Molecular and Microbial Microenvironments in Chronically Diseased Lungs Associated with Cystic Fibrosis
Alexey V. Melnik,
Yoshiki Vázquez-Baeza,
Alexander A. Aksenov,
Embriette Hyde,
Andrew C. McAvoy,
Mingxun Wang,
Ricardo R. da Silva,
Ivan Protsyuk,
Jason V. Wu,
Amina Bouslimani,
Yan Wei Lim,
Tal Luzzatto-Knaan,
William Comstock,
Robert A. Quinn,
Richard Wong,
Greg Humphrey,
Gail Ackermann,
Timothy Spivey,
Sharon S. Brouha,
Nuno Bandeira,
Grace Y. Lin,
Forest Rohwer,
Douglas J. Conrad,
Theodore Alexandrov,
Rob Knight,
Pieter C. Dorrestein,
Neha Garg
Affiliations
Alexey V. Melnik
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Yoshiki Vázquez-Baeza
Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA
Alexander A. Aksenov
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Embriette Hyde
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
Andrew C. McAvoy
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USA
Mingxun Wang
Department of Computer Science & Engineering, University of California, San Diego, La Jolla, California, USA
Ricardo R. da Silva
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Ivan Protsyuk
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
Jason V. Wu
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Amina Bouslimani
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Yan Wei Lim
Biology Department, San Diego State University, San Diego, California, USA
Tal Luzzatto-Knaan
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
William Comstock
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Robert A. Quinn
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Richard Wong
Department of Pathology, University of California, San Diego, La Jolla, California, USA
Greg Humphrey
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
Gail Ackermann
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
Timothy Spivey
Department of Radiology, University of California, San Diego, La Jolla, California, USA
Sharon S. Brouha
Department of Medicine, University of California, San Diego, La Jolla, California, USA
Nuno Bandeira
Department of Computer Science & Engineering, University of California, San Diego, La Jolla, California, USA
Grace Y. Lin
Department of Pathology, University of California, San Diego, La Jolla, California, USA
Forest Rohwer
Biology Department, San Diego State University, San Diego, California, USA
Douglas J. Conrad
Department of Medicine, University of California, San Diego, La Jolla, California, USA
Theodore Alexandrov
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Rob Knight
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
Pieter C. Dorrestein
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
Neha Garg
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA
ABSTRACT To visualize the personalized distributions of pathogens and chemical environments, including microbial metabolites, pharmaceuticals, and their metabolic products, within and between human lungs afflicted with cystic fibrosis (CF), we generated three-dimensional (3D) microbiome and metabolome maps of six explanted lungs from three cystic fibrosis patients. These 3D spatial maps revealed that the chemical environments differ between patients and within the lungs of each patient. Although the microbial ecosystems of the patients were defined by the dominant pathogen, their chemical diversity was not. Additionally, the chemical diversity between locales in the lungs of the same individual sometimes exceeded interindividual variation. Thus, the chemistry and microbiome of the explanted lungs appear to be not only personalized but also regiospecific. Previously undescribed analogs of microbial quinolones and antibiotic metabolites were also detected. Furthermore, mapping the chemical and microbial distributions allowed visualization of microbial community interactions, such as increased production of quorum sensing quinolones in locations where Pseudomonas was in contact with Staphylococcus and Granulicatella, consistent with in vitro observations of bacteria isolated from these patients. Visualization of microbe-metabolite associations within a host organ in early-stage CF disease in animal models will help elucidate the complex interplay between the presence of a given microbial structure, antibiotics, metabolism of antibiotics, microbial virulence factors, and host responses. IMPORTANCE Microbial infections are now recognized to be polymicrobial and personalized in nature. Comprehensive analysis and understanding of the factors underlying the polymicrobial and personalized nature of infections remain limited, especially in the context of the host. By visualizing microbiomes and metabolomes of diseased human lungs, we reveal how different the chemical environments are between hosts that are dominated by the same pathogen and how community interactions shape the chemical environment or vice versa. We highlight that three-dimensional organ mapping methods represent hypothesis-building tools that allow us to design mechanistic studies aimed at addressing microbial responses to other microbes, the host, and pharmaceutical drugs.
