Version May 2024
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 are gram-negative purple bacteria within the class Alphaproteobacteria. 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 more than 12 separate pathogenic species (see "Other spotted fever group rickettsial infections"). Phylogenetic studies utilizing the 16S ribosome have shown that R. rickettsii is closely related to other members of the spotted fever group such as Rickettsia conorii and Rickettsia sibirica, whereas its phylogenetic relationship to other spotted fever members such as Rickettsia akari, Rickettsia australis, and Rickettsia 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].
Studies using real-time polymerase chain reaction techniques to quantitate the levels of rickettsial DNA in patients with Rocky Mountain spotted fever (RMSF) revealed a diurnal variation in the amount of rickettsial DNA in the bloodstream of infected patients, with higher levels in the early morning hours when body temperatures are lower [3]. In addition, copy numbers of rickettsial DNA in the blood were higher in patients with fatal outcomes.
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 [4]. 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) [5]. Other antigens have been developed for complement fixation, agglutination, indirect hemagglutination, indirect fluorescent antibody, and enzyme-linked immunosorbent assay tests. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Serologic testing'.)
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 [6].
BASIS FOR VIRULENCE — Individual strains of R. rickettsii can mutate in vitro from highly virulent to relatively avirulent [7]. Virulence can vary strikingly among strains, but is also affected by the feeding status of the tick, inoculum dose, and certain host factors [8].
Strain variations in virulence — There are striking variations in the virulence of individual strains of R. rickettsia, but the incidence and underlying molecular mechanism for these differences are poorly defined. (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 widely in virulence. Strains triggering more fulminant disease have been reported to exhibit rapid growth characteristics with increased expression of multiple known and suspected virulence factors compared to strains associated with milder illness.
Tick feeding status — RMSF is usually transmitted via a tick bite. 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 andersoni (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 [9]. Other species of ticks, such as Amblyomma aureolatum, are vectors for R. rickettsii in regions such as Brazil [10].
Animal studies suggest that infectious organisms can be transmitted even if the tick is attached for a short period of time. A study in guinea pigs found that starved ticks seem able to transmit active rickettsial organisms almost immediately upon biting the host, although the severity of R. rickettsii infection is increased with the length of tick attachment [11]. This differs somewhat from studies done almost 100 years ago, which suggested that 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 37°C for one to two days [12].
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 [13].
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), as well as other surface-exposed proteins (SEPs), which act as adhesions. The 190 kDa and 120 kDa rOmps and several additional SEPs are also immunogens capable of eliciting protective immune responses in experimental animals [1,14].
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. Endothelial cellular processes are normally modulated by the ubiquitous second messenger cAMP, which in turn acts upon the cAMP receptors protein kinase A and an exchange protein called Epac. These Epac exchange proteins may also be involved in the pathogenesis of rickettsial infection as treatment with specific inhibitors of Epac protect experimental animals after challenge with lethal doses of spotted fever group rickettsiae [15]. Additionally, OmpB has been demonstrated to play a key role in immune evasion in some rickettsial species by obstructing autophagy recognition in macrophages through ubiquitination of OmpA and other bacterial surface proteins [16].
Additionally, in vitro and animal model studies have found that spotted fever group rickettsia also utilize cell surface heparin sulfate proteoglycans (HSPGs) and fibroblast growth factor receptors to facilitate their cellular invasion in a manner similar to that used by other intracellular pathogens, such as Chlamydia trachomatis [17].
The complex interactions discussed above provoke a signaling cascade that causes the rearrangement of cellular actin and allows the cell to engulf the rickettsia via endocytosis [18,19]. Once inside cells, rickettsiae utilize two enzymes (phospholipase D and tlyC) to lyse the phagosomal membrane and escape into the cytosol [20,21]. 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 [1,4,21,22]. 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 rickettsia-induced cell death is cell necrosis [20]. Infected cells can also be eliminated by immune effector mechanisms, such as CD8+ cytotoxic T-lymphocyte induced apoptosis [22,23]. 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 [20]. 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 [20].
Host factors — A number of host factors have been associated with an increase in severity of or fatal RMSF [24,25]:
●Increasing age
●Male gender
●Presence of glucose-6-phosphate dehydrogenase deficiency
Black race and alcoholism 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 [26].
SUMMARY
●Taxonomy – Rickettsia rickettsii are gram negative bacteria that are a member of the order Rickettsiales and the family Rickettsiaceae. (See 'Taxonomy' above.)
●Microbiology – R. rickettsii are obligate intracellular parasites that can be visualized using Giemsa, Machiavello, Gimenez, and direct fluorescent antibody staining techniques. (See 'Microbiology' above.)
●Virulence – The virulence of R. rickettsii can vary among strains, and is also affected by the feeding status of the tick, the inoculum dose, and the presence of certain host factors. (See 'Basis for virulence' above.)
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