Rickettsia rickettsii & other Rickettsia species – causes, symptoms, diagnosis, treatment, pathology

Rickettsia rickettsii & other Rickettsia species – causes, symptoms, diagnosis, treatment, pathology


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. 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. 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. Over time, these macules turn into petechiae,
which are red or purple spots on the skin. The rash is a delayed manifestation of infection
and it typically starts at wrists and ankles and then spreads to the trunk, palms and soles. 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.