Francisella tularensis Harvests Nutrients Derived via ATG5-Independent Autophagy to Support Intracellular Growth

Abstract

Francisella tularensis is a highly virulent intracellular pathogen that invades and replicates within numerous host cell types including macrophages, hepatocytes and pneumocytes. By 24 hours post invasion, F. tularensis replicates up to 1000-fold in the cytoplasm of infected cells. To achieve such rapid intracellular proliferation, F. tularensis must scavenge large quantities of essential carbon and energy sources from the host cell while evading anti-microbial immune responses. We found that macroautophagy, a eukaryotic cell process that primarily degrades host cell proteins and organelles as well as intracellular pathogens, was induced in F. tularensis infected cells. F. tularensis not only survived macroautophagy, but optimal intracellular bacterial growth was found to require macroautophagy. Intracellular growth upon macroautophagy inhibition was rescued by supplying excess nonessential amino acids or pyruvate, demonstrating that autophagy derived nutrients provide carbon and energy sources that support F. tularensis proliferation. Furthermore, F. tularensis did not require canonical, ATG5-dependent autophagy pathway induction but instead induced an ATG5-independent autophagy pathway. ATG5-independent autophagy induction caused the degradation of cellular constituents resulting in the release of nutrients that the bacteria harvested to support bacterial replication. Canonical macroautophagy limits the growth of several different bacterial species. However, our data demonstrate that ATG5-independent macroautophagy may be beneficial to some cytoplasmic bacteria by supplying nutrients to support bacterial growth.

Essential roles of methionine and S -adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis

“…Many intracellular pathogens modulate the host response to satisfy their nutritional needs and as a result have become auxotrophic for several essential amino acids and cofactors (4)(5)(6). Mycobacterium tuberculosis (Mtb), arguably the most deadly bacterial pathogen in the world (7), adopted a different strategy.…”

Role of Host Cell-Derived Amino Acids in Nutrition of Intracellular Salmonella enterica

“…In addition to being building blocks for protein biosynthesis, amino acids have been shown to be important C sources for various intracellular pathogens, such as Legionella, Francisella, or Chlamydia (3)(4)(5). Legionella pneumophila, for example, exploits the host cell degradation machinery by injecting effector proteins into its host cells, mimicking typical eukaryotic domains to increase the cytosolic level of free amino acids.…”

Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

“…To add further complexity, there is recent evidence that manipulation of autophagy is used as a means by pathogens to acquire energy and nutrients. With regard to Francisella tularensis, indirect evidence implies that it uses autophagy to increase the cytosolic nutrient pool and thereby provides energy for its rapid cytosolic replication (20,21).…”