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Biology of Rickettsia rickettsii infection
Author
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Morven S Edwards, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: mar 28, 2008.
INTRODUCTION — Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever
(RMSF) and the prototypic member of the genus Rickettsia. The basic biologic features of R.
rickettsii and how it produces disease will be reviewed here. The clinical manifestations of RMSF
and its treatment are discussed separately. (See "Clinical manifestations and diagnosis of Rocky
Mountain spotted fever" and"Treatment of Rocky Mountain spotted fever".)
TAXONOMY — Like other gram-negative bacteria, R. rickettsii is a member of the alpha-group of
purple bacteria. It is a member of the order Rickettsiales and the family Rickettsiaceae. The family
Rickettsiaceae, in turn, contains the genera Rickettsia and Orientia. The genus Rickettsia is divided
into the typhus and spotted fever groups.
R. rickettsii is the prototype of the spotted fever group, which has nine separate pathogenic species.
Phylogenetic studies utilizing the 16S ribosome have shown that R. rickettsii is closely related to
other members of the spotted fever group such as R. conorii and R. sibirica, whereas its
phylogenetic relationship to other spotted fever members such as R. akari, R. australis, and R. belli
is substantially more distant.
MICROBIOLOGY — R. rickettsii is a weakly gram-negative non-motile coccobacillus measuring 0.3 to 0.7 mcm by 0.8 to 2.0 mcm. R. rickettsii are difficult to see in tissue without special stains, but they can be visualized using Giemsa, Machiavello, and Gimenez staining and by the use of direct fluorescent antibody staining techniques.
Ultrastructure — R rickettsii has ribosomes and a single circular chromosome located in an
amorphous cytosol surrounded by a plasma membrane. In addition, an indistinct microcapsular
layer is present on the outer surface of the cell wall. An electron-lucent zone separates this layer
from the host cytosol. This zone is thought to represent a slime layer which may be important in
pathogenicity [1].
Growth and survival characteristics — R. rickettsii is an obligate intracellular parasite that cannot
be propagated on cell-free media. It can be grown in vitro in the yolk sac of developing chicken
embryos, but it is more conveniently cultured on primary or established cell culture monolayers,
such as chicken embryo fibroblasts, mouse L cells, and golden hamster cells. Like all members of
the spotted fever group, R. rickettsii proliferates by binary fission and grows in both the nucleus and cytoplasm of host cells. When inside host cells, R. rickettsii resides directly in the cytosol or nucleus rather than being surrounded by a host cell membrane.
R. rickettsii has the curious ability to spread from cell to cell by traversing cell membranes without
causing obvious damage. Individual rickettsial organisms exit from infected cells via host cell
filopodia and rarely accumulate in large numbers inside individual cells [1]. R. rickettsii moves
between cells at astonishing speeds (up to 4.8 m/minute) by recruiting and polymerizing host cell
actin filaments [2].
Metabolism — R. rickettsii largely depends on the host cell for its nutritional needs. R. rickettsii
lacks enzymes for sugar metabolism lipid and nucleotide synthesis and amino acid metabolism.
Numerous specialized adaptations allow R. rickettsii to exist as an intracellular parasite. These
include the ability to acquire host ATP using a rickettsia-derived ATP translocator protein, and the
ability to utilize host-derived glutamine as an energy source [3]. In addition, R. rickettsii thrives in the presence of high concentrations of potassium and proteins [1].
Antigenic structure — Studies of the antigenic structure of rickettsiae led to the current
classification of the multiple rickettsial species. A still poorly understood cross-reacting surface
antigen is responsible for the Weil-Felix reaction in which sera from patients with a primary
rickettsial infection cross-react with somatic antigens of three strains of Proteus (OX19, OX2, and
OXK) [4]. Other antigens have been developed for complement fixation, agglutination, indirect
hemagglutination, indirect fluorescent antibody, and enzyme-lined immunosorbent assay tests.
(See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)
Lipopolysaccharides (LPS) in the rickettsial cell membrane elicit a strong but nonspecific immune
response. Such antibodies are not protective and they cross-react with other members of the
spotted fever group and to a lesser extent with LPS from members of the typhus group [5].
BASIS FOR VIRULENCE — Individual strains of R. rickettsii can mutate in vitro from highly virulent to relatively avirulent [6]. Virulence can vary strikingly among strains, but is also affected by the feeding status of the tick, inoculum dose, and certain host factors.
Strain variations in virulence — No satisfactory biologic explanation has been made to explain a
number of curious observations about striking variations in the virulence of individual strains of R.
rickettsii. Except for limited information on rickettsial adhesions, other rickettsial virulence factors
have not yet been identified. (See 'Pathophysiology' below.)
· It was noted almost 100 years ago that the mortality rate in RMSF was over 80 percent in
the Bitterroot Valley of Montana, versus only 3 percent in the adjacent Snake River Valley.
However, the etiologic agent appeared to be identical when isolated from patients in both
locations and injected into laboratory animals.
· Individual strains of R. rickettsii isolated from ticks vary in virulence, but isolates made from
humans with fulminant and mild disease appear to be identical when injected into laboratory
animals [6]. Attempts to correlate laboratory growth characteristics (such as plaque
morphology) with pathogenicity in animal models of infection have been unsuccessful or
inconclusive [6].
Tick feeding status — The principal vector of RMSF in the eastern and south central United States
is Dermacentor variabilis (the American dog tick) (picture 1). In contrast, Dermacentor andersonii
(the Rocky Mountain wood tick) (picture 2) is the primary vector in the mountain states west of the
Mississippi River. The common brown dog tick (Rhipicephalus sanguineus) (picture 3) was
implicated as the vector for RMSF in an outbreak during 2002 to 2004 in eastern Arizona [7]. The
disease is usually transmitted via a tick bite.
PICTURE 1:An adult female dermacentor variabilis (American dog tick)
PICTURE 2: An adult female Dermacentor andersoni (rocky mountain wood tick)
PICTURE 3: An adult female rhipicephalus sanguineus (brown dog tick)
The virulence of R. rickettsii strains in ticks is dependent upon the feeding status of the individual
tick. The virulence of R. rickettsii in over-wintered or starved ticks is restored only after the ingestion of a blood meal or after incubation at 37ºC for one to two days. The mechanism for this
"reactivation" phenomenon is uncertain but it may be related in part to the size of extracellular slime
layer [3].
Dose of inoculum — The dose of the inoculum is an additional important virulence factor in
humans. Humans inoculated with ten median guinea pig infectious doses of R. rickettsii had shorter
incubation periods, longer duration of fever after institution of anti-rickettsial treatment, and higher
attack rates than subjects inoculated with one median infectious dose [8].
Pathophysiology — Following inoculation from a feeding tick, the process by which rickettsiae gain
entry into endothelial cells involves a complex interaction between lipopolysaccharides and
rickettsial outer membrane proteins (rOmps), which act as adhesions. Three rOmps on the surface
of R. rickettsii with molecular sizes of 190, 120, and 17 kDa have been cloned in vitro and
sequenced. The 190 kDA and the 120 kDa rOmps are also immunogens capable of eliciting
protective immune responses in experimental animals [1]. OmpB binds to a protein (Ku70) in the
membrane of susceptible host cells. Subsequently, this activated Ku70 protein recruits an enzyme
(ubiquitin ligase) that causes ubiquitination of Ku70. This process, in turn, sets off a signaling
cascade that causes the rearrangement of cellular actin and allows the cell to engulf the rickettsia
via endocytosis [9,10]. Once inside cells, rickettsiae utilize two enzymes (phospholipase D and tlyC) to lyse the phagosomal membrane and escape into the cytosol [11,12]. R. rickettsii then express a series of other proteins that lead to polymerization of host cell monomeric actin filaments in the cytoplasm, which allows for invagination of host cell membranes and passage into neighboring cells via filopodia derived from host cell membranes [1,3,12,13]. R. rickettsii subsequently spread throughout the body via the bloodstream or lymphatics.
The mechanism by which R. rickettsii produces its characteristic damage to small blood vessels is
not known. Rickettsia do not secrete exotoxins and they can kill infected cells independent of any
host immune response. Cell injury and death has been associated with phospholipase A activity,
protease activity, and free radical-induced lipid peroxidation [1]. The primary mode of rickettsiainduced cell death is cell necrosis [11]. Infected cells can also be eliminated by immune effector mechanisms, such as CD8+ cytotoxic T-lymphocyte induced apoptosis [13,14]. The net effect of these processes is endothelial cell injury, which is followed by immune and phagocytic cellular responses via the local accumulation of lymphocytes and macrophages, resulting in a
lymphohistiocytic vasculitis.
Widespread rickettsii-induced vasculitis leads to minute foci of hemorrhage, increased vascular
permeability, edema, and the activation of humoral inflammatory and coagulation mechanisms.
Leakage of fluid from the bloodstream to tissue can have devastating results when the lung or brain
are involved, since both sites lack lymphatic vessels to remove interstitial fluid [11]. Although R.
rickettsii and other spotted fever group rickettsial infections induce a procoagulant state,
disseminated intravascular coagulation is rare in patients with RMSF. Thus, vascular thrombosis
and hemorrhage that results in widespread organ dysfunction is probably a physiological result of
widespread endothelial denudation [11].
Host factors — A number of host factors have been associated with an increase in severity of or
fatal RMSF [15,16]:
· Increasing age
· Male gender
· Presence of glucose-6-phosphate dehydrogenase deficiency
Black race and alcohol have also been associated with more severe disease and higher fatality, but
it is difficult to exclude the role of a delay in seeking or receiving antimicrobial therapy in these
patients [17].
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