMP) levels. Additionally, transcriptome sequencing and RT-qPCR confirmed significant differences in the expression of ECL_03795, a gene with an unknown function but speculated to be involved in c-di-GMP metabolism due to its EAL domain known for phosphodiesterase activity. Interestingly, in ECL_03795 knockout strains, a notable reduction in the virulence was observed, and virulence was rescued upon complementation with ECL_03795. Consequently, our study suggests that NagZ’s function on virulence is partially mediated through the ECL_03795→c-di-GMP pathway, providing insight into the development of novel therapies and strongly supporting the interest in creating highly efficient NagZ inhibitors.
DOI: 10.6084/m9.figshare.26089792.v1
title: NagZ modulates the virulence of <i>E. cloacae</i> by acting through the gene of unknown function, ECL_03795

description: β-N-acetylglucosaminidase (NagZ), a cytosolic glucosaminidase, plays a pivotal role in peptidoglycan recycling. Previous research demonstrated that NagZ knockout significantly eradicated AmpC-dependent β-lactam resistance in <i>Enterobacter cloacae</i>. However, NagZ’s role in the virulence of <i>E. cloacae</i> remains unclear. Our study, incorporating data on mouse and <i>Galleria mellonella</i> larval mortality rates, inflammation markers, and histopathological examinations, revealed a substantial reduction in the virulence of <i>E. cloacae</i> following NagZ knockout. Transcriptome sequencing uncovered differential gene expression between NagZ knockout and wild-type strains, particularly in nucleotide metabolism pathways. Further investigation demonstrated that NagZ deletion led to a significant increase in cyclic diguanosine monophosphate (c-di-GMP) levels. Additionally, transcriptome sequencing and RT-qPCR confirmed significant differences in the expression of ECL_03795, a gene with an unknown function but speculated to be involved in c-di-GMP metabolism due to its EAL domain known for phosphodiesterase activity. Interestingly, in ECL_03795 knockout strains, a notable reduction in the virulence was observed, and virulence was rescued upon complementation with ECL_03795. Consequently, our study suggests that NagZ’s function on virulence is partially mediated through the ECL_03795→c-di-GMP pathway, providing insight into the development of novel therapies and strongly supporting the interest in creating highly efficient NagZ inhibitors.
DOI: 10.6084/m9.figshare.27177641
title: Histone-like transcription factor Hfl1p in <i>Candida albicans</i> harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development

description: <i>Candida albicans</i> is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p’s diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the <i>hfl1Δ/hfl1Δ</i> mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p’s critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of <i>C. albicans</i>’ metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in <i>C. albicans.</i>
DOI: 10.6084/m9.figshare.27177641.v1
title: Histone-like transcription factor Hfl1p in <i>Candida albicans</i> harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development

description: <i>Candida albicans</i> is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p’s diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the <i>hfl1Δ/hfl1Δ</i> mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p’s critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of <i>C. albicans</i>’ metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in <i>C. albicans.</i>
DOI: 10.6084/m9.figshare.24796026.v1
title: Synergistic effects of putative Ca<sup>2+</sup>-binding sites of calmodulin in fungal development, temperature stress and virulence of <i>Aspergillus fumigatus</i>

description: In pathogenic fungi, calcium-calmodulin-dependent serine-threonine-specific phosphatase calcineurin is involved in morphogenesis and virulence. Therefore, calcineurin and its tightly related protein complexes are attractive antifungal drug targets. However, there is limited knowledge available on the relationship between <i>in vivo</i> Ca<sup>2+</sup>-binding sites of calmodulin (CaM) and its functions in regulating stress responses, morphogenesis, and pathogenesis. In the current study, we demonstrated that calmodulin is required for hyphal growth, conidiation, and virulence in the human fungal pathogen, <i>Aspergillus fumigatus</i>. Site-directed mutations of calmodulin revealed that a single Ca<sup>2+</sup>-binding site mutation had no significant effect on <i>A. fumigatus</i> hyphal development, but multiple Ca<sup>2+</sup>-binding site mutations exhibited synergistic effects, especially when cultured at 42 °C, indicating that calmodulin function in response to temperature stress depends on its Ca<sup>2+</sup>-binding sites. Western blotting implied that mutations in Ca<sup>2+</sup>-binding sites caused highly degraded calmodulin fragments, suggesting that the loss of Ca<sup>2+</sup>-binding sites results in reduced protein stability. Moreover, normal intracellular calcium homeostasis and the nuclear translocation of the transcriptional factor CrzA are dependent on Ca<sup>2+</sup>-binding sites of <i>Af</i>CaM, demonstrating that Ca<sup>2+</sup>-binding sites of calmodulin are required for calcium signalling and its major transcription factor CrzA. Importantly, <i>in situ</i> mutations for four Ca<sup>2+</sup>-binding sites of calmodulin resulted in an almost complete loss of virulence in the <i>Galleria mellonella</i> wax moth model. This study shed more light on the functional characterization of putative calcium-binding sites of calmodulin in the morphogenesis and virulence of <i>A. fumigatus</i>, which enhances our understanding of calmodulin biological functions in cells of opportunistic fungal pathogens.
DOI: 10.6084/m9.figshare.25182510
title: Safety and immunogenicity of CoronaVac in healthy adults: A prospective observational multicenter real-world study in Henan Province, China

description: Vaccination has emerged as the primar approach for managing the COVID-19 pandemic. Despite certain clinical trials reporting the safety and immunogenicity of CoronaVac, additional multicenter real-world studies are still necessary. In this study, we recruited 506 healthy volunteers who were not infected with COVID-19 or vaccinated. Each participant provided peripheral blood samples three times: prior to the first dose of vaccine, prior to the second dose, and 8 weeks following the second dose. Ultimately, 388 participants completed the entire follow-up process. No serious adverse events were observed among any of the participants. Within 1 week of vaccination, 13.4% of participants experienced systemic adverse reactions, with fatigue (5.93%) and dizziness (3.35%) being the most frequent. Although some clinical indicators, including creatinine, significantly changed after vaccination (<i>p</i> &lt; 0.05), the mean of all altered indicators remained within the normal range. The positive rates of neutralizing antibodies (NAb), IgG, and IgM were 12.3%, 18.85%, and 5.24% prior to the second dose, respectively; and 57.99%, 86.34%, and 2.32% at 8 weeks following the second dose, respectively. Additionally, seven indicators, such as sex, age, and BMI, were significantly correlated with NAb (<i>p</i> &lt; 0.05). Finally, a prediction model was developed based on age, monocytes, and alanine aminotransferase (ALT) with an AUC value of 87.56% in the train set and 80.71% in the test set. This study demonstrated that safety and immunogenicity of CoronaVac were good. The prediction model based on the baseline clinical characteristics prior to vaccination can help to develop more suitable vaccination strategies.
DOI: 10.6084/m9.figshare.25182510.v1
title: Safety and immunogenicity of CoronaVac in healthy adults: A prospective observational multicenter real-world study in Henan Province, China

description: Vaccination has emerged as the primar approach for managing the COVID-19 pandemic. Despite certain clinical trials reporting the safety and immunogenicity of CoronaVac, additional multicenter real-world studies are still necessary. In this study, we recruited 506 healthy volunteers who were not infected with COVID-19 or vaccinated. Each participant provided peripheral blood samples three times: prior to the first dose of vaccine, prior to the second dose, and 8 weeks following the second dose. Ultimately, 388 participants completed the entire follow-up process. No serious adverse events were observed among any of the participants. Within 1 week of vaccination, 13.4% of participants experienced systemic adverse reactions, with fatigue (5.93%) and dizziness (3.35%) being the most frequent. Although some clinical indicators, including creatinine, significantly changed after vaccination (<i>p</i> &lt; 0.05), the mean of all altered indicators remained within the normal range. The positive rates of neutralizing antibodies (NAb), IgG, and IgM were 12.3%, 18.85%, and 5.24% prior to the second dose, respectively; and 57.99%, 86.34%, and 2.32% at 8 weeks following the second dose, respectively. Additionally, seven indicators, such as sex, age, and BMI, were significantly correlated with NAb (<i>p</i> &lt; 0.05). Finally, a prediction model was developed based on age, monocytes, and alanine aminotransferase (ALT) with an AUC value of 87.56% in the train set and 80.71% in the test set. This study demonstrated that safety and immunogenicity of CoronaVac were good. The prediction model based on the baseline clinical characteristics prior to vaccination can help to develop more suitable vaccination strategies.
DOI: 10.6084/m9.figshare.25449464
title: Iron depletion has different consequences on the growth and survival of <i>Toxoplasma gondii</i> strains

description: <i>Toxoplasma gondii</i> is an obligate intracellular parasite responsible for a pathology called toxoplasmosis, which primarily affects immunocompromised individuals and developing foetuses. The parasite can scavenge essential nutrients from its host to support its growth and survival. Among them, iron is one of the most important elements needed to sustain basic cellular functions as it is involved in a number of key metabolic processes, including oxygen transport, redox balance, and electron transport. We evaluated the effects of an iron chelator on the development of several parasite strains and found that they differed in their ability to tolerate iron depletion. The growth of parasites usually associated with a model of acute toxoplasmosis was strongly affected by iron depletion, whereas cystogenic strains were less sensitive as they were able to convert into persisting developmental forms that are associated with the chronic form of the disease. Ultrastructural and biochemical characterization of the impact of iron depletion on parasites also highlighted striking changes in both their metabolism and that of the host, with a marked accumulation of lipid droplets and perturbation of lipid homoeostasis. Overall, our study demonstrates that although acute iron depletion has an important effect on the growth of <i>T. gondii</i>, it has a more profound impact on actively dividing parasites, whereas less metabolically active parasite forms may be able to avoid some of the most detrimental consequences.
DOI: 10.6084/m9.figshare.25450395
title: Extracellular vesicles from virulent <i>P. brasiliensis</i> induce TLR4 and dectin-1 expression in innate cells and promote enhanced Th1/Th17 response

description: Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that transport several biomolecules and are involved in important mechanisms and functions related to the pathophysiology of fungal diseases. EVs from <i>Paracoccidioides brasiliensis</i>, the main causative agent of Paracoccidioidomycosis (PCM), modulate the immune response of macrophages. In this study, we assessed the EVs proteome from a virulent <i>P. brasiliensis</i> isolated from granulomatous lesions and compared their immunomodulatory ability with EVs isolated from the fungus before the animal passage (control EVs) when challenging macrophages and dendritic cells (DCs). Proteome showed that virulent EVs have a higher abundance of virulence factors such as GP43, protein 14-3-3, GAPDH, as well as virulence factors never described in PCM, such as aspartyl aminopeptidase and a SidJ analogue compared with control EVs. Virulent extracellular vesicles induced higher expression of TLR4 and Dectin-1 than control EVs in macrophages and dendritic cells (DCs). In opposition, a lower TLR2 expression was induced by virulent EVs. Additionally, virulent EVs induced lower expression of CD80, CD86 and TNF-α, but promoted a higher expression of IL-6 and IL-10, suggesting that EVs isolated from virulent <i>P. brasiliensis</i>-yeast promote a milder DCs and macrophage maturation. Herein, we showed that EVs from virulent fungi stimulated a higher frequency of Th1/Tc1, Th17, and Treg cells, which gives new insights into fungal extracellular vesicles. Taken together, our results suggest that <i>P. brasiliensis</i> utilizes its EVs as virulence bags that manipulate the immune system in its favour, creating a milder immune response and helping with fungal evasion from the immune system.
DOI: 10.6084/m9.figshare.25450395.v1
title: Extracellular vesicles from virulent <i>P. brasiliensis</i> induce TLR4 and dectin-1 expression in innate cells and promote enhanced Th1/Th17 response

description: Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that transport several biomolecules and are involved in important mechanisms and functions related to the pathophysiology of fungal diseases. EVs from <i>Paracoccidioides brasiliensis</i>, the main causative agent of Paracoccidioidomycosis (PCM), modulate the immune response of macrophages. In this study, we assessed the EVs proteome from a virulent <i>P. brasiliensis</i> isolated from granulomatous lesions and compared their immunomodulatory ability with EVs isolated from the fungus before the animal passage (control EVs) when challenging macrophages and dendritic cells (DCs). Proteome showed that virulent EVs have a higher abundance of virulence factors such as GP43, protein 14-3-3, GAPDH, as well as virulence factors never described in PCM, such as aspartyl aminopeptidase and a SidJ analogue compared with control EVs. Virulent extracellular vesicles induced higher expression of TLR4 and Dectin-1 than control EVs in macrophages and dendritic cells (DCs). In opposition, a lower TLR2 expression was induced by virulent EVs. Additionally, virulent EVs induced lower expression of CD80, CD86 and TNF-α, but promoted a higher expression of IL-6 and IL-10, suggesting that EVs isolated from virulent <i>P. brasiliensis</i>-yeast promote a milder DCs and macrophage maturation. Herein, we showed that EVs from virulent fungi stimulated a higher frequency of Th1/Tc1, Th17, and Treg cells, which gives new insights into fungal extracellular vesicles. Taken together, our results suggest that <i>P. brasiliensis</i> utilizes its EVs as virulence bags that manipulate the immune system in its favour, creating a milder immune response and helping with fungal evasion from the immune system.