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Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut

  1. Denise M. Monacka,1
  1. aDepartment of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305;
  2. bLaboratoire d'Ingénierie des Systèmes Macromoléculaires (UMR7255), Institut de Microbiologie de la Méditerranée, Aix-Marseille Université - CNRS, 13402 Marseille, France;
  3. cDivision of Oncology, Department of Medicine and Pathology, Stanford School of Medicine, Stanford University, Stanford, CA 94305

  1. Edited by Scott J. Hultgren, Washington University School of Medicine, St. Louis, MO, and approved June 30, 2016 (received for review June 2, 2016)

Significance

Gram-negative bacteria use the type VI secretion system (T6SS) to deliver effectors into adjacent cells. Salmonella Typhimurium is an enteric pathogen that causes disease in millions of individuals each year. Its ability to infect the mammalian gut is a key factor that contributes to its virulence and transmission to new hosts. However, many of the details on how Salmonella successfully colonizes the gut and persists among members of the gut microbiota remain to be deciphered. In this work, we provide evidence that Salmonella uses an antibacterial weapon, the type VI secretion system, to establish infection in the gut. In addition, our results suggest that S. Typhimurium selectively targets specific members of the microbiota to invade the gastrointestinal tract.

Abstract

The mammalian gastrointestinal tract is colonized by a high-density polymicrobial community where bacteria compete for niches and resources. One key competition strategy includes cell contact-dependent mechanisms of interbacterial antagonism, such as the type VI secretion system (T6SS), a multiprotein needle-like apparatus that injects effector proteins into prokaryotic and/or eukaryotic target cells. However, the contribution of T6SS antibacterial activity during pathogen invasion of the gut has not been demonstrated. We report that successful establishment in the gut by the enteropathogenic bacterium Salmonella enterica serovar Typhimurium requires a T6SS encoded within Salmonella pathogenicity island-6 (SPI-6). In an in vitro setting, we demonstrate that bile salts increase SPI-6 antibacterial activity and that S. Typhimurium kills commensal bacteria in a T6SS-dependent manner. Furthermore, we provide evidence that one of the two T6SS nanotube subunits, Hcp1, is required for killing Klebsiella oxytoca in vitro and that this activity is mediated by the specific interaction of Hcp1 with the antibacterial amidase Tae4. Finally, we show that K. oxytoca is killed in the host gut in an Hcp1-dependent manner and that the T6SS antibacterial activity is essential for Salmonella to establish infection within the host gut. Our findings provide an example of pathogen T6SS-dependent killing of commensal bacteria as a mechanism to successfully colonize the host gut.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: dmonack{at}stanford.edu.

  • Author contributions: T.G.S., E.C., and D.M.M. designed research; T.G.S., N.F., K.A.L., L.H.L., A.J., V.B., and E.D. performed research; T.G.S., N.F., K.A.L., E.D., L.J., E.C., and D.M.M. analyzed data; and T.G.S., E.C., and D.M.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1608858113/-/DCSupplemental.

Freely available online through the PNAS open access option.

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