Rickettsia rickettsii (Rocky Mountain spotted fever) and other Rickettsia species
Definitions & Key takeaways
Rickettsiae are a genus of Gram-negative coccobacilli, which includes Rickettsia rickettsii known to cause Rocky Mountain spotted fever (RMSF); and Rickettsia prowazekii that causes epidemic typhus; and Rickettsia typhi, which is known to cause endemic typhus. Rickettsia rickettsii is transmitted through ticks; Rickettsia prowazekii through lice; whereas Rickettsia typhi is transmitted through rat fleas. Symptoms of Rickettsiae infections depend on the type but may include fever, headache, malaise, myalgias, arthralgias, and skin rashes. Rickettsiae can be diagnosed with serologic tests such as indirect immunofluorescence or with special stains on a skin biopsy and they can be treated with antibiotics like doxycycline or chloramphenicol.
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. This group includes Rickettsia prowazekii, which causes a disease called epidemic typhus, and Rickettsia typhi, which causes murine typhus, also called endemic 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.
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.
This results in edema, hypovolemia, hypotension and hypoalbuminemia. Also, if fluid builds up in the brain, it may cause encephalitis.
In the heart, it may cause myocarditis. And in the lungs, it may cause pulmonary edema.
Finally, the inflammation and damage to the blood vessels and capillaries activate platelets, generate thrombin, and activate the fibrinolytic system, creating a procoagulant status that uses up platelets and clotting factors.
As Rickettsiae proliferate in the endothelial lining, it also causes thrombi to form and in severe cases, extensive vasculitis can lead to small-vessel occlusion.
Alright! Now, Rickettsia rickettsii is transmitted through ticks such as Dermacentor variabilis, or the American dog tick, which can be found in Eastern and South-central US, Dermacentor andersoni, or the Rocky Mountain wood tick, which can be found west of Mississippi River and Rhipicephalus sanguineus, or the common brown dog tick which can be found in Southwestern US.
All of these vectors can pass the bacteria to humans and cause a disease called Rocky Mountain spotted fever, or RMSF for short.
Risk factors for this disease include age between 40 and 64 years, living in endemic areas or travelling there, especially in spring and summer, living near wooded areas or areas with high grass, or frequent exposure to dogs.
Now, in the early phase of illness, there are usually non-specific symptoms, like fever, headache, malaise, myalgias, arthralgias and nausea.
Later on, an erythematous rash appears, which is the hallmark of the disease. The rash starts out as small, flat, pink, non-itchy spots called macules, which turn pale if pressure is applied to them.
In severe cases, the rash may become confluent, with some areas of skin becoming necrotic due to damage induced by the bacteria to the microcirculation, especially in regions supplied by terminal arteries such as the fingers, toes, nose, ears and genitals.
On the other hand, Rickettsia prowazekii is spread through lice feces, and it causes epidemic typhus, which is a form of typhus named so because the disease often causes epidemics following wars and natural disasters.
In fact, it’s thought that epidemic typhus has caused more deaths than all the wars in history. An interesting fact is that Rickettsia prowazekii can remain latent in humans for decades and reactivate months or years later, causing a delayed relapse of epidemic typhus called Brill-Zinsser disease.
Now, in the early phase of epidemic typhus, there are usually non-specific symptoms, like fever, headache, malaise, myalgias, arthralgias and nausea.
Later on, a red macular rash appears, which is the hallmark of the disease. The rash starts at trunk and then spread to the extremities but it spares the hands, feet and head.
Brill-Zinsser disease may occur 10 to 50 years after primary infection, and symptoms include chills, fever, malaise, headache and a rash, similar to the one in epidemic typhus, which appears a couple of days later.
Finally, Rickettsia typhi is spread by rat fleas, and it causes murine or endemic typhus, which is a flu-like illness that can be easily mistaken for a viral illness - mainly because people are rarely aware of having flea bites and most cases resolve spontaneously.
Also, the symptoms are nonspecific, and they include fever, headache, chills, myalgias, nausea, vomiting, abdominal pain and diarrhea, and after several days a rash appears on the trunk and spread to extremities, sparing the palms and soles.
Finally, symptoms of complications are the same for all diseases. With encephalitis, there may be confusion, drowsiness, coma or seizures.
With myocarditis, there may be electrocardiographic abnormalities. And with pulmonary edema, there may be a cough and dyspnea, which means difficulty breathing.
Now, Rickettsiae cannot be cultured in most clinical laboratories, so the clinical diagnosis must be confirmed with serologic testing or with special stains on a skin biopsy.
Serologic testing is done with indirect immunofluorescence, or IFA for short, which identifies the antibodies against Rickettsia.
For Rickettsia rickettsii, both IgM and IgG antibodies typically appear after 7 to 10 days after the onset of the illness.
For Rickettsia prowazekii and Rickettsia typhi, IgM and IgG antibody titers appear 10 to 21 days after the onset of illness.
Lab tests may also show thrombocytopenia, or low platelet levels, and prolongation of the prothrombin and the partial thromboplastin time.
Sometimes hyponatremia may occur. Finally, a chest X-ray can be done to identify interstitial infiltrates and an echocardiogram can assess for myocardial dysfunction.
Treatment for all Rickettsia-associated diseases is done with doxycycline, as a first line, or chloramphenicol, as an alternative.
Alright, as a quick recap. Rickettsiae are a genus of Gram-negative coccobacilli, which includes Rickettsia rickettsii of the spotted-fever group, and Rickettsia prowazekii and Rickettsia typhi of the typhus group.
Rickettsia rickettsii is transmitted through ticks and causes a disease called Rocky Mountain spotted fever. Rickettsia prowazekii is transmitted through lice and causes a disease called epidemic typhus.
Rickettsia typhi is transmitted through rat fleas and causes a disease called murine or endemic typhus. They’re small gram-negative coccobacilli, non-motile, obligate intracellular which can be visualized on special stainings such as Giemsa, Gimenez and Machiavello and they can be grown only on cell cultures.
They have virulence factors, such as a rickettsial outer membrane proteins, called rOmpS, as well as other surface-exposed proteins, or SEPs, enzymes such as phospholipase D and tlyC involved in the adhesion and invasion of endothelial cells and also, in the injury of small blood vessels.
They can be diagnosed with serologic tests such as indirect immunofluorescence or with special stains on a skin biopsy and they can be treated with doxycycline or chloramphenicol.
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