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 spread through the bloodstream and infect the endothelium. Adherence to the host cell is the first step of rickettsial pathogenesis. The adhesins are presumed to be outer membrane proteins. The outer membrane protein OmpA has been implicated in adherence of R. rickettsii because antibodies to OmpA have been shown to block adherence.

The host cell receptor for any Rickettsia has yet to be identified. Although the main target cells of Rickettsia in vivo are endothelial cells, rickettsiae can infect virtually every cell line in vitro. Thus, either the receptor for Rickettsia is ubiquitous among cells, or 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 cell phagocytosis because they can enter cells that normally do not phagocytose particles. Once phagocytosed by the host cell, rickettsiae are observed to quickly escape from the phagosome membrane and enter the cytoplasm. The mechanism of escape from the phagosome membrane is not well understood, but it is thought to be mediated by a rickettsial enzyme, phospholipase A2.

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 the spotted fever group and typhus group rickettsiae.

Typhus group rickettsiae are released from host cells by lysis of the cells. After infection with R. prowazekii or R. typhi, the rickettsiae continue to multiply until the cell is packed with organisms and then bursts. Phospholipase A2 may be involved in cell lysis. Typhus group rickettsia-infected host cells have a normal ultrastructural appearance.

Spotted fever group rickettsiae seldom accumulate in large numbers and do not lyse the host cells. They escape from the cell by stimulating polymerization of host cell-derived actin tails, which propel them through the cytoplasm and into tips of membranous extrusions, from which they emerge. Infected cells exhibit signs of membrane damage associated with an influx of water, but the means by which rickettsiae damage host cell membranes is uncertain. There is evidence to suggest a role for free radicals of oxygen, phospholipase, and a protease. The protein responsible for the actin-based movement in  spotted fever group  rickettsiae has yet to be identified, but it is apparently different than the proteins responsible for actin polymerization by Listeria monocytogenes and Shigella flexneri.

Diseases

Rickettsial diseases vary in clinical severity according to the virulence of the Rickettsia and host factors, such as age, male gender, alcoholism, and other underlying diseases. The most virulent rickettsiae are R. rickettsii and R. prowazekii, which kill a significant portion of infected persons, unless the diseases are treated sufficiently early in the course of infection with an effective antimicrobial agent, usually doxycycline.

All rickettsial infections begin with introduction of the organisms into the skin, either through a tick bite or cutaneous abrasions contaminated by flea or louse feces. Rickettsiae enter dermal cells including endothelium and proliferate locally intracellularly with endothelial cell-to-cell spread for most SFG rickettsioses resulting in an eschar or tache noire, a zone of dermal and epidermal necrosis approximately 1 cm in diameter with a surrounding zone of erythema. Eschars do not occur in epidemic and murine typhus and are rarely observed in Rocky Mountain spotted fever.

SFG rickettsioses often manifest regional lymphadenopathy in the drainage of the eschar, suggesting that rickettsiae may spread via lymphatic vessels from the tick bite inoculation site early in the infection. Rickettsiae spread throughout the body and infect mainly endothelial cells, establishing many foci of contiguous infected blood vessel-lining cells. Injury in these local sites causes vascular damage manifesting as rash, interstitial pneumonia, encephalitis, interstitial nephritis, and interstitial myocarditis, as well as lesions in the liver, gastrointestinal wall, pancreas, and potentially any vascularized tissue of the body.

The most important pathophysiologic effect is increased vascular permeability with consequent edema, loss of blood volume, hypoalbuminemia, decreased osmotic pressure, and hypotension. These effects can be life threatening resulting in pulmonary edema and adult respiratory distress syndrome, shock, or acute tubular necrosis.

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever is the most severe and most frequently reported rickettsial disease in the United States. In the pre-antibiotic era, 20-25% of previously healthy, infected persons died of the illness. Today, even with antimicrobial agents that are highly effective, 3-5% of 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. The onset of disease follows an infective bite by a week (range 2-14 days), beginning with fever, severe headache, and muscle pain, followed by development of 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 bite, which is painless and may go unnoticed or be forgotten, and that the rash does not usually appear until 3-5 days after onset of illness. To further confound the diagnosis, symptoms such as nausea, vomiting, diarrhea, abdominal pain, and cough may suggest other diagnoses such as enterocolitis, 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 fluid from the affected blood vessels, with the development of a hemorrhage (petechia) in the center of the lesions.

Figure 2.  Characteristic spotted rash of late-stage Rocky Mountain spotted fever on legs of a patient. (CDC)

Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called "black measles" because of the characteristic rash. It was a dreaded and frequently fatal disease that affected hundreds of people in this area. By the early 1900s, the geographic distribution of the disease in United States was recognized 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 infectious organism that causes Rocky Mountain spotted fever at the turn of the Twentieth Century. He and others characterized the basic epidemiologic features of the disease, including the role of tick vectors. Studies showed that Rocky Mountain spotted fever is caused by Rickettsia rickettsii, and involves a complex cycle between ticks and mammals. Humans are accidental hosts, but are not involved in the natural transmission cycle of the pathogen.

The name Rocky Mountain spotted fever is somewhat of a misnomer. Beginning 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 recognized that this disease is broadly distributed throughout the continental United States, as well as southern Canada, Central America, Mexico, and parts of South America.  Between 1981 and 1996, this disease was reported from every U.S. state except Hawaii, Vermont, Maine and Alaska.

Rocky Mountain spotted fever remains a serious and potentially life-threatening infectious disease today. Despite the availability of effective treatment and advances in medical care, approximately 3- 5% of individuals who become ill with Rocky Mountain spotted fever die from the infection. However, effective antibiotic therapy has dramatically reduced the number of deaths caused by Rocky Mountain spotted fever. Before the discovery of tetracycline and chloramphenicol in the late 1940s, as many as 30% of individuals infected with R. rickettsii died.

Figure 3. Discovery of chloramphenicol and tetracycline antibiotics in the 1940s led to a sharp decline in RMSF-related mortality. Today, doxycycline is the drug of choice 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 live inside the cells of its hosts. Consequently, they are difficult to see in tissues by using routine histologic stains and generally require the use of special staining methods.