Abstract
Francisella tularensisis subsp. tularensis is an intracellular bacterial pathogen and the causative agent of the life-threatening zoonotic disease tularemia. The Francisella Pathogenicity Island encodes a large secretion apparatus, known as a Type VI Secretion System (T6SS), which is essential for Francisella to escape from its phagosome and multiply within host macrophages and to cause disease in animals. The T6SS, found in one-quarter of Gram-negative bacteria including many highly pathogenic ones, is a recently discovered secretion system that is not yet fully understood. Nevertheless, there have been remarkable advances in our understanding of the structure, composition, and function of T6SSs of several bacteria in the past few years. The system operates like an inside-out headless contractile phage that is anchored to the bacterial membrane via a baseplate and membrane complex. The system injects effector molecules across the inner and outer bacterial membrane and into host prokaryotic or eukaryotic targets to kill, intoxicate, or in the case of Francisella, hijack the target cell. Recent advances include an atomic model of the contractile sheath, insights into the mechanics of sheath contraction, the composition of the baseplate and membrane complex, the process of assembly of the apparatus, and identification of numerous effector molecules and activities. While Francisella T6SS appears to be an outlier among T6SSs, with limited or no sequence homology with other systems, its structure and organization are strikingly similar to other systems. Nevertheless, we have only scratched the surface in uncovering the mysteries of the Francisella T6SS, and there are numerous questions that remain to be answered.
Highlights
Francisella tularensis subsp. tularensis is a Gram-negative bacterium that causes a serious and potentially fatal zoonotic infection, tularemia, in animals and humans (Ellis et al, 2002)
Our structure-based mutagenesis studies of the F. novicida T6SS have demonstrated that mutations in the sheath proteins IglA and IglB that interfere with contraction of the sheath block T6SS secretion, phagosomal escape, and replication in human macrophage-like cells (Clemens et al, 2015)
We found that the bacteria were not fluorescent when grown in standard broth culture, but that they rapidly acquired fluorescent foci after uptake by macrophages (Clemens et al, 2015; Figure 4)
Summary
Francisella tularensis subsp. tularensis is a Gram-negative bacterium that causes a serious and potentially fatal zoonotic infection, tularemia, in animals and humans (Ellis et al, 2002). Because of its high infectivity and lethality, the ease with which it can be cultured and dispersed, and the history of its use as a bioweapon, it is considered a potential agent of bioterrorism and is classified as a Tier 1 Select Agent. This has led to renewed interest and investigation of its cell biology and the pathogenic mechanisms underlying its remarkable infectivity
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