November 2013

Francisella tularensis: a biological weapon

cysteine heart agar
Colonization of Francisella tularensis on cysteine heart agar after 72 hours. Image credit: Centers for Disease Control and Prevention/Larry Stauffer, Oregon State Public Health Laboratory (Wikimedia Commons)

The bacterium Francisella tularensis, which causes tularemia, is categorized as a class A bioterrorism agent, putting it among the likes of plague, smallpox and ebola.
 
Known in some parts of the world as rabbit fever, the bacterial infection can cause large die-offs of rabbits, hares and rodents. Francisella is transmitted to humans by arthropods, including ticks, and can enter the body through damaged skin, if infected animal carcasses are handled, or through inhalation, if those carcasses are mowed over, which explains why it also has been called lawnmower disease.
 
Upon infection, the bacterium lives as an intracellular pathogen and can survive in a multitude of cells, including macrophages, thus winning over the body’s first and second lines of defense, resulting in a lethal infection.
 
This Gram-negative bacterium has four known subspecies, which have varying degrees of virulence in humans. Tularensis is the most virulent; holarctica can infect humans but rarely is fatal; novicida is usually nonlethal; and mediasiatica — well, it’s still a bit of a mystery.
 
Recent papers in the Journal of Biological Chemistry and the journal Molecular & Cellular Proteomics report probable mechanisms by which Francisella leads to a lethal infection.
 
Writing in the JBC, Meenakshi Malik’s group at Albany College of Pharmacy and Health Sciences reported how tularensis represses inflammasome during early stages, thus resulting in an infection. The team used naive macrophages for infection with a mutant of F. tularensis. This mutant bears a gene that encodes for OmpA-like protein, which is responsible for the repression of inflammasome activation, delaying the death of infected macrophages.
 
Although this OmpA-like protein checks early activation of inflammasome, the authors witnessed an increased activation after 24 hours. This increased activation might be happening via another independent pathway. The results reinforce that there is a lot to be learned about the mechanism of infection by this pathogen.
 
Meanwhile, a research team led by Fred Heffron at Oregon Health & Science University used F. novicida to manifest a tularemialike disease in animal models. The team reported in MCP that it used isobaric tags for relative and absolute quantification to analyze alterations in the host cell phosphoproteome as Francisella invades. It takes just four hours for the bacterium to escape from the phagosome to the host cell cytoplasm. This infection in the host cell involves all three types of cytoskeleton filaments.

 
The entry of Francisella into the host cells triggers the signaling pathways, resulting in massive changes in the phosphoproteome of the host cell. Heffron’s team pointed out that tristetrapolin, a component of mRNA degradation machinery, is inhibited due to hyper-phosphorylation, which affects the regulation of cytokine production, resulting in apoptosis of host cells.
 
The ability of Francisella to breach the defense mechanisms of the human body could be exploited in biological warfare. These two studies enhance our knowledge of the bacterium’s mechanism of infection and might help to one day design drugs against this deadly organism.

Khyati KapoorKhyati Kapoor (khyati.kapoor@nih.gov) is a postdoctoral fellow at the National Cancer Institute in Bethesda, Md.


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