cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.5517/ccdc.csd.cc2hgtsl
title: CCDC 2308160: Experimental Crystal Structure Determination

description: Related Article: Gary C. George III, Mahshad Karimi, Navkiran Juneja, Daniel K. Unruh, Ryan H. Groeneman, Kristin M. Hutchins|2024|Cryst.Growth Des.|24|2468|doi:10.1021/acs.cgd.3c01435
description: An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
DOI: 10.6084/m9.figshare.13713068.v1
title: The transcription factor Ndt80 is a repressor of Candida parapsilosis virulence attributes

description: <i>Candida parapsilosis</i> is an emergent opportunistic yeast among hospital settings that affects mainly neonates and immunocompromised patients. Its most remarkable virulence traits are the ability to adhere to prosthetic materials, as well as the formation of biofilm on abiotic surfaces. The Ndt80 transcription factor was identified as one of the regulators of biofilm formation by <i>C. parapsilosis</i>; however, its function in this process was not yet clarified. By knocking out <i>NDT80</i> (<i>CPAR2-213640</i>) gene, or even just one single copy of the gene, we observed substantial alterations of virulence attributes, including morphogenetic changes, adhesion and biofilm growth profiles. Both <i>ndt80Δ</i> and <i>ndt80ΔΔ</i> mutants changed colony and cell morphologies from smooth, yeast-shaped to crepe and pseudohyphal elongated forms, exhibiting promoted adherence to polystyrene microspheres and notably, forming a higher amount of biofilm compared to wild-type strain. Interestingly, we identified transcription factors Ume6, Cph2, Cwh41, Ace2, Bcr1, protein kinase Mkc1 and adhesin Als7 to be under Ndt80 negative regulation, partially explaining the phenotypes displayed by the <i>ndt80ΔΔ</i> mutant. Furthermore, <i>ndt80ΔΔ</i> pseudohyphae adhered more rapidly and were more resistant to murine macrophage attack, becoming deleterious to such cells after phagocytosis. Unexpectedly, our findings provide the first evidence for a direct role of Ndt80 as a repressor of <i>C. parapsilosis</i> virulence attributes. This finding shows that <i>C. parapsilosis</i> Ndt80 functionally diverges from its homolog in the close related fungal pathogen <i>C. albicans</i>.
DOI: 10.6084/m9.figshare.15134664.v2
title: Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A

description: Drug-resistant pathogenic <i>Staphylococcus aureus</i> (<i>S. aureus</i>) has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of <i>S. aureus</i>, which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against <i>S. aureus</i> infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC<sub>50</sub> of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of <i>S. aureus</i> to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall <i>in vitro</i>. Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated <i>S. aureus</i> virulence of <i>in vivo</i> and protected mice against <i>S. aureus</i>-induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter <i>S. aureus</i> infections and limit the development of drug resistance.
DOI: 10.6084/m9.figshare.13312495
title: The novel outer membrane protein from OprD/Occ family is associated with hypervirulence of carbapenem resistant Acinetobacter baumannii ST2/KL22

description: <i>Acinetobacter baumannii</i> has become a major healthcare threat that causes nosocomial infections, especially in critically ill patients. The spread of carbapenem-resistant <i>A. baumannii</i> (CRAB) strains has long been a clinical concern. It is important to study the epidemiology and virulence characteristics of different CRAB isolates in order to tailor infection prevention and antibiotic prescribing. In this study, a total of 71 CRAB isolates were collected in the hospital, and clinical characteristics of infections were analyzed. The genomic characteristics and phylogenetic relationships were elucidated based on genome sequencing and analysis. The isolates were assigned to three sequence types (STs, Pasteur) and nine capsular polysaccharide (KL) types, among which ST2/KL22 was the most prevalent CRAB in the hospital. Even though all the ST2/KL22 isolates contained the same reported virulence genes, one specific clade of ST2/KL22 showed more pathogenic in mouse infection model. Complete genomic analysis revealed differences at the <i>oprD</i> locus between the low- and high-virulent isolates. More specifically, a premature stop codon in the low-virulence strains resulted in truncated OprD expression. By evaluating pathogenicity in C57BL/6 J mice, knock-out of <i>oprD</i> in high-virulent isolate resulted in virulence attenuation, and complementing the avirulent strain with full-length <i>oprD</i> from high-virulent isolate enhanced virulence of the former. The <i>oprD</i> gene may be associated with the enhanced virulence of the specific ST2/KL22 clone, which provides a potential molecular marker for screening the hypervirulent <i>A. baumannii</i> strains.
DOI: 10.6084/m9.figshare.13312495.v2
title: The novel outer membrane protein from OprD/Occ family is associated with hypervirulence of carbapenem resistant Acinetobacter baumannii ST2/KL22

description: <i>Acinetobacter baumannii</i> has become a major healthcare threat that causes nosocomial infections, especially in critically ill patients. The spread of carbapenem-resistant <i>A. baumannii</i> (CRAB) strains has long been a clinical concern. It is important to study the epidemiology and virulence characteristics of different CRAB isolates in order to tailor infection prevention and antibiotic prescribing. In this study, a total of 71 CRAB isolates were collected in the hospital, and clinical characteristics of infections were analyzed. The genomic characteristics and phylogenetic relationships were elucidated based on genome sequencing and analysis. The isolates were assigned to three sequence types (STs, Pasteur) and nine capsular polysaccharide (KL) types, among which ST2/KL22 was the most prevalent CRAB in the hospital. Even though all the ST2/KL22 isolates contained the same reported virulence genes, one specific clade of ST2/KL22 showed more pathogenic in mouse infection model. Complete genomic analysis revealed differences at the <i>oprD</i> locus between the low- and high-virulent isolates. More specifically, a premature stop codon in the low-virulence strains resulted in truncated OprD expression. By evaluating pathogenicity in C57BL/6 J mice, knock-out of <i>oprD</i> in high-virulent isolate resulted in virulence attenuation, and complementing the avirulent strain with full-length <i>oprD</i> from high-virulent isolate enhanced virulence of the former. The <i>oprD</i> gene may be associated with the enhanced virulence of the specific ST2/KL22 clone, which provides a potential molecular marker for screening the hypervirulent <i>A. baumannii</i> strains.
DOI: 10.6084/m9.figshare.13312495.v1
title: The novel outer membrane protein from OprD/Occ family is associated with hypervirulence of carbapenem resistant <i>Acinetobacter baumannii</i> ST2/KL22

description: <i>Acinetobacter baumannii</i> has become a major healthcare threat that causes nosocomial infections, especially in critically ill patients. The spread of carbapenem resistant <i>A. baumannii</i> (CRAB) strains has long been a clinical concern. It is important to study the epidemiology and virulence characteristics of different CRAB isolates in order to tailor infection prevention and antibiotic prescribing. In this study, a total of 71 CRAB isolates were collected in the hospital, and clinical characteristics of infections were analyzed. The genomic characteristics and phylogenetic relationships were elucidated based on genome sequencing and analysis. The isolates were assigned to three sequence types (STs, Pasteur) and nine capsular polysaccharide (KL) types, among which ST2/KL22 was the most prevalent CRAB in the hospital. Even though all the ST2/KL22 isolates contained the same reported virulence genes, one specific clade of ST2/KL22 showed more pathogenic in mouse infection model. Complete genomic analysis revealed differences at the <i>oprD</i> locus between the low- and high-virulent isolates. More specifically, a pre-mature stop codon in the low-virulence strains resulted in truncated OprD expression. By evaluating pathogenicity in C57BL/6J mice, knock-out of <i>oprD</i> in high-virulent isolate resulted in virulence attenuation, and complementing the avirulent strain with full-length <i>oprD</i> from high-virulent isolate enhanced virulence of the former. The <i>oprD</i> gene may be associated with the enhanced virulence of the specific ST2/KL22 clone, which provides a potential molecular marker for screening the hypervirulent <i>A. baumannii</i> strains.
DOI: 10.6084/m9.figshare.14401735.v1
title: Tribolium castaneum defensin 1 kills Moraxella catarrhalisin an in vitro infection model but does not harm commensal bacteria

description: <i>Moraxella catarrhalis</i> is a bacterial pathogen that causes respiratory tract infections in humans. The increasing prevalence of antibiotic-resistant <i>M. catarrhalis</i> strains has created a demand for alternative treatment options. We therefore tested 23 insect antimicrobial peptides (AMPs) for their activity against <i>M. catarrhalis</i> in a human <i>in vitro</i> infection model with primary macrophages, and against commensal bacteria. Effects on bacterial growth were determined by colony counting and growth curve analysis. The inflammatory macrophage response was characterized by qPCR and multiplex ELISA. Eleven of the AMPs were active against <i>M. catarrhalis</i>. Defensin 1 from the red flour beetle <i>Tribolium castaneum</i> significantly inhibited bacterial growth and reduced the number of colony forming units. This AMP also showed antibacterial activity in the <i>in vitro</i> infection model, reducing cytokine expression and release by macrophages. Defensin 1 had no effect on the commensal bacteria <i>Escherichia coli</i> and <i>Enterococcus faecalis</i>. However, sarcotoxin 1 C from the green bottle fly <i>Lucilia sericata</i> was active against <i>M. catarrhalis</i> and <i>E. coli</i>, but not against <i>E. faecalis</i>. The ability of <i>T. castaneum</i> defensin 1 to inhibit <i>M. catarrhalis</i> but not selected commensal bacteria, and the absence of cytotoxic or inflammatory effects against human blood-derived macrophages, suggests this AMP may be suitable for development as a new therapeutic lead against antibiotic-resistant <i>M. catarrhalis</i>.
DOI: 10.6084/m9.figshare.16571390.v1
title: Cleavage of E-cadherin by porcine respiratory bacterial pathogens facilitates airway epithelial barrier disruption and bacterial paracellular transmigration

description: Airway epithelial cells are the first line of defense against respiratory pathogens. Porcine bacterial pathogens, such as <i>Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Glaesserella</i> (<i>Haemophilus</i>) <i>parasuis</i>, and <i>Pasteurella multocida</i>, breach this barrier to lead to local or systematic infections. Here, we demonstrated that respiratory bacterial pathogen infection disrupted the airway epithelial intercellular junction protein, E-cadherin, thus contributing to impaired epithelial cell integrity. E-cadherin knocking-out in newborn pig tracheal cells via CRISPR/Cas9 editing technology confirmed that E-cadherin was sufficient to suppress the paracellular transmigration of these porcine respiratory bacterial pathogens, including <i>G. parasuis, A. pleuropneumoniae, P. multocida</i>, and <i>B. bronchiseptica</i>. The E-cadherin ectodomain cleavage by these pathogens was probably attributed to bacterial HtrA/DegQ protease, but not host HtrA1, MMP7 and ADAM10, and the prominent proteolytic activity was further confirmed by a serine-to-alanine substitution mutation in the active center of HtrA/DegQ protein. Moreover, deletion of the <i>htrA</i> gene in <i>G. parasuis</i> led to severe defects in E-cadherin ectodomain cleavage, cell adherence and paracellular transmigration <i>in vitro</i>, as well as bacterial breaking through the tracheal epithelial cells, systemic invasion and dissemination <i>in vivo</i>. This common pathogenic mechanism shared by other porcine respiratory bacterial pathogens explains how these bacterial pathogens destroy the airway epithelial cell barriers and proliferate in respiratory mucosal surface or other systemic tissues.
DOI: 10.6084/m9.figshare.16571390.v2
title: Cleavage of E-cadherin by porcine respiratory bacterial pathogens facilitates airway epithelial barrier disruption and bacterial paracellular transmigration

description: Airway epithelial cells are the first line of defense against respiratory pathogens. Porcine bacterial pathogens, such as <i>Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Glaesserella</i> (<i>Haemophilus</i>) <i>parasuis</i>, and <i>Pasteurella multocida</i>, breach this barrier to lead to local or systematic infections. Here, we demonstrated that respiratory bacterial pathogen infection disrupted the airway epithelial intercellular junction protein, E-cadherin, thus contributing to impaired epithelial cell integrity. E-cadherin knocking-out in newborn pig tracheal cells via CRISPR/Cas9 editing technology confirmed that E-cadherin was sufficient to suppress the paracellular transmigration of these porcine respiratory bacterial pathogens, including <i>G. parasuis, A. pleuropneumoniae, P. multocida</i>, and <i>B. bronchiseptica</i>. The E-cadherin ectodomain cleavage by these pathogens was probably attributed to bacterial HtrA/DegQ protease, but not host HtrA1, MMP7 and ADAM10, and the prominent proteolytic activity was further confirmed by a serine-to-alanine substitution mutation in the active center of HtrA/DegQ protein. Moreover, deletion of the <i>htrA</i> gene in <i>G. parasuis</i> led to severe defects in E-cadherin ectodomain cleavage, cell adherence and paracellular transmigration <i>in vitro</i>, as well as bacterial breaking through the tracheal epithelial cells, systemic invasion and dissemination <i>in vivo</i>. This common pathogenic mechanism shared by other porcine respiratory bacterial pathogens explains how these bacterial pathogens destroy the airway epithelial cell barriers and proliferate in respiratory mucosal surface or other systemic tissues.
DOI: 10.6084/m9.figshare.16653244.v1
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.14178756.v1
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.17695941
title: Exacerbation of <i>Mycobacterium avium</i> pulmonary infection by comorbid allergic asthma is associated with diminished mycobacterium-specific Th17 responses

description: Accumulating evidence suggests that two chronic respiratory diseases, nontuberculous mycobacterium (NTM)-pulmonary disease (PD) and allergic asthma, are frequently present together and that they likely influence the disease development and progression of each other. However, their precise interactions regarding the pathogenesis of comorbid diseases versus that of individual diseases are not well understood. In this study, comorbid diseases (<i>i.e., Mycobacteria avium</i> (Mav) pulmonary infection (PI) (Mav-PI) and ovalbumin-induced allergic asthma) were established in mice in different orders and at different time periods. Individual disease-specific characteristics, including alterations in immune cell populations and antigen-specific immune responses, were analyzed and compared. To assess Mav-PI pathogenesis, lung inflammation and bacterial burden levels were also determined. Allergic asthma induction in the presence of Mav-PI markedly aggravated Mav-PI pathogenesis by increasing the bacterial burden and the severity of lung inflammation. Interestingly, the general outcome of allergic asthma with goblet cell hyperplasia was alleviated at a chronic stage in the comorbid mouse model. Overall, the increase in the number of Mav CFUs was inversely correlated with the Mav-specific Th17 response, as confirmed by comparing BALB/c and C57BL/6J mice. Overall, the pathogenesis of existing Mav-PI is more severely affected by allergen exposure than vice versa. This Mav-PI exacerbation is associated with disruption of Mav-specific Th17 responses. This study provides the first evidence that the Mav-specific Th17 response plays an important role in the control of Mav pathogenesis in the presence of allergic asthma, indicating that targeting the Th17 response has therapeutic potential for NTM-PD accompanied by allergic asthma.
DOI: 10.6084/m9.figshare.13686217.v1
title: TREM1 regulates antifungal immune responses in invasive pulmonary aspergillosis

description: Pattern recognition receptors (PRRs) are responsible for <i>Aspergillus fumigatus</i> recognition by innate immunity and its subsequent immune signaling. The triggering receptor expressed on myeloid cells 1 (TREM1) is a recently characterized pro-inflammatory receptor constitutively expressed on the surface of neutrophils and macrophages. A soluble form (sTREM1) of this protein that can be detected in human body fluids has been identified. Here we investigated the role of TREM1 during invasive pulmonary aspergillosis (IPA). IPA patients displayed significantly higher levels of sTREM1 in bronchoalveolar lavages when compared to control patients. Functional analysis in TREM1 showed that the levels of sTREM1 and TREM1 pathway-related cytokines were influenced by single nucleotide polymorphisms in TREM1. In addition, we confirmed a role of TREM1 on antifungal host defense against <i>A. fumigatus</i> in a murine model of IPA. TREM1 deficiency increased susceptibility to infection in the immunosuppressed murine host. Deletion of TREM1 showed delayed innate and adaptive immune responses and impaired pro-inflammatory cytokine responses. The absence of TREM1 in primary macrophages attenuated the TLR signaling by altering the expression of both receptor and effector proteins that are critical to the response against <i>A. fumigatus</i>. In this study, and for the first time, we demonstrate the key role for the TREM1 receptor pathway during IPA.