AssessmentsRickettsia rickettsii (Rocky Mountain spotted fever) and other Rickettsia species
Rickettsia rickettsii (Rocky Mountain spotted fever) and other Rickettsia species
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A 40-year-old man comes to the office because of chills and a headache. His temperature is 39°C (102.2°F), pulse is 85/min, respirations are 18/min, and blood pressure is 120/80 mm Hg. He has an erythematous maculopapular eruption that he says began on his trunk and spread to his arms and legs. Ten days ago, he returned from working in a clinic in Algeria. His infection is determined to be caused by a microbe closely related to mitochondria. Which of the following is the most likely causative agent?
The Rickettsiae are a genus of Gram-negative coccobacilli, which includes two major groups of bacteria.
First, there’s the spotted-fever group, the main species in this group is Rickettsia rickettsii, which causes a disease called Rocky Mountain spotted fever.
Second, there’s the typhus group of Rickettsia species - which cause different forms of typhus.
Now, Rickettsiae are small bacteria, measuring only 0.7 to 2 micrometers in diameter.
They have a plasma membrane that’s surrounded by a microcapsule.
And inside the bacteria, there’s cytosol, which contains ribosomes and a single circular chromosome.
Also, these bacteria have a thin wall, that doesn’t retain the crystal violet dye during gram staining, so they’re classically considered Gram-negative bacteria.
However, they are very weak Gram-negative bacteria, so special staining methods are needed to visualize them, such as Giemsa, Gimenez or Machiavello.
So, on Giemsa staining, the bacteria appear bluish-purple, on Gimenez staining they look red, on a bluish-green background and on Machiavello staining they look bright red, on a blue background.
Finally, they’re non-motile and obligate intracellular which means they can survive only inside cells and this is because it can’t make two important energetic compounds, NAD+ and coenzyme A, by itself, and instead it gets them from eukaryotic cells.
So, they can be grown in vitro in the yolk sac of developing chicken embryos, but they are more conveniently cultured on cell culture monolayers, such as chicken embryo fibroblasts, mouse L cells, and golden hamster cells.
Now, each of these species has different vectors.
Rickettsia rickettsii is spread through tick bites, Rickettsia prowakezii is spread via lice feces, and Rickettsia typhi is transmitted through rat fleas.
But once they get inside the body, they cause disease in very similar ways.
First, they attach to endothelial cells that line the blood vessels, and invade them.
This process involves a complex interaction between lipopolysaccharides and rickettsial outer membrane proteins, called rOmps, as well as other surface-exposed proteins, or SEPs, which act as adhesins.
There’s two types of rOmps: rOmpA and rOmpB, and Rickettsia rickettsii has both of them, while Rickettsia prowazekii and Rickettsia typhi only have rOmpB.
But at the end of the day, all Rickettsiae use the rOmps they have, as well as the SEPs, to adhere to the endothelial cells.
After adhesion, the rOmps bind to a protein, called Ku70, which is found in the membrane of host cells, and activates it.
Once active, Ku70 recruits an enzyme, called ubiquitin ligase.
Ubiquitin ligase causes ubiquitination of Ku70, which means that a ubiquitin molecule is added to Ku70.
This process activates several signaling pathways which leads to polymerization and rearrangement of cellular actin, so that the cell membrane invaginates to form a vesicle, with the bacteria snuggled up inside it.
The vesicle then separates from the cell membrane forming a phagosome inside the cell.
Inside the phagosome, the Rickettsiae use two enzymes, phospholipase D and tlyC, to break the phagosomal membrane and escape into the cytoplasm, where they replicate by binary fission.
This means the bacteria split in two identical copies - and if it sounds similar to mitosis...well, it is! But the term binary fission is used to describe division of prokaryotic cells, which don’t have a nucleus, and therefore some steps in replication are different from mitosis.
And here’s where we get a major difference between Rickettsia rickettsii and the other two species, Rickettsia prowazekii and Rickettsia typhi.
Interestingly, Rickettsia rickettsii has the ability to spread from cell to cell by traversing cell membranes without causing obvious damage.
So, it has an actin-based motility which means it has a bunch of proteins which recruits host cell actin filaments at one end to form a tail.
As more and more actin filaments get recruited and polymerized behind the bacteria’s end pole, that propels the bacteria forward, like a rocket, through the cytosol and into finger-like protrusions at the lateral side of the cell, called filopodia.
The bacterium-containing protrusions can extend several bacterial lengths away from the cell surface, with the bacterium at the tip and then, the bacterium-containing protrusion tips are phagocytosed by adjacent cells, thereby transferring the bacterium into the adjacent cell.
This process allows Rickettsia to move at astonishing speeds - up to 4.8 meters per minute.
On the other hand, Rickettsia prowazekii and Rickettsia typhi choose to multiply inside the endothelial cell instead. Eventually, the cell bursts, and releases them into the extracellular space, where they adhere to other cells and invade them, repeating the cycle over and over again.
Eventually, all Rickettsiae cause damage to the endothelial cells and small blood vessels, but the mechanism is not well understood.
Afterwards, damaged endothelial cells can then undergo either necrosis or apoptosis.
Cell necrosis is induced by the bacteria, whereas apoptosis is a programmed cell death induced by immune effector mechanisms, such as CD8+ cytotoxic T-lymphocytes. With necrosis, the cell bursts and spills its internal contents on neighboring cells, and this attracts nearby immune cells and triggers an inflammatory response.
Immune cells release proteases, which are enzymes that degrade proteins, and also reactive oxygen species - which are unstable and damage other cells.
With apoptosis, on the other hand, the cell membrane develops blebs - or bulges in the cell membrane.
The blebs are structurally weak, so they start to break off from the cell membrane, and this attracts nearby macrophages, which begin to clean up the mess by eating up the cell fragments.
So this process is a lot cleaner and doesn’t cause so much damage to surrounding cells.
But with both necrosis and apoptosis, the leukocytes also gobble up some bacteria along with cellular debris, and bacteria digestion during phagocytosis releases damaging microbial substances, which cause collateral damage to surrounding tissues.
The end result is lymphohistiocytic vasculitis, which is inflammation of blood vessels caused by lymphocytes and macrophages.
The injury of small blood vessels causes increased permeability, and leads to leakage of fluid from the bloodstream to tissue.
More specifically, fluid goes from the small blood vessels into the interstitial space, which is the space between cells.