Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection
ABSTRACT Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we exam...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-08-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01440-19 |
| _version_ | 1818990157232078848 |
|---|---|
| author | Aleeza C. Gerstein Katrina M. Jackson Tami R. McDonald Yina Wang Benjamin D. Lueck Sara Bohjanen Kyle D. Smith Andrew Akampurira David B. Meya Chaoyang Xue David R. Boulware Kirsten Nielsen |
| author_facet | Aleeza C. Gerstein Katrina M. Jackson Tami R. McDonald Yina Wang Benjamin D. Lueck Sara Bohjanen Kyle D. Smith Andrew Akampurira David B. Meya Chaoyang Xue David R. Boulware Kirsten Nielsen |
| author_sort | Aleeza C. Gerstein |
| collection | DOAJ |
| description | ABSTRACT Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections. IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality. |
| first_indexed | 2024-12-20T19:49:54Z |
| format | Article |
| id | doaj.art-86bf418b72984328b1699eeb06de61c9 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T19:49:54Z |
| publishDate | 2019-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-86bf418b72984328b1699eeb06de61c92022-12-21T19:28:20ZengAmerican Society for MicrobiologymBio2150-75112019-08-0110410.1128/mBio.01440-19Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> InfectionAleeza C. Gerstein0Katrina M. Jackson1Tami R. McDonald2Yina Wang3Benjamin D. Lueck4Sara Bohjanen5Kyle D. Smith6Andrew Akampurira7David B. Meya8Chaoyang Xue9David R. Boulware10Kirsten Nielsen11Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USAPublic Health Research Institute, Rutgers University, Newark, New Jersey, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USAInfectious Diseases Institute and School of Medicine, College of Health Sciences, Makerere University, Kampala, UgandaInfectious Diseases Institute and School of Medicine, College of Health Sciences, Makerere University, Kampala, UgandaPublic Health Research Institute, Rutgers University, Newark, New Jersey, USADepartment of Medicine, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USAABSTRACT Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections. IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.https://journals.asm.org/doi/10.1128/mBio.01440-19fungusHIVcryptococcosismeningitisGWASpolymorphism |
| spellingShingle | Aleeza C. Gerstein Katrina M. Jackson Tami R. McDonald Yina Wang Benjamin D. Lueck Sara Bohjanen Kyle D. Smith Andrew Akampurira David B. Meya Chaoyang Xue David R. Boulware Kirsten Nielsen Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection mBio fungus HIV cryptococcosis meningitis GWAS polymorphism |
| title | Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection |
| title_full | Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection |
| title_fullStr | Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection |
| title_full_unstemmed | Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection |
| title_short | Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Infection |
| title_sort | identification of pathogen genomic differences that impact human immune response and disease during named content content type genus species cryptococcus neoformans named content infection |
| topic | fungus HIV cryptococcosis meningitis GWAS polymorphism |
| url | https://journals.asm.org/doi/10.1128/mBio.01440-19 |
| work_keys_str_mv | AT aleezacgerstein identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT katrinamjackson identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT tamirmcdonald identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT yinawang identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT benjamindlueck identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT sarabohjanen identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT kyledsmith identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT andrewakampurira identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT davidbmeya identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT chaoyangxue identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT davidrboulware identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection AT kirstennielsen identificationofpathogengenomicdifferencesthatimpacthumanimmuneresponseanddiseaseduringnamedcontentcontenttypegenusspeciescryptococcusneoformansnamedcontentinfection |