Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases

Kaustubh Parashar; Erik Kopping; David Frank; Vinaya Sampath; David G Thanassi; Nick Carpino

doi:10.1128/IAI.00406-17

Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases

Infect Immun. 2017 Aug 18;85(9):e00406-17. doi: 10.1128/IAI.00406-17. Print 2017 Sep.

Authors

Kaustubh Parashar¹, Erik Kopping^{1

2}, David Frank^{1

3}, Vinaya Sampath^{1

2}, David G Thanassi^{1

2}, Nick Carpino⁴

Affiliations

¹ Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
² Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA.
³ Graduate Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York, USA.
⁴ Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA nicholas.carpino@stonybrook.edu.

Abstract

The Suppressor of TCR signaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated that Sts^-/- mice are profoundly resistant to systemic infection by Candida albicans, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response of Sts^-/- mice to infection by a Gram-negative bacterial pathogen. Francisella tularensis is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia. Francisella infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by the live vaccine strain (LVS) of F. tularensis Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs. Sts^-/- bone marrow-derived monocytes and neutrophils, infected with F. tularensis LVS ex vivo, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways.

Keywords: Francisella; host resistance; host-pathogen interactions.

MeSH terms

Animal Structures / microbiology
Animal Structures / pathology
Animals
Bacterial Load
Cytokines / analysis
Disease Models, Animal
Disease Susceptibility*
Francisella tularensis / immunology*
Male
Mice
Mice, Knockout
Phosphoric Monoester Hydrolases / deficiency
Phosphoric Monoester Hydrolases / metabolism*
Protein Tyrosine Phosphatases / deficiency
Protein Tyrosine Phosphatases / metabolism*
Receptors, Antigen, T-Cell / deficiency
Receptors, Antigen, T-Cell / metabolism*
Survival Analysis
Tularemia / immunology*

Substances

Cytokines
Receptors, Antigen, T-Cell
Sts-2 protein, mouse
Phosphoric Monoester Hydrolases
Protein Tyrosine Phosphatases
TULA-2 protein, mouse

Abstract

MeSH terms

Substances

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