Friday, June 29, 2018

I've got the power: How the potential bioterrorism agent Francisella tularensis manipulates host cells

In an age of advanced weaponry and warfare, the risk of bioterrorism is increasingly acute. One potential bioterrorism agent is the bacterium Francisella tularensis, which is responsible for the similarly named disease tularemia. F. tularensis is classified as a category A potential bioterrorism agent, the same classification as anthrax and the plague. A low number of bacteria are capable of causing disease, which can be fatal in up to 60% of cases if untreated. Outside the potential threat for bioterrorism, F. tularensis infection also happens naturally. While cases of tularemia in the United States have largely declined since the 1950s, this is not the case throughout the world, with multiple outbreaks occurring in Europe in the last 10 years.

F. tularemia.
CDC's Public Health Image Library.
Image # 1903; photo credit: Larry Stauffer, 
Oregon State Public Health Laboratory.
Disease management and bacterial elimination can be difficult because F. tularensis can survive in over 100 species of mammals, birds, cold-blooded animals, and arthropods, including rabbits, mice, rats, squirrels, cats, dogs, horses, pigs, and sheep. To further complicate matters, transmission of F. tularensis can occur in several ways, including the consumption of contaminated water or food; contact with urine, excrement, or blood from infected animals; bites from blood-sucking arthropods like ticks, flies, and mosquitoes; and inhalation of aerosolized bacteria. The symptoms of tularemia depend on the route of transmission and can include a skin ulcer at the site of bacterial entry; swollen glands; sore throat; and high fever. F. tularensis is naturally resistant to many antibiotics because it is an intracellular bacterium that spends most of its life hiding inside a host cell; an antibiotic must first get into the host cell before it can have any effect on the pathogen. Aminoglycosides, tetracyclines, and fluoroquinolones have been shown to be effective, but 5-15% of infections relapse following treatment, and the side effects from these antibiotics can be unmanageable, limiting their use.

Due to the low infectious dose, high mortality rate, ease of transmission, and difficulty in treatment, natural F. tularensis infection is a serious threat to public health, and a weaponized version of the bacteria could be catastrophic. To counteract these risks, researchers have been studying how F. tularensis causes infection to identify ways to inhibit or kill the bacteria. We know that once in the human body, F. tularensis is taken up by phagocytic cells, such as macrophages. The job of these phagocytic cells is to engulf the bacterium into a compartment called a phagosome for degradation. Typically, this is how the immune system would capture and kill a pathogen. However, in the case of F. tularensis, the bacterium escapes from the phagosome through a process that is not well understood to begin replicating in the cytosol of the host cell. A recent study shed a little light on this process and found that F. tularensis is manipulating the host macrophage in a unique way.

Macrophage (right) containing rickettsial microbes.
CDC's Public Health Image Library.
Image # 8731; photo credit: CDC, Dr. Ed Ewing.
Dr. Forrest Jessop and colleagues at the National Institute of Allergy and Infectious Disease found that F. tularensis alters the function of the mitochondria in the macrophage. The mitochondria are essential cellular organelles that are responsible for providing “power” to the cell, much like a battery provides power to a flashlight. When F. tularensis first enters the macrophage, it improves the function of the mitochondria, which keeps the macrophage alive and prevents an inflammatory response from the immune system. A few hours later, the bacterium reverses these effects and decreases mitochondrial function, decreasing the macrophage's power supply and leading to rapid bacterial replication and oncosis, a type of cell death that involves the swelling of the cell. This facilitates the pathogen’s ability to get out of the cell after replicating and move on to a new host cell.

The researchers were able to take this new-found knowledge of the bacteria’s effect on mitochondria a step further and test a therapeutic treatment in culture. They found that by treating F. tularensis-infected macrophages with drugs that protect typical mitochondrial function, they were able to reduce macrophage cell death and decrease levels of bacterial replication. It remains to be seen if this type of intervention will work in an animal system, but this is a promising step in the right direction towards increasing the number of treatments available for these infections. Since the environmental reservoir for F. tularensis is so vast, increased awareness of the risks of disease and research focus are important to stem the outbreaks and prevent future bioterrorism threats.