Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus
ABSTRACT Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low- and middle-income countries. Hydrocephalus preceded by an infection, or postinfectious hydrocephalus, accounts for up to 60% of hydrocephalus in these areas. Since many children wit...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02688-22 |
| _version_ | 1811289954193506304 |
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| author | Christine Hehnly Aiqin Shi Paddy Ssentongo Lijun Zhang Albert Isaacs Sarah U. Morton Nicholas Streck Petra Erdmann-Gilmore Igor Tolstoy R. Reid Townsend David D. Limbrick Joseph N. Paulson Jessica E. Ericson Michael Y. Galperin Steven J. Schiff James R. Broach |
| author_facet | Christine Hehnly Aiqin Shi Paddy Ssentongo Lijun Zhang Albert Isaacs Sarah U. Morton Nicholas Streck Petra Erdmann-Gilmore Igor Tolstoy R. Reid Townsend David D. Limbrick Joseph N. Paulson Jessica E. Ericson Michael Y. Galperin Steven J. Schiff James R. Broach |
| author_sort | Christine Hehnly |
| collection | DOAJ |
| description | ABSTRACT Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low- and middle-income countries. Hydrocephalus preceded by an infection, or postinfectious hydrocephalus, accounts for up to 60% of hydrocephalus in these areas. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen, Paenibacillus thiaminolyticus, as a causal agent of neonatal sepsis and postinfectious hydrocephalus in Uganda. Here, we report the isolation of three P. thiaminolyticus strains, Mbale, Mbale2, and Mbale3, from patients with postinfectious hydrocephalus. We constructed complete genome assemblies of the clinical isolates as well as the nonpathogenic P. thiaminolyticus reference strain and performed comparative genomic and proteomic analyses to identify potential virulence factors. All three isolates carry a unique beta-lactamase gene, and two of the three isolates exhibit resistance in culture to the beta-lactam antibiotics penicillin and ampicillin. In addition, a cluster of genes carried on a mobile genetic element that encodes a putative type IV pilus operon is present in all three clinical isolates but absent in the reference strain. CRISPR-mediated deletion of the gene cluster substantially reduced the virulence of the Mbale strain in mice. Comparative proteogenomic analysis identified various additional potential virulence factors likely acquired on mobile genetic elements in the virulent strains. These results provide insight into the emergence of virulence in P. thiaminolyticus and suggest avenues for the diagnosis and treatment of this novel bacterial pathogen. IMPORTANCE Postinfectious hydrocephalus, a devastating sequela of neonatal infection, is associated with increased childhood mortality and morbidity. A novel bacterial pathogen, Paenibacillus thiaminolyticus, is highly associated with postinfectious hydrocephalus in an African cohort. Whole-genome sequencing, RNA sequencing, and proteomics of clinical isolates and a reference strain in combination with CRISPR editing identified type IV pili as a critical virulence factor for P. thiaminolyticus infection. Acquisition of a type IV pilus-encoding mobile genetic element critically contributed to converting a nonpathogenic strain of P. thiaminolyticus into a pathogen capable of causing devastating diseases. Given the widespread presence of type IV pilus in pathogens, the presence of the type IV pilus operon could serve as a diagnostic and therapeutic target in P. thiaminolyticus and related bacteria. |
| first_indexed | 2024-04-13T04:04:28Z |
| format | Article |
| id | doaj.art-4ed3d517da8341ba9e490b66a1529316 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-13T04:04:28Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-4ed3d517da8341ba9e490b66a15293162022-12-22T03:03:23ZengAmerican Society for MicrobiologymBio2150-75112022-12-0113610.1128/mbio.02688-22Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticusChristine Hehnly0Aiqin Shi1Paddy Ssentongo2Lijun Zhang3Albert Isaacs4Sarah U. Morton5Nicholas Streck6Petra Erdmann-Gilmore7Igor Tolstoy8R. Reid Townsend9David D. Limbrick10Joseph N. Paulson11Jessica E. Ericson12Michael Y. Galperin13Steven J. Schiff14James R. Broach15Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USAInstitute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USADepartment of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USADepartment of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USADivision of Neurosurgery, Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, CanadaDivision of Newborn Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USADepartment of Pathology and Laboratory Medicine Division of Clinical Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USADepartment of Medicine, Washington University School of Medicine, St. Louis, Missouri, USANational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USADepartment of Medicine, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USAInstitute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USADivision of Pediatric Infectious Disease, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USANational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USADepartment of Neurosurgery, Yale University, New Haven, Connecticut, USAInstitute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USAABSTRACT Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low- and middle-income countries. Hydrocephalus preceded by an infection, or postinfectious hydrocephalus, accounts for up to 60% of hydrocephalus in these areas. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen, Paenibacillus thiaminolyticus, as a causal agent of neonatal sepsis and postinfectious hydrocephalus in Uganda. Here, we report the isolation of three P. thiaminolyticus strains, Mbale, Mbale2, and Mbale3, from patients with postinfectious hydrocephalus. We constructed complete genome assemblies of the clinical isolates as well as the nonpathogenic P. thiaminolyticus reference strain and performed comparative genomic and proteomic analyses to identify potential virulence factors. All three isolates carry a unique beta-lactamase gene, and two of the three isolates exhibit resistance in culture to the beta-lactam antibiotics penicillin and ampicillin. In addition, a cluster of genes carried on a mobile genetic element that encodes a putative type IV pilus operon is present in all three clinical isolates but absent in the reference strain. CRISPR-mediated deletion of the gene cluster substantially reduced the virulence of the Mbale strain in mice. Comparative proteogenomic analysis identified various additional potential virulence factors likely acquired on mobile genetic elements in the virulent strains. These results provide insight into the emergence of virulence in P. thiaminolyticus and suggest avenues for the diagnosis and treatment of this novel bacterial pathogen. IMPORTANCE Postinfectious hydrocephalus, a devastating sequela of neonatal infection, is associated with increased childhood mortality and morbidity. A novel bacterial pathogen, Paenibacillus thiaminolyticus, is highly associated with postinfectious hydrocephalus in an African cohort. Whole-genome sequencing, RNA sequencing, and proteomics of clinical isolates and a reference strain in combination with CRISPR editing identified type IV pili as a critical virulence factor for P. thiaminolyticus infection. Acquisition of a type IV pilus-encoding mobile genetic element critically contributed to converting a nonpathogenic strain of P. thiaminolyticus into a pathogen capable of causing devastating diseases. Given the widespread presence of type IV pilus in pathogens, the presence of the type IV pilus operon could serve as a diagnostic and therapeutic target in P. thiaminolyticus and related bacteria.https://journals.asm.org/doi/10.1128/mbio.02688-22Paenibacillus thiaminolyticuspostinfectious hydrocephalustype IV pilusvirulence factors |
| spellingShingle | Christine Hehnly Aiqin Shi Paddy Ssentongo Lijun Zhang Albert Isaacs Sarah U. Morton Nicholas Streck Petra Erdmann-Gilmore Igor Tolstoy R. Reid Townsend David D. Limbrick Joseph N. Paulson Jessica E. Ericson Michael Y. Galperin Steven J. Schiff James R. Broach Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus mBio Paenibacillus thiaminolyticus postinfectious hydrocephalus type IV pilus virulence factors |
| title | Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus |
| title_full | Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus |
| title_fullStr | Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus |
| title_full_unstemmed | Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus |
| title_short | Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus |
| title_sort | type iv pili are a critical virulence factor in clinical isolates of paenibacillus thiaminolyticus |
| topic | Paenibacillus thiaminolyticus postinfectious hydrocephalus type IV pilus virulence factors |
| url | https://journals.asm.org/doi/10.1128/mbio.02688-22 |
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