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Francisella tularensis (Tularemia)

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Francisella tularensis (Tularemia)

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A 45-year-old man comes to the emergency department because of a high fever, chills, and a painful ulcer on his right upper arm. He developed these symptoms after returning from a camping trip in Nebraska last weekend. His temperature is 39.4°C (103°F), pulse is 90/min, respirations are 18/min, and blood pressure is 110/70 mm Hg. Physical examination shows nodular lymphangitis and enlarged right axillary and cervical lymph nodes. Palpation does not show any hepatosplenomegaly. He does not recall any animal bite. Which of the following microbes is most likely responsible for his condition?

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Content Reviewers:

Contributors:

Alexandru Duhaniuc

Francisella tularensis is a Gram-negative coccobacillus, which means that shape-wise, it’s somewhere between a spherical coccus and a rod-like bacillus.

In humans, it causes a zoonotic infection called tularemia, also called rabbit fever.

This bacteria is also considered a category A bioterrorism agent which means it is of highest concern for bioterrorism use, because of its low infectious dose and high associated mortality.

Now, Francisella tularensis has a thin peptidoglycan layer, so it doesn’t retain the crystal violet dye during Gram staining.

Instead, like any other Gram-negative bacteria, it stains pink with safranin dye.

Alright, now Francisella tularensis is non-motile, non-spore forming, facultative intracellular which means it can survive both outside and inside the cell and aerobic which means it can survive only in the presence of oxygen.

Also, it’s oxidase and urease negative which means it doesn’t produce these enzymes.

Finally, Francisella tularensis is a fastidious bacteria which requires enriched medium for growth.

And Francisella tularensis really loves cysteine, so it only grows in about 47 to 72 hours on cysteine-enriched mediums like cysteine enriched chocolate agar, BCYE and CHAB.

Cysteine enriched chocolate agar, named so for its color, actually contains cysteine and lysed red blood cells - so no chocolate products were harmed in the making of this medium.

BCYE stands for buffered charcoal yeast extract, so it contains activated charcoal, yeast extract, and L-cysteine.

On these two mediums, Francisella tularensis forms round, grey-white colonies.

Finally, CHAB is a glucose cysteine agar that contains thiamine and blood, and on CHAB, Francisella tularensis forms greenish-white, round, smooth, mucoid colonies.

Now, Francisella tularensis has a number of virulence factors, that are like assault weaponry that help it attack and destroy the host cells, and evade the immune system.

So first, Francisella tularensis is encapsulated, meaning it’s covered by a polysaccharide layer called a capsule.

And right underneath that capsule, there’s also an outer membrane, which consists of lipopolysaccharide - or LPS for short.

The most interesting part is that normally, the LPS of Gram-negative bacteria binds to a protein found on immune cells like macrophages, called Toll-like receptor 4, or TLR4 for short, which is involved in the activation of innate immune system.

And this leads to the production of pro-inflammatory cytokines and nitric oxide that neutralize the invader.

However, the LPS of Francisella tularensis is inactive which means that TLR4 does not bind to it, so the innate immune system does not get activated - so it’s kinda like a thief breaking into a house without triggering the alarm.

So next, Francisella tularensis uses its type IV pili, which are hair-like extensions found on its capsule, to attach to macrophages.

Once attached to macrophages, the bacteria is ingested, and it gets wrapped up in a vesicle called a phagosome.

Normally, the phagosome would merge with the lysosome, to form a phagolysosome and subject the invader to oxidative burst - which is when damaging free radicals are released inside the phagolysosome.

However, Francisella tularensis produce an acid phosphatase, called AcpA, which inhibits the fusion between phagosome and lysosome, helping it avoid intracellular destruction.

And now, Francisella tularensis can replicate safely inside the macrophage.

And to replicate, it needs iron, so it also produces a siderophore, which is a term used for a group of small, high-affinity, iron chelating compounds that snatch iron from host cells.

Eventually, after Francisella tularensis has replicated enough, the macrophage bursts and releases the bacteria into the bloodstream, causing sepsis.

From the bloodstream, it can spread to other organs like the lymph nodes, causing inflammation and suppuration, or pus formation.

Alternatively, it can spread to the liver, causing hepatitis, the kidneys, causing renal failure, or the lungs, causing pneumonia.