1. Seham M. Rabadi1,
2. Belkys C. Sanchez1,
3. Mrudula Varanat1,
4. Zhuo Ma2,
5. Sally V. Catlett2,
6. Juan Andres Melendez3,
7. Meenakshi Malik2 and
8. Chandra Shekhar Bakshi1*

1. New York Medical College, United States;
2. Albany College of Pharmacy and Health Sciences, United States;
3. SUNY Polytechnic Institute, United States

* Corresponding author; email: shekhar_bakshi@nymc.edu

Author contributions: CSB, MM and JAM conceived, designed and coordinated the study. CSB and MM wrote the paper. BCS performed and analyzed the experiments shown in Figure 2. SMR, ZM and SVC performed and analyzed the experiments shown in Figure 1, 4, 5, 6, 7 and 9. MV performed and analyzed the experiments shown in Figure 3 and 8. All authors reviewed the results and approved the final version of the manuscript.

Abstract

Francisella tularensis, the causative agent of a fatal human disease known as tularemia has been used in the bioweapon programs of several countries in the past, and now is considered a potential bioterror agent. Extreme infectivity and virulence of F. tularensis is due to its ability to evade immune detection and to suppress hosts innate immune responses. However, Francisella encoded factors and mechanisms responsible for causing immune suppression are not completely understood. Macrophages and neutrophils generate Reactive Oxygen-Nitrogen Species (ROS,RNS) as a defense mechanism for the clearance of phagocytosed microorganisms. ROS serve a dual role; at high concentrations they act as microbicidal effector molecules that destroy intracellular pathogens and at low concentrations, they serve as secondary signaling messengers that regulate the expression of various inflammatory mediators. We hypothesized that antioxidant defenses of F. tularensis maintain redox-homeostasis in infected macrophages to prevent activation of redox-sensitive signaling components which ultimately result in suppression of pro-inflammatory cytokine production and macrophage microbicidal activity. We demonstrate that antioxidant enzymes of F. tularensis prevent the activation of redox-sensitive MAPK signaling components, NF-kappaB signaling and the production of pro-inflammatory cytokines by inhibiting the accumulation of ROS in infected macrophages. We also report that F. tularensis inhibits ROS-dependent autophagy to promote its intramacrophage survival. Collectively, this study reveals novel pathogenic mechanisms adopted by F. tularensis to modulate macrophage innate immune functions to create an environment permissive for its intracellular survival and growth.

Received July 27, 2015.

Accepted December 7, 2015.

Copyright © 2015, The American Society for Biochemistry and Molecular Biology