50th World Congress on Microbiology
University of Rijeka, Faculty of Medicine, Croatia
Title: The important role of Atg5 in the pathogenesis of tularemia
Biography: Ina Kelava
Statement of the Problem: Francisella tularensis is a gram-negative, facultative intracellular bacterium that causes tularemia in humans and animals. Francisella escapes the phagosome early after infection and reaches the macrophage cytosol where the bacteria replicates. After the replication, bacteria re-enter the double-membrane vacuole via autophagy. The role of autophagy in the replication of this cytosolic pathogen has not been fully elucidated. Previous studies showed that Francisella avoids degradation via autophagy mechanism in vitro. Also, Atg5-independent autophagy provides nutrients that support Francisella intracellular replication in vitro. Although the previous studies showed the role of autophagy in the in vitro models, the in vivo role is unknown.
Methodology & Theoretical Orientation: We explored the role of Atg5- dependent autophagy on Francisella infection in vivo, by using mice deficient for Atg5 in the myeloid lineage. We determined intracellular replication of F. tularensis strain LVS in the lung, liver, and spleen of Atg5 deficient mice, as well as histopathological changes within the organs in comparison to the control group. Also, we determined the localization of bacteria within the autophagic vacuole during the infection.
Findings: Intradermal infection Atg5-deficient mice resulted in significantly reduced bacterial burden and less severe histopathological changes in the lung, liver, and spleen tissues.
Conclusion & Significance: We showed for the first time the in vivo role of Atg5-dependent autophagy in the pathogenesis of tularemia. We demonstrated that Atg5 supports Francisella intracellular growth and affects the pathology of the tissues in vivo.
1. Miller C, Celli J (2016) Avoidance and Subversion of Eukaryotic Homeostatic Autophagy Mechanisms by Bacterial Pathogens. J Mol Biol 428:3387-3398.
2. Man SM, Kanneganti TD (2016) Regulation of lysosomal dynamics and autophagy by CTSB/cathepsin B. Autophagy 12:2504-2505.
3. Ozanic M, Marecic V, Abu Kwaik Y, Santic M (2015) The Divergent Intracellular Lifestyle of Francisella tularensis in Evolutionarily Distinct Host Cells. PLoS Pathog 11:1005208.
4. Härtlova A, Link M, Balounova J, Benesova M, Resch U, Straskova A, et al. (2014) Quantitative proteomics analysis of macrophage-derived lipid rafts reveals induction of autophagy pathway at the early time of Francisella tularensis LVS infection. J Proteome Res 13:796-804.
5. Case ED, Chong A, Wehrly TD, Hansen B, Child R, Hwang S, et al. (2014) The Francisella O-antigen mediates survival in the macrophage cytosol via autophagy avoidance. Cell Microbiol 16:862-77.
6. Steele S, Brunton J, Ziehr B, Taft-Benz S, Moorman N, Kawula T (2013) Francisella tularensis harvests nutrients derived via ATG5- independent autophagy to support intracellular growth. PLoS Pathog 9:1003562.