Rickettsial Diseases
Introduction to the Rickettsiae
The Rickettsiae are small (0.3-0.5 x 0.8-2.0 um), Gram-negative, aerobic, coccobacilli that are obligate intracellular parasites of eucaryotic cells. They may reside in the cytoplasm or within the nucleus of the cell that they invade. They divide by binary fission and they metabolize host-derived glutamate via aerobic respiration and the citric acid (TCA) cycle. They have typical Gram-negative cell walls, and they lack flagella. The rickettsiae frequently have a close relationship with arthropod vectors that may transmit the organism to mammalian hosts. The rickettsiae have very small genomes of about 1.0-1.5 million bases.
Rickettsia prowazekii, the cause of epidemic typhus, is the prototypical rickettsia. Typhus has plagued humanity throughout history. The American bacteriologist,Hans Zinsser, to whom this textbook is dedicated, was able to grow the elusive intracellular pathogen and develop a protective vaccine for typhus fever. He wrote a book about the bacterium, published in 1935, Rats, Lice, and History: "being a study in biography, which, after 12 preliminary chapters indispensable for the preparation of the lay reader, deals with the life history of typhus fever".
Rickettsia prowazekii has made science news recently since it has been shown to be the probable origin of eucaryotic mitochondria. Its complete genome sequence of 1,111,523 base pairs has been shown to contain 834 protein-coding genes. The functional profiles of these genes show similarities to those of mitochondrial genes. No genes required for glycolysis are found in either R. prowazekii or mitochondrial genomes, but a complete set of genes encoding components of the tricarboxylic acid cycle and the respiratory-chain complex is found in both. In effect, ATP production in the rickettsia is the same as that in mitochondria. Many genes involved in the biosynthesis and regulation of biosynthesis of amino acids and nucleosides in free-living bacteria are absent from R. prowazekii and mitochondria. Such genes seem to have been replaced by homologues in the nuclear (host) genome. Phylogenetic analyses indicate that R. prowazekii is more closely related to mitochondria than it is to any bacterium on the Tree of Life.
Rickettsiae must be grown in the laboratory by co-cultivation with eucaryotic cells, and they have not been grown by in axenic culture. The basis of their obligate relationship with eucaryotic cells has been explained by rickettsial possession of "leaky membranes" that require the osmolarity and nutritional environment supplied by an intracellular habitat.
The rickettsiae, in spite of their small size and obligate intracellular habitat, are a group of alphaproteobacteria, which include many well-known organisms such as Acetobacter, Rhodobacter, Rhizobium and Agrobacterium. Very few of the alphaproteobacteria are pathogens of humans. Brucella, Bartonella, Rickettsia,and a related intracellular parasite, Ehrlichia, are the main exceptions.
The genus Rickettsia is included in the bacterial family Rickettsiaceae of the order Rickettsiales. This genus includes many species associated with human disease, including those in the spotted fever group and the typhus group (figure 1). The rickettsiae that are pathogens of humans are subdivided into threemajor groups based on clinical characteristics of disease: 1. spotted fever group; 2. typhus group; and 3. scrub typhus group.
Figure 1. Taxonomic classification of the order Rickettsiales
Spotted Fever Group (SFG)
Rickettsia rickettsii is the cause of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae. Rickettsia rickettsii is found in the Americas and is transmitted to humans through the bite of infected ticks. The bacterium infects human vascular endothelial cells, producing an inflammatory response. The pathogenesis of RMSF is discussed in some detail below.
Other spotted fever group rickettsiae that produce human rickettsioses includeR. conorii, R. mongolotimonae and R. slovaca (boutonneuse fever and similar illnesses), R. japonica (Japanese spotted fever), R. sibirica (North Asian tick typhus), R. africae (African tick bite fever), R. helvetica (perimyocarditis), andR. honei (Flinders Island spotted fever). The spotted fever rickettsiae have been found on every continent except Antarctica.
Two "transitional group" (other) rickettsias cause spotted fever-like diseases: R. akari (rickettsial pox), and R. australis (Queensland tick typhus).
Typhus Group (TG)
Rickettsia prowazekii is the cause of epidemic or louse-borne typhus and is the prototypical bacterium from the typhus group of rickettsiae. R. prowazekiiinfects human vascular endothelial cells, producing widespread vasculitis. In contrast to RMSF, louse-borne typhus tends to occur in the winter. Infection usually is transmitted from person to person by the body louse and, therefore, tends to manifest under conditions of crowding and poor hygiene. The southern flying squirrel is apparently the reservoir in the United States, but the vector involved in transmission from the flying squirrel to humans is unknown. The disease has a worldwide distribution.
Other rickettsiae in the typhus group include R. typhi and R. felis. Murine typhus is caused by transmission of R. typhi from rats, cats and opossums to humans via a flea vector. Murine typhus is found worldwide and is endemic to areas of Texas and southern California in the United States. Although R. felis is phylogenetically more closely related to the spotted fever group of rickettsiae than the typhus group, it shares antigens with R. typhi and produces a murine typhus-like illness. Rickettsia felis has been detected in cat fleas and opossums.
Introduction to the Rickettsiae
The Rickettsiae are small (0.3-0.5 x 0.8-2.0 um), Gram-negative, aerobic, coccobacilli that are obligate intracellular parasites of eucaryotic cells. They may reside in the cytoplasm or within the nucleus of the cell that they invade. They divide by binary fission and they metabolize host-derived glutamate via aerobic respiration and the citric acid (TCA) cycle. They have typical Gram-negative cell walls, and they lack flagella. The rickettsiae frequently have a close relationship with arthropod vectors that may transmit the organism to mammalian hosts. The rickettsiae have very small genomes of about 1.0-1.5 million bases.
Rickettsia prowazekii, the cause of epidemic typhus, is the prototypical rickettsia. Typhus has plagued humanity throughout history. The American bacteriologist,Hans Zinsser, to whom this textbook is dedicated, was able to grow the elusive intracellular pathogen and develop a protective vaccine for typhus fever. He wrote a book about the bacterium, published in 1935, Rats, Lice, and History: "being a study in biography, which, after 12 preliminary chapters indispensable for the preparation of the lay reader, deals with the life history of typhus fever".
Rickettsia prowazekii has made science news recently since it has been shown to be the probable origin of eucaryotic mitochondria. Its complete genome sequence of 1,111,523 base pairs has been shown to contain 834 protein-coding genes. The functional profiles of these genes show similarities to those of mitochondrial genes. No genes required for glycolysis are found in either R. prowazekii or mitochondrial genomes, but a complete set of genes encoding components of the tricarboxylic acid cycle and the respiratory-chain complex is found in both. In effect, ATP production in the rickettsia is the same as that in mitochondria. Many genes involved in the biosynthesis and regulation of biosynthesis of amino acids and nucleosides in free-living bacteria are absent from R. prowazekii and mitochondria. Such genes seem to have been replaced by homologues in the nuclear (host) genome. Phylogenetic analyses indicate that R. prowazekii is more closely related to mitochondria than it is to any bacterium on the Tree of Life.
Rickettsiae must be grown in the laboratory by co-cultivation with eucaryotic cells, and they have not been grown by in axenic culture. The basis of their obligate relationship with eucaryotic cells has been explained by rickettsial possession of "leaky membranes" that require the osmolarity and nutritional environment supplied by an intracellular habitat.
The rickettsiae, in spite of their small size and obligate intracellular habitat, are a group of alphaproteobacteria, which include many well-known organisms such as Acetobacter, Rhodobacter, Rhizobium and Agrobacterium. Very few of the alphaproteobacteria are pathogens of humans. Brucella, Bartonella, Rickettsia,and a related intracellular parasite, Ehrlichia, are the main exceptions.
The genus Rickettsia is included in the bacterial family Rickettsiaceae of the order Rickettsiales. This genus includes many species associated with human disease, including those in the spotted fever group and the typhus group (figure 1). The rickettsiae that are pathogens of humans are subdivided into threemajor groups based on clinical characteristics of disease: 1. spotted fever group; 2. typhus group; and 3. scrub typhus group.
Figure 1. Taxonomic classification of the order Rickettsiales
Spotted Fever Group (SFG)
Rickettsia rickettsii is the cause of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae. Rickettsia rickettsii is found in the Americas and is transmitted to humans through the bite of infected ticks. The bacterium infects human vascular endothelial cells, producing an inflammatory response. The pathogenesis of RMSF is discussed in some detail below.
Other spotted fever group rickettsiae that produce human rickettsioses includeR. conorii, R. mongolotimonae and R. slovaca (boutonneuse fever and similar illnesses), R. japonica (Japanese spotted fever), R. sibirica (North Asian tick typhus), R. africae (African tick bite fever), R. helvetica (perimyocarditis), andR. honei (Flinders Island spotted fever). The spotted fever rickettsiae have been found on every continent except Antarctica.
Two "transitional group" (other) rickettsias cause spotted fever-like diseases: R. akari (rickettsial pox), and R. australis (Queensland tick typhus).
Typhus Group (TG)
Rickettsia prowazekii is the cause of epidemic or louse-borne typhus and is the prototypical bacterium from the typhus group of rickettsiae. R. prowazekiiinfects human vascular endothelial cells, producing widespread vasculitis. In contrast to RMSF, louse-borne typhus tends to occur in the winter. Infection usually is transmitted from person to person by the body louse and, therefore, tends to manifest under conditions of crowding and poor hygiene. The southern flying squirrel is apparently the reservoir in the United States, but the vector involved in transmission from the flying squirrel to humans is unknown. The disease has a worldwide distribution.
Other rickettsiae in the typhus group include R. typhi and R. felis. Murine typhus is caused by transmission of R. typhi from rats, cats and opossums to humans via a flea vector. Murine typhus is found worldwide and is endemic to areas of Texas and southern California in the United States. Although R. felis is phylogenetically more closely related to the spotted fever group of rickettsiae than the typhus group, it shares antigens with R. typhi and produces a murine typhus-like illness. Rickettsia felis has been detected in cat fleas and opossums.
Scrub Typhus Group (STG)
Orientia (Rickettsia) tsutsugamushi is the cause of scrub typhus. Originally called Rickettsia tsutsugamushi, this organism was given its own genus designation because it is phylogenetically distinct from the other rickettsiae, though closely related. Orientia tsutsugamushi is transmitted to humans by the bite of trombiculid mites (chiggers), which are the vector and host. Scrub typhus occurs throughout much of Asia and Australia.
Orientia (Rickettsia) tsutsugamushi is the cause of scrub typhus. Originally called Rickettsia tsutsugamushi, this organism was given its own genus designation because it is phylogenetically distinct from the other rickettsiae, though closely related. Orientia tsutsugamushi is transmitted to humans by the bite of trombiculid mites (chiggers), which are the vector and host. Scrub typhus occurs throughout much of Asia and Australia.
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.
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.
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.
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 theRickettsia 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.
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