title: A Commensal Bacterium Promotes Virulence of an Opportunistic Pathogen via Cross-Respiration.
abstract: Bacteria rarely inhabit infection sites alone, instead residing in diverse, multispecies communities. Despite this fact, bacterial pathogenesis studies primarily focus on monoculture infections, overlooking how community interactions influence the course of disease. In this study, we used global mutant fitness profiling (transposon sequencing [Tn-seq]) to determine the genetic requirements for the pathogenic bacterium Aggregatibacter actinomycetemcomitans to cause disease when coinfecting with the commensal bacterium Streptococcus gordonii Our results show that S. gordonii extensively alters A. actinomycetemcomitans requirements for virulence factors and biosynthetic pathways during infection. In addition, we discovered that the presence of S. gordonii enhances the bioavailability of oxygen during infection, allowing A. actinomycetemcomitans to shift from a primarily fermentative to a respiratory metabolism that enhances its growth yields and persistence. Mechanistically, respiratory metabolism enhances the fitness of A. actinomycetemcomitans in vivo by increasing ATP yields via central metabolism and creating a proton motive force. Our results reveal that, similar to cross-feeding, where one species provides another species with a nutrient, commensal bacteria can also provide electron acceptors that promote the respiratory growth and fitness of pathogens in vivo, an interaction that we term cross-respiration.
  
  
  
  Commensal bacteria can enhance the virulence of pathogens in mixed-species infections. However, knowledge of the mechanisms underlying this clinically relevant phenomenon is lacking. To bridge this gap, we comprehensively determined the genes a pathogen needs to establish coinfection with a commensal. Our findings show that the metabolism of the pathogen is low-energy-yielding in monoinfection, but in coinfection, the commensal improves the fitness of the pathogen by increasing the bioavailability of oxygen, thereby shifting the pathogen toward a high-energy-yielding metabolism. Similar to cross-feeding, this interaction, which we term cross-respiration, illustrates that commensal bacteria can provide electron acceptors that enhance the virulence of pathogens during infection.
authors.affiliation: Department of Molecular Biosciences, Institute of Cellular and Molecular Biology, Center for Infectious Disease, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Apollo
authors.initials: A
authors.lastname: Stacy
authors.affiliation: Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Fleming
authors.affiliation: Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
authors.affiliation: Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
authors.forename: Kendra P
authors.initials: KP
authors.lastname: Rumbaugh
authors.affiliation: Department of Molecular Biosciences, Institute of Cellular and Molecular Biology, Center for Infectious Disease, The University of Texas at Austin, Austin, Texas, USA mwhiteley@austin.utexas.edu.
authors.forename: Marvin
authors.initials: M
authors.lastname: Whiteley
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016976:Aggregatibacter actinomycetemcomitans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D000693:Anaerobiosis; D000818:Animals; D060085:Coinfection / Q000382:microbiology* / Q000503:physiopathology; D004251:DNA Transposable Elements / Q000235:genetics*; D020869:Gene Expression Profiling; D056084:Genetic Fitness; D059014:High-Throughput Nucleotide Sequencing; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D016871:Pasteurellaceae Infections / Q000382:microbiology / Q000503:physiopathology; D018892:Proton-Motive Force; D054773:Streptococcus gordonii / Q000378:metabolism*; D013559:Symbiosis; D014774:Virulence
chemical_list: D004251:DNA Transposable Elements; D000255:Adenosine Triphosphate; D010100:Oxygen