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

• Published in: Infection and immunity 2017-09, Vol.85 (9)
• Main Authors: Parashar, Kaustubh, Kopping, Erik, Frank, David, Sampath, Vinaya, Thanassi, David G, Carpino, Nick
• Format: Article
• Language: English
• Subjects: Animal Structures - microbiology; Animal Structures - pathology; Animals; Bacterial Load; Cytokines - analysis; Disease Models, Animal; Disease Susceptibility; Francisella tularensis - immunology; Host Response and Inflammation; 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
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00406-17

The uppressor of CR ignaling 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 mice are profoundly resistant to systemic infection by , 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 mice to infection by a Gram-negative bacterial pathogen. is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia. 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 ive accine train (LVS) of 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. bone marrow-derived monocytes and neutrophils, infected with LVS , 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.