Rickettsial Diseases, including Typhus and Rocky Mountain Spotted Fever (page 2)
(This chapter has 6 pages)
© Kenneth Todar, PhD
Virulence of Rickettsiae
Adherence to the Host Cell
Rickettsiae are inoculated into the dermis of the skin by a tick bite
or through damaged skin from the feces of lice or fleas. The bacteria
through the bloodstream and infect the endothelium. Adherence to the
cell is the first step of rickettsial pathogenesis. The adhesins are
to be outer membrane proteins. The outer membrane protein OmpA has been
implicated in adherence of R. rickettsii because antibodies to
have been shown to block adherence.
The host cell receptor for any Rickettsia has yet to be
Although the main target cells of Rickettsia in vivo are
cells, rickettsiae can infect virtually every cell line in vitro. Thus,
either the receptor for Rickettsia is ubiquitous among cells,
rickettsiae can bind to different receptors.
Invasion of Host Cells
Upon attaching to the host cell membrane, rickettsiae are phagocytosed
by the host cell. The rickettsiae are believed to induce host
phagocytosis because they can enter cells that normally do not
particles. Once phagocytosed by the host cell, rickettsiae are observed
to quickly escape from the phagosome membrane and enter the cytoplasm.
mechanism of escape from the phagosome membrane is not well understood,
but it is thought to be mediated by a rickettsial enzyme, phospholipase
Movement within and Release from the Host Cell
Observations in cell culture systems suggest that the mechanisms of
intracellular movement and destruction of the host cells differ among
spotted fever group and typhus group rickettsiae.
Typhus group rickettsiae are released from host cells by lysis of
cells. After infection with R. prowazekii or R. typhi,
rickettsiae continue to multiply until the cell is packed with
and then bursts. Phospholipase A2 may be involved in cell lysis.
group rickettsia-infected host cells have a normal ultrastructural
Spotted fever group rickettsiae seldom accumulate in large numbers
do not lyse the host cells. They escape from the cell by stimulating
of host cell-derived actin tails, which propel them through the
and into tips of membranous extrusions, from which they emerge.
cells exhibit signs of membrane damage associated with an influx of
but the means by which rickettsiae damage host cell membranes is
There is evidence to suggest a role for free radicals of oxygen,
and a protease. The protein responsible for the actin-based movement
spotted fever group rickettsiae has yet to be identified, but it
is apparently different than the proteins responsible for actin
by Listeria monocytogenes and Shigella flexneri.
Rickettsial diseases vary in clinical severity according to the
of the Rickettsia and host factors, such as age, male gender,
and other underlying diseases. The most virulent rickettsiae are R.
rickettsii and R. prowazekii, which kill a significant
of infected persons, unless the diseases are treated sufficiently
early in the course of infection with an effective antimicrobial agent,
All rickettsial infections begin with introduction of the organisms
into the skin, either through a tick bite or cutaneous abrasions
by flea or louse feces. Rickettsiae enter dermal cells including
and proliferate locally intracellularly with endothelial cell-to-cell
for most SFG rickettsioses resulting in an eschar or tache noire, a
of dermal and epidermal necrosis approximately 1 cm in diameter with a
surrounding zone of erythema. Eschars do not occur in epidemic
murine typhus and are rarely observed in Rocky Mountain spotted fever.
SFG rickettsioses often manifest regional lymphadenopathy in the
of the eschar, suggesting that rickettsiae may spread via lymphatic
from the tick bite inoculation site early in the infection. Rickettsiae
spread throughout the body and infect mainly endothelial cells,
many foci of contiguous infected blood vessel-lining cells. Injury in
local sites causes vascular damage manifesting as rash, interstitial
encephalitis, interstitial nephritis, and interstitial myocarditis, as
well as lesions in the liver, gastrointestinal wall, pancreas, and
any vascularized tissue of the body.
The most important pathophysiologic effect is increased vascular
with consequent edema, loss of blood volume, hypoalbuminemia, decreased
osmotic pressure, and hypotension. These effects can be life
resulting in pulmonary edema and adult respiratory distress syndrome,
or acute tubular necrosis.
Rocky Mountain Spotted Fever
Rocky Mountain spotted fever is the most severe and most
reported rickettsial disease in the United States. In the
era, 20-25% of previously healthy, infected persons died of the
Today, even with antimicrobial agents that are highly effective, 3-5%
persons die mainly because of late or mis-diagnosed infection and
delayed or ineffective antimicrobial treatment.
The disease is caused by Rickettsia rickettsii, and the
bacteria are spread to humans by ixodid (hard) ticks.
of disease follows an infective bite by a week (range 2-14 days),
with fever, severe headache, and muscle pain, followed by development
rash. The disease can be difficult to diagnose in the early stages, and
without prompt and appropriate treatment, it can be fatal.
The reasons are that up to 40% of patients are unaware of a tick
which is painless and may go unnoticed or be forgotten, and that the
does not usually appear until 3-5 days after onset of illness. To
further confound the diagnosis, symptoms such as nausea, vomiting,
abdominal pain, and cough may suggest other diagnoses such as
acute surgical abdomen, or pneumonia. The rash typically appears
on the ankles and wrists as faint pink 1-5 mm macules that represent a
focus of vascular infection and surrounding vasodilation. These lesions
may progress to become maculopapular, owing to the leakage of edema
from the affected blood vessels, with the development of a hemorrhage
in the center of the lesions.
Figure 2. Characteristic
spotted rash of late-stage Rocky Mountain spotted fever on legs of a
Rocky Mountain spotted fever was first recognized in 1896 in the
River Valley of Idaho and was originally called "black measles" because
of the characteristic rash. It was a dreaded and frequently fatal
that affected hundreds of people in this area. By the early 1900s, the
geographic distribution of the disease in United States was
as far north as Washington and Montana and as far south as California,
Arizona and New Mexico.
Howard Ricketts was the first to establish the identity of the
organism that causes Rocky Mountain spotted fever at the turn of the
Twentieth Century. He and
characterized the basic epidemiologic features of the disease,
the role of tick vectors. Studies showed that Rocky Mountain
fever is caused by Rickettsia rickettsii, and involves a
cycle between ticks and mammals. Humans are accidental hosts, but are
involved in the natural transmission cycle of the pathogen.
The name Rocky Mountain spotted fever is somewhat of a misnomer.
in the 1930s, it became clear that this disease occurred in many areas
of the United States other than the Rocky Mountain region. It is now
that this disease is broadly distributed throughout the continental
States, as well as southern Canada, Central America, Mexico, and parts
of South America. Between 1981 and 1996, this disease was
from every U.S. state except Hawaii, Vermont, Maine and Alaska.
Rocky Mountain spotted fever remains a serious and potentially
infectious disease today. Despite the availability of effective
and advances in medical care, approximately 3- 5% of individuals who
ill with Rocky Mountain spotted fever die from the infection. However,
effective antibiotic therapy has dramatically reduced the number of
caused by Rocky Mountain spotted fever. Before the discovery of
and chloramphenicol in the late 1940s, as many as 30% of individuals
with R. rickettsii died.
Figure 3. Discovery of
chloramphenicol and tetracycline antibiotics in the 1940s led to a
decline in RMSF-related mortality. Today, doxycycline is the drug of
for treatment of RMSF. (CDC)
Figure 4. Gimenez stain
of tick hemolymph cells infected with R. rickettsii. (CDC)
Rickettsia rickettsii, is a very small bacterium that must
inside the cells of its hosts. Consequently, they are difficult
see in tissues by using routine histologic stains and generally require
the use of special staining methods.
In humans, Rickettsia rickettsii live and multiply primarily
within cells that line small- to medium-sized blood vessels. Spotted
group rickettsiae can grow in the nucleus or in the cytoplasm of the
cell. Once inside the host the rickettsiae multiply, resulting in
and death of these cells. This causes blood to leak through tiny holes
in vessel walls into adjacent tissues. This process causes the rash
is traditionally associated with Rocky Mountain spotted fever and
damage to organs and tissues.