cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.16653244.v2
title: Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model

description: Invasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection occurring mainly in immunocompromised patients. We recently identified IPA as an emerging co-infection with high mortality in critically ill, but otherwise immunocompetent influenza patients. The neuraminidase inhibitor oseltamivir is the current standard-of-care treatment in hospitalized influenza patients; however, its efficacy in influenza-associated pulmonary aspergillosis (IAPA) is not known. Therefore, we have established an imaging-supported double-hit mouse model to investigate the therapeutic effect of oseltamivir on the development of IAPA. Immunocompetent mice received intranasal instillation influenza A or PBS followed by orotracheal inoculation with <i>Aspergillus fumigatus</i> 4 days later. Oseltamivir treatment or placebo was started at day 0, day 2, or day 4. Daily monitoring included micro-computed tomography and bioluminescence imaging of pneumonia and fungal burden. Non-invasive biomarkers were complemented with imaging, molecular, immunological, and pathological analysis. Influenza virus-infected immunocompetent mice developed proven airway IPA upon co-infection with <i>Aspergillus fumigatus</i>, whereas non-influenza-infected mice fully cleared <i>Aspergillus</i>, confirming influenza as a risk factor for developing IPA. Longitudinal micro-CT showed pulmonary lesions after influenza infection worsening after <i>Aspergillus</i> co-infection, congruent with bioluminescence imaging and histology confirming <i>Aspergillus</i> pneumonia. Early oseltamivir treatment prevented severe influenza pneumonia and mitigated the development of IPA and associated mortality. A time-dependent treatment effect was consistently observed with imaging, molecular, and pathological analyses. Hence, our findings underscore the importance of initiating oseltamivir as soon as possible, to suppress influenza infection and mitigate the risk of potentially lethal IAPA disease.
DOI: 10.6084/m9.figshare.13554347
title: <i>MSS2</i> maintains mitochondrial function and is required for chitosan resistance, invasive growth, biofilm formation and virulence in <i>Candida albicans</i>

description: <i>Candida albicans</i> is the most prevalent fungal pathogen in humans, particularly in immunocompromised patients. In this study, by screening a <i>C. albicans</i> mutant library, we first identified that the <i>MSS2</i> gene, an ortholog of <i>Saccharomyces cerevisiae MSS2</i> required for mitochondrial respiration, mediates chitosan resistance. Upon treatment with 0.2% chitosan, the growth of <i>mss2Δ</i> strains was strikingly impaired, and <i>MSS2</i> expression was significantly repressed by chitosan. Furthermore, <i>mss2Δ</i> strains exhibited slow growth on medium supplemented with glycerol as the sole carbon source. Similar to the chitosan-treated wild-type strain, the <i>mss2Δ</i> strain exhibited a significantly impaired ATP production ability. These data suggest that an antifungal mechanism of chitosan against <i>C. albicans</i> acts by inhibiting <i>MSS2</i> gene expression, leading to repression of mitochondrial function. Normal respiratory function is suggested to be required for fungal virulence. Interestingly, the <i>mss2Δ</i> mutant strains exhibited significantly impaired invasive ability <i>in vitro</i> and <i>ex vivo</i> but retained normal hyphal development ability in liquid medium. Furthermore, the <i>MSS2</i> deletion strains could not form robust biofilms and exhibited significantly reduced virulence. Collectively, these results demonstrated that the antifungal effect of chitosan against <i>C. albicans</i> is mediated via inhibition of mitochondrial biogenesis. These data may provide another strategy for antifungal drug development via inhibition of fungal mitochondria.
DOI: 10.6084/m9.figshare.13554347.v1
title: <i>MSS2</i> maintains mitochondrial function and is required for chitosan resistance, invasive growth, biofilm formation and virulence in <i>Candida albicans</i>

description: <i>Candida albicans</i> is the most prevalent fungal pathogen in humans, particularly in immunocompromised patients. In this study, by screening a <i>C. albicans</i> mutant library, we first identified that the <i>MSS2</i> gene, an ortholog of <i>Saccharomyces cerevisiae MSS2</i> required for mitochondrial respiration, mediates chitosan resistance. Upon treatment with 0.2% chitosan, the growth of <i>mss2Δ</i> strains was strikingly impaired, and <i>MSS2</i> expression was significantly repressed by chitosan. Furthermore, <i>mss2Δ</i> strains exhibited slow growth on medium supplemented with glycerol as the sole carbon source. Similar to the chitosan-treated wild-type strain, the <i>mss2Δ</i> strain exhibited a significantly impaired ATP production ability. These data suggest that an antifungal mechanism of chitosan against <i>C. albicans</i> acts by inhibiting <i>MSS2</i> gene expression, leading to repression of mitochondrial function. Normal respiratory function is suggested to be required for fungal virulence. Interestingly, the <i>mss2Δ</i> mutant strains exhibited significantly impaired invasive ability <i>in vitro</i> and <i>ex vivo</i> but retained normal hyphal development ability in liquid medium. Furthermore, the <i>MSS2</i> deletion strains could not form robust biofilms and exhibited significantly reduced virulence. Collectively, these results demonstrated that the antifungal effect of chitosan against <i>C. albicans</i> is mediated via inhibition of mitochondrial biogenesis. These data may provide another strategy for antifungal drug development via inhibition of fungal mitochondria.
DOI: 10.6084/m9.figshare.14709827
title: A biological and genomic comparison of a drug-resistant and a drug-susceptible strain of <i>Candida auris</i> isolated from Beijing, China

description: The fungal pathogen <i>Candida auris</i> has emerged as a new threat to human health. We previously reported the first isolate of <i>C. auris</i> (BJCA001) in China, which belongs to the South Asian clade (I) and was susceptible to all antifungals tested. In this study, we report the isolation of a drug-resistant <i>C. auris</i> strain (BJCA002) from the same city (Beijing). Strain BJCA002 belongs to the South African clade (III) and is resistant to fluconazole and amphotericin B based on the tentative MIC breakpoints. Taking advantage of the two isolates with distinct antifungal susceptibility and genetic origins, we performed a biological and genomic comparative study. Besides antifungal susceptibility, strains BJCA001 and BJCA002 showed differences in multiple aspects including morphologies, expression of virulence factors, virulence, mating type, and genomic sequence and organization. Notably, strain BJCA002 was less virulent than BJCA001 in both the <i>Galleria mellonella</i> and mouse systemic infection models. Genomic analysis demonstrated that strain BJCA002 but not BJCA001 had multiple mutations in drug resistance-associated genes, including a hot-spot mutation of <i>ERG11</i> (VF125AL, namely V125A and F126L) and some missense mutations in <i>CDR1, MDR1</i>, and <i>TAC1</i>. Notably, strain BJCA001 carried 64 copies of the Zorro3 retrotransposon, whereas BJCA002 had only 3 copies in the genome. Taken together, our findings not only reveal the genetic and phenotypic diversities of the two isolates from Beijing, China, but also shed new light on the genetic basis of the antifungal resistance and virulence of <i>C. auris.</i>
DOI: 10.6084/m9.figshare.14709827.v1
title: A biological and genomic comparison of a drug-resistant and a drug-susceptible strain of <i>Candida auris</i> isolated from Beijing, China

description: The fungal pathogen <i>Candida auris</i> has emerged as a new threat to human health. We previously reported the first isolate of <i>C. auris</i> (BJCA001) in China, which belongs to the South Asian clade (I) and was susceptible to all antifungals tested. In this study, we report the isolation of a drug-resistant <i>C. auris</i> strain (BJCA002) from the same city (Beijing). Strain BJCA002 belongs to the South African clade (III) and is resistant to fluconazole and amphotericin B based on the tentative MIC breakpoints. Taking advantage of the two isolates with distinct antifungal susceptibility and genetic origins, we performed a biological and genomic comparative study. Besides antifungal susceptibility, strains BJCA001 and BJCA002 showed differences in multiple aspects including morphologies, expression of virulence factors, virulence, mating type, and genomic sequence and organization. Notably, strain BJCA002 was less virulent than BJCA001 in both the <i>Galleria mellonella</i> and mouse systemic infection models. Genomic analysis demonstrated that strain BJCA002 but not BJCA001 had multiple mutations in drug resistance-associated genes, including a hot-spot mutation of <i>ERG11</i> (VF125AL, namely V125A and F126L) and some missense mutations in <i>CDR1, MDR1</i>, and <i>TAC1</i>. Notably, strain BJCA001 carried 64 copies of the Zorro3 retrotransposon, whereas BJCA002 had only 3 copies in the genome. Taken together, our findings not only reveal the genetic and phenotypic diversities of the two isolates from Beijing, China, but also shed new light on the genetic basis of the antifungal resistance and virulence of <i>C. auris.</i>
DOI: 10.6084/m9.figshare.17257315
title: Site-specific SUMOylation of viral polymerase processivity factor: a way of localizingtoND10 subnuclear domains for restricted and self-controlled reproduction of herpesvirus

description: Lytic replication of human cytomegalovirus (HCMV), a member of β-herpesvirus, is a highly complicated and organized process that requires its DNA polymerase processivity factor, UL44, the first-reported HCMV replication protein subjected to SUMO post-translational modification (PTM). SUMOylation plays a pleiotropic role in protein functions of host cells and infecting viruses. Particularly, formation of herpesviral replication compartments (RCs) upon infection is induced in proximity to ND10 subnuclear domains, the host cell’s intrinsic antiviral immune devices and hot SUMOylation spots, relying just on SUMOylation of their protein components to become mature and functional in restriction of the viral replication. In this study, to unveil the exact role of SUMO PTM on UL44 involved in HCMV replication, we screened and identified PIAS3, an annotated E3 SUMO ligase, as a novel UL44-interacting protein engaged in cellular SUMOylation pathway. Co-existence of PIAS3 could enhance the UBC9-based SUMO modification of UL44 specifically at its conserved <sup>410</sup>lysine residue lying within the single canonical ψKxE SUMO Conjugation Motif (SCM). Intriguingly, we found this SCM-specific SUMOylation contributes to UL44 co-localization and interaction with subnuclear ND10 domains during infection, which in turn exerts an inhibitory effect on HCMV replication and growth. Together, these results highlight the importance of SUMOylation in regulating viral protein subnuclear localization, representing a novel way of utilizing ND10-based restriction to achieve the self-controlled slower replication and reproduction of herpesviruses.
DOI: 10.6084/m9.figshare.17257315.v1
title: Site-specific SUMOylation of viral polymerase processivity factor: a way of localizingtoND10 subnuclear domains for restricted and self-controlled reproduction of herpesvirus

description: Lytic replication of human cytomegalovirus (HCMV), a member of β-herpesvirus, is a highly complicated and organized process that requires its DNA polymerase processivity factor, UL44, the first-reported HCMV replication protein subjected to SUMO post-translational modification (PTM). SUMOylation plays a pleiotropic role in protein functions of host cells and infecting viruses. Particularly, formation of herpesviral replication compartments (RCs) upon infection is induced in proximity to ND10 subnuclear domains, the host cell’s intrinsic antiviral immune devices and hot SUMOylation spots, relying just on SUMOylation of their protein components to become mature and functional in restriction of the viral replication. In this study, to unveil the exact role of SUMO PTM on UL44 involved in HCMV replication, we screened and identified PIAS3, an annotated E3 SUMO ligase, as a novel UL44-interacting protein engaged in cellular SUMOylation pathway. Co-existence of PIAS3 could enhance the UBC9-based SUMO modification of UL44 specifically at its conserved <sup>410</sup>lysine residue lying within the single canonical ψKxE SUMO Conjugation Motif (SCM). Intriguingly, we found this SCM-specific SUMOylation contributes to UL44 co-localization and interaction with subnuclear ND10 domains during infection, which in turn exerts an inhibitory effect on HCMV replication and growth. Together, these results highlight the importance of SUMOylation in regulating viral protein subnuclear localization, representing a novel way of utilizing ND10-based restriction to achieve the self-controlled slower replication and reproduction of herpesviruses.
DOI: 10.6084/m9.figshare.17153035
title: sRNA23, a novel small RNA, regulates to the pathogenesis of <i>Streptococcus suis</i> serotype 2

description: <i>Streptococcus suis</i> serotype 2 (<i>S. suis</i> 2) is an important ubiquitous zoonotic pathogen. To date, regulatory factors and their implication in <i>S. suis</i> pathogenesis are not fully understood. Small non-coding RNAs (sRNAs) have been proven to function as important regulatory factors in bacterial pathogenesis and stress adaptation. Here, we identified a differentially downregulated <i>S. suis</i> 05ZYH33 sRNA after iron starvation by RNA-seq, which we named sRNA23. The presence of sRNA23 was further confirmed by RACE and Northern blot. Expression of sRNA23 was significantly altered under different environmental stresses such as nutritional starvation, osmotic pressure, oxidative stress, and lysozymal exposure. A sRNA23-deleted mutant exhibited relatively shorter streptococcal chains and weakened biofilm-forming ability. The mutation also resulted in decreased adherence of the <i>S. suis</i> 05ZYH33 to human laryngeal epidermoid carcinoma (HEp-2) cells, increased sensitivity to phagocytosis by RAW264.7 macrophages, and significantly reduced hemolytic activity. Furthermore, we observed that a sRNA23-deleted mutant had a low survival rate in pig whole blood and attenuated virulence in a mouse model. Moreover, based on RNA pull-down and electrophoretic mobility shift assay, we found that sRNA23 can directly bind to two proteins involved in adhesion and biofilm formation, namely, moonlighting protein FBA (fructose diphosphate aldolase) and rplB (50S ribosomal protein L2), respectively. Collectively, sRNA23 enhances <i>S. suis</i> 2 pathogenicity and the binding between sRNA23 and FBA/rplB might play an essential role in the adherence and biofilm-forming ability of <i>S. suis</i> 2. sRNA: small noncoding RNA; FBA: fructose diphosphate aldolase; rplB: 50S ribosomal protein L2; RACE: rapid amplification of cDNA ends; EMSA: electrophoretic mobility shift assay; THB: Todd-Hewitt broth; FBS: fetal bovine serum; BIP: 2,2ʹ-Bipyridine
DOI: 10.6084/m9.figshare.17153035.v1
title: sRNA23, a novel small RNA, regulates to the pathogenesis of <i>Streptococcus suis</i> serotype 2

description: <i>Streptococcus suis</i> serotype 2 (<i>S. suis</i> 2) is an important ubiquitous zoonotic pathogen. To date, regulatory factors and their implication in <i>S. suis</i> pathogenesis are not fully understood. Small non-coding RNAs (sRNAs) have been proven to function as important regulatory factors in bacterial pathogenesis and stress adaptation. Here, we identified a differentially downregulated <i>S. suis</i> 05ZYH33 sRNA after iron starvation by RNA-seq, which we named sRNA23. The presence of sRNA23 was further confirmed by RACE and Northern blot. Expression of sRNA23 was significantly altered under different environmental stresses such as nutritional starvation, osmotic pressure, oxidative stress, and lysozymal exposure. A sRNA23-deleted mutant exhibited relatively shorter streptococcal chains and weakened biofilm-forming ability. The mutation also resulted in decreased adherence of the <i>S. suis</i> 05ZYH33 to human laryngeal epidermoid carcinoma (HEp-2) cells, increased sensitivity to phagocytosis by RAW264.7 macrophages, and significantly reduced hemolytic activity. Furthermore, we observed that a sRNA23-deleted mutant had a low survival rate in pig whole blood and attenuated virulence in a mouse model. Moreover, based on RNA pull-down and electrophoretic mobility shift assay, we found that sRNA23 can directly bind to two proteins involved in adhesion and biofilm formation, namely, moonlighting protein FBA (fructose diphosphate aldolase) and rplB (50S ribosomal protein L2), respectively. Collectively, sRNA23 enhances <i>S. suis</i> 2 pathogenicity and the binding between sRNA23 and FBA/rplB might play an essential role in the adherence and biofilm-forming ability of <i>S. suis</i> 2. sRNA: small noncoding RNA; FBA: fructose diphosphate aldolase; rplB: 50S ribosomal protein L2; RACE: rapid amplification of cDNA ends; EMSA: electrophoretic mobility shift assay; THB: Todd-Hewitt broth; FBS: fetal bovine serum; BIP: 2,2ʹ-Bipyridine
DOI: 10.6084/m9.figshare.17153035.v2
title: sRNA23, a novel small RNA, regulates to the pathogenesis of <i>Streptococcus suis</i> serotype 2

description: <i>Streptococcus suis</i> serotype 2 (<i>S. suis</i> 2) is an important ubiquitous zoonotic pathogen. To date, regulatory factors and their implication in <i>S. suis</i> pathogenesis are not fully understood. Small non-coding RNAs (sRNAs) have been proven to function as important regulatory factors in bacterial pathogenesis and stress adaptation. Here, we identified a differentially downregulated <i>S. suis</i> 05ZYH33 sRNA after iron starvation by RNA-seq, which we named sRNA23. The presence of sRNA23 was further confirmed by RACE and Northern blot. Expression of sRNA23 was significantly altered under different environmental stresses such as nutritional starvation, osmotic pressure, oxidative stress, and lysozymal exposure. A sRNA23-deleted mutant exhibited relatively shorter streptococcal chains and weakened biofilm-forming ability. The mutation also resulted in decreased adherence of the <i>S. suis</i> 05ZYH33 to human laryngeal epidermoid carcinoma (HEp-2) cells, increased sensitivity to phagocytosis by RAW264.7 macrophages, and significantly reduced hemolytic activity. Furthermore, we observed that a sRNA23-deleted mutant had a low survival rate in pig whole blood and attenuated virulence in a mouse model. Moreover, based on RNA pull-down and electrophoretic mobility shift assay, we found that sRNA23 can directly bind to two proteins involved in adhesion and biofilm formation, namely, moonlighting protein FBA (fructose diphosphate aldolase) and rplB (50S ribosomal protein L2), respectively. Collectively, sRNA23 enhances <i>S. suis</i> 2 pathogenicity and the binding between sRNA23 and FBA/rplB might play an essential role in the adherence and biofilm-forming ability of <i>S. suis</i> 2. sRNA: small noncoding RNA; FBA: fructose diphosphate aldolase; rplB: 50S ribosomal protein L2; RACE: rapid amplification of cDNA ends; EMSA: electrophoretic mobility shift assay; THB: Todd-Hewitt broth; FBS: fetal bovine serum; BIP: 2,2ʹ-Bipyridine
DOI: 10.6084/m9.figshare.14178756
title: Therapeutic implications of <i>C. albicans-S. aureus</i> mixed biofilm in a murine subcutaneous catheter model of polymicrobial infection

description: Biofilm-associated polymicrobial infections tend to be challenging to treat. <i>Candida albicans</i> and <i>Staphylococcus aureus</i> are leading pathogens due to their ability to form biofilms on medical devices. However, the therapeutic implications of their interactions in a host is largely unexplored. In this study, we used a mouse subcutaneous catheter model for <i>in vivo</i>-grown polymicrobial biofilms to validate our in vitro findings on <i>C. albicans</i>-mediated enhanced S. aureus tolerance to vancomycin <i>in vivo</i>. Comparative assessment of <i>S. aureus</i> recovery from catheters with single- or mixed-species infection demonstrated failure of vancomycin against <i>S. aureus</i> in mice with co-infected catheters. To provide some mechanistic insights, RNA-seq analysis was performed on catheter biofilms to delineate transcriptional modulations during polymicrobial infections. <i>C. albicans</i> induced the activation of the <i>S. aureus</i> biofilm formation network <i>via</i> down-regulation of the lrg operon, repressor of autolysis, and up-regulation of the ica operon and production of polysaccharide intercellular adhesin (PIA), indicating an increase in eDNA production, and extracellular polysaccharide matrix, respectively. Interestingly, virulence factors important for disseminated infections, and superantigen-like proteins were down-regulated during mixed-species infection, whereas capsular polysaccharide genes were up-regulated, signifying a strategy favoring survival, persistence and host immune evasion. <i>In vitro</i> follow-up experiments using DNA enzymatic digestion, lrg operon mutant strains, and confocal scanning microscopy confirmed the role of <i>C. albicans</i>-mediated enhanced eDNA production in mixed-biofilms on <i>S. aureus</i> tolerance to vancomycin. Combined, these findings provide mechanistic insights into the therapeutic implications of interspecies interactions, underscoring the need for novel strategies to overcome limitations of current therapies.
DOI: 10.6084/m9.figshare.14761553
title: Transcriptional adaptation of <i>Mycobacterium ulcerans</i> in an original mouse model: New insights into the regulation of mycolactone

description: <i>Mycobacterium ulcerans</i> is the causal agent of Buruli ulcer, a chronic infectious disease and the third most common mycobacterial disease worldwide. Without early treatment, <i>M. ulcerans</i> provokes massive skin ulcers, caused by the mycolactone toxin, its main virulence factor. However, spontaneous healing may occur in Buruli ulcer patients several months or years after the disease onset. We have shown, in an original mouse model, that bacterial load remains high and viable in spontaneously healed tissues, with a switch of <i>M. ulcerans</i> to low levels of mycolactone production, adapting its strategy to survive in such a hostile environment. This original model offers the possibility to investigate the regulation of mycolactone production, by using an RNA-seq strategy to study bacterial adaptation during mouse infection. Pathway analysis and characterization of the tissue environment showed that the bacillus adapted to its new environment by modifying its metabolic activity and switching nutrient sources. Thus, <i>M. ulcerans</i> ensures its survival in healing tissues by reducing its secondary metabolism, leading to an inhibition of mycolactone synthesis. These findings shed new light on mycolactone regulation and pave the way for new therapeutic strategies.