title: Implementation of a Pan-Genomic Approach to Investigate Holobiont-Infecting Microbe Interaction: A Case Report of a Leukemic Patient with Invasive Mucormycosis.
abstract: Disease can be conceptualized as the result of interactions between infecting microbe and holobiont, the combination of a host and its microbial communities. It is likely that genomic variation in the host, infecting microbe, and commensal microbiota are key determinants of infectious disease clinical outcomes. However, until recently, simultaneous, multiomic investigation of infecting microbe and holobiont components has rarely been explored. Herein, we characterized the infecting microbe, host, micro- and mycobiomes leading up to infection onset in a leukemia patient that developed invasive mucormycosis. We discovered that the patient was infected with a strain of the recently described Mucor velutinosus species which we determined was hypervirulent in a Drosophila challenge model and has a predisposition for skin dissemination. After completing the infecting M. velutinosus genome and genomes from four other Mucor species, comparative pathogenomics was performed and assisted in identifying 66 M. velutinosus-specific putatively secreted proteins, including multiple novel secreted aspartyl proteinases which may contribute to the unique clinical presentation of skin dissemination. Whole exome sequencing of the patient revealed multiple non-synonymous polymorphisms in genes critical to control of fungal proliferation, such as TLR6 and PTX3. Moreover, the patient had a non-synonymous polymorphism in the NOD2 gene and a missense mutation in FUT2, which have been linked to microbial dysbiosis and microbiome diversity maintenance during physiologic stress, respectively. In concert with host genetic polymorphism data, the micro- and mycobiome analyses revealed that the infection developed amid a dysbiotic microbiome with low α-diversity, dominated by staphylococci. Additionally, longitudinal mycobiome data showed that M. velutinosus DNA was detectable in oral samples preceding disease onset. Our genome-level study of the host-infecting microbe-commensal triad extends the concept of personalized genomic medicine to the holobiont-infecting microbe interface thereby offering novel opportunities for using synergistic genetic methods to increase understanding of infectious diseases pathogenesis and clinical outcomes.
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Ajami
authors.affiliation: Department of Microbiology & Immunology and Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marcus C
authors.initials: MC
authors.lastname: Chibucos
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Beird
authors.affiliation: Department of Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tarrand
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Galloway-Peña
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Albert
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Roy F
authors.initials: RF
authors.lastname: Chemaly
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Shashank S
authors.initials: SS
authors.lastname: Ghantoji
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marsh
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Naveen
authors.initials: N
authors.lastname: Pemmaraju
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.|Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Amin
authors.initials: A
authors.lastname: Alousi
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Bruno
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Petrosino
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D064146:Chemotherapy-Induced Febrile Neutropenia; D005656:Fungal Proteins / Q000235:genetics; D016469:Fungemia / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D016681:Genome, Fungal; D054884:Host-Pathogen Interactions; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009089:Mucor / Q000235:genetics* / Q000302:isolation & purification; D009091:Mucormycosis / Q000188:drug therapy / Q000382:microbiology*; D009363:Neoplasm Proteins / Q000235:genetics; D014009:Onychomycosis / Q000150:complications; D009894:Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D009363:Neoplasm Proteins