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Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection

Nature Microbiology volume 2, Article number: 17079 (2017) Cite this article

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Abstract

Identifying genes required by pathogens during infection is critical for antimicrobial development. Here, we use a Monte Carlo simulation-based method to analyse high-throughput transposon sequencing data to determine the role of infection site and co-infecting microorganisms on the in vivo ‘essential’ genome of Staphylococcus aureus. We discovered that co-infection of murine surgical wounds with Pseudomonas aeruginosa results in conversion of ∼25% of the in vivo S. aureus mono-culture essential genes to non-essential. Furthermore, 182 S. aureus genes are uniquely essential during co-infection. These ‘community dependent essential’ (CoDE) genes illustrate the importance of studying pathogen gene essentiality in polymicrobial communities.

To cause infection, bacteria must possess the genetic requirements to colonize and proliferate within a host. These genes can be classified into two primary categories, those that are essential during all growth conditions (in vitro and in vivo) and those that are solely essential in the infection site (in vivo). Identification of essential genes is important for developing new therapeutics against human pathogens1. Although most antimicrobials target factors essential under all growth conditions, there is increasing interest in targeting genes that are essential solely during infection2–4.

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Figure 1: The S. aureus in vivo essential genome in three monoculture infections and during co-infection with P. aeruginosa.
Figure 2: Confirmation of S. aureus mutant Tn-seq phenotypes.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH, grants R01GM116547-01A1 and 1R01DE023193-01 to M.W.) and a grant from Human Frontiers Science (to M.W.). C.B.I. is supported by postdoctoral fellowship IBBERS16F0 from the Cystic Fibrosis Foundation. Contributions by M.S.G. were supported by PHS grant AI107248 and the Harvard-wide Program on Antibiotic Resistance (AI083214). A.S. is supported by a predoctoral fellowship from the NIH (F31DE024931). The authors thank M. Ramsey for generating pMR361-K, K. Michie for assistance with the chronic surgical wound experiments, S. Leonard for computational assistance and D. Cornforth for discussion of the manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, LaMontagne Center for Infectious Disease, The University of Texas at Austin, 1 University Station, A5000, Austin, 78712, Texas, USA

    Carolyn B. Ibberson, Apollo Stacy, Justine L. Dees & Marvin Whiteley

  2. Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, 79430, Texas, USA

    Derek Fleming & Kendra Rumbaugh

  3. Department of Ophthalmology and Department of Microbiology and Immunobiology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, 02115, Massachusetts, USA

    Michael S. Gilmore

Authors
  1. Carolyn B. Ibberson
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Contributions

C.B.I., A.S., K.R. and M.W. designed experiments. C.B.I., A.S. and M.W. analysed data. C.B.I., A.S. and D.F. performed experiments. J.L.D. prepared sequencing libraries. M.S.G. provided S. aureus HG003 transposon library and provided the raw data from previous studies7,8 included in the analysis. C.B.I., A.S., J.L.D., M.S.G., K.R. and M.W. wrote the paper.

Corresponding author

Correspondence to Marvin Whiteley.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Figures 1–3, Supplementary Tables 2 and 3, Supplementary References (PDF 766 kb)

Supplementary Table 1

The essential genes for S. aureus and A. actinomycetemcomitans. (XLSX 851 kb)

Supplementary Table 4

Sequencing data for each replicate in this study. (XLSX 9 kb)

Supplementary Table 5

A list of all of the ‘TA’ dinucleotide positions in the S. aureus NCTC8325 reference genome. (XLSX 2454 kb)

Supplementary Table 6

A list of all of the ‘TA’ dinucleotide positions in the A. actinomycetemcomitans strain 624 reference genome. (XLSX 1259 kb)

Supplementary Table 7

Homologues in S. aureus strain NCTC8325 and S. aureus strain USA300_FPR3757 for the transposon mutants used in this study. (XLSX 48 kb)

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Ibberson, C., Stacy, A., Fleming, D. et al. Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nat Microbiol 2, 17079 (2017). https://doi.org/10.1038/nmicrobiol.2017.79

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