Perforin-2 protects host cells and mice by restricting the vacuole to cytosol transitioning of a bacterial pathogen

Ryan McCormack, Wael Bahnan, Niraj Shrestha, Justin Boucher, Marcella Barreto, Carlos M. Barrera, Edward A. Dauer, Nancy E. Freitag, Wasif N. Khan, Eckhard R. Podack, Kurt Schesser

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes. Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2-/- mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2-/- cells that the vacuole-to-cytosol transitioning of L. monocytogenes is greatly accelerated. Unexpectedly, we found that in Perforin-2-/- macrophages, Listeria-containing vacuoles quickly (≤15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that a L. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2+/+ and Perforin-2-/- macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.

Original languageEnglish (US)
Pages (from-to)1083-1091
Number of pages9
JournalInfection and immunity
Volume84
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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