Perspectives

Rickettsial Pathogens and their

Arthropod Vectors
Abdu F. Azad* and Charles B. Beard†
*University of Maryland School of Medicine, Baltimore, Maryland, USA; and
†Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Rickettsial diseases, important causes of illness and death worldwide, exist

primarily in endemic and enzootic foci that occasionally give rise to sporadic or seasonal
outbreaks. Rickettsial pathogens are highly specialized for obligate intracellular survival
in both the vertebrate host and the invertebrate vector. While studies often focus
primarily on the vertebrate host, the arthropod vector is often more important in the
natural maintenance of the pathogen. Consequently, coevolution of rickettsiae with
arthropods is responsible for many features of the host-pathogen relationship that are
unique among arthropod-borne diseases, including efficient pathogen replication, long-
term maintenance of infection, and transstadial and transovarial transmission. This
article examines the common features of the host-pathogen relationship and of the
arthropod vectors of the typhus and spotted fever group rickettsiae.

Rickettsial diseases, widely distributed associations with obligate blood-sucking

throughout the world in endemic foci with arthropods represent the highly adapted end-
sporadic and often seasonal outbreaks, from time product of eons of biologic evolution. The ecologic
to time have reemerged in epidemic form in separation and reduced selective pressure due to
human populations. Throughout history, epi- these associations may explain rickettsial genetic
demics of louse-borne typhus have caused more conservation. Their intimate relationships with
deaths than all the wars combined (1). The vector hosts (Table 1) are characterized by
ongoing outbreak of this disease in refugee camps efficient multiplication, long-term maintenance,
in Burundi involving more than 30,000 human transstadial and transovarial transmission, and
cases is a reminder that rickettsial diseases can extensive geographic and ecologic distribution.
reemerge in epidemic form as a result of the Although rickettsiae have a symbiotic relation-
catastrophic breakdown of social conditions (2). ship with their arthropod hosts, in some
In addition to explosive epidemics, sporadic but instances, they act as true parasites—for
limited outbreaks of louse-borne typhus and example, members of the Wolbachia and Orientia
other rickettsial diseases have been reported tsutsugamushi alter reproduction and manipulate
throughout the world. In the United States, a cellular processes in their arthropod hosts (4), and
drastic increase of murine typhus in the 1940s, the agent of epidemic typhus, Rickettsia prowazekii,
Rocky Mountain spotted fever (RMSF) in the late kills its vector, the human body louse (5).
1970s, and the human ehrlichioses in the 1990s Although rickettsiae are maintained in
attests to the potential emergence of these nature through arthropod vectors, they fre-
infections in populations at risk (3). quently infect vertebrates, which in turn allow
The rickettsiae’s obligate intracellular exist- new lines of vectors to acquire infection from the
ence in both mammalian and arthropod hosts rickettsemic hosts. The involvement of verte-
serves as an excellent model for the study of brates, including humans, in the rickettsial cycle is
complex host-parasite interactions. Rickettsial variable and in some cases complicated (Figure).
With the exception of epidemic typhus, humans are
not essential in the rickettsial cycle. Humans
Address for correspondence: Abdu F. Azad, Department of acquire rickettsial infection from the infected
Microbiology and Immunology, University of Maryland vectors. While tick-borne rickettsiae are transmit-
School of Medicine, 655 W. Baltimore Street, Baltimore, MD
21201 USA; fax: 410-706-0282; e-mail: [email protected].
ted to humans by tick salivary secretions, flea- and

Vol. 4, No. 2, April–June 1998 179 Emerging Infectious Diseases

 Perspectives

Table 1. Epidemiologic features of the pathogenic rickettsiaea

Rickettsia Natural cycleb Geographic
species Disease Vectors Hosts distribution
Typhus group:
Rickettsia prowazekii Epidemic typhus Human body lice Humans Worldwide
Recrudescent typhus None Humans Worldwide
Lice, fleas Flying squirrels Eastern USA
R. typhi Murine typhus Fleas Rodents Worldwide
Fleas Opossums USA
R. felis Murine typhuslike Fleas Opossums USA
Spotted Fever group:
R. rickettsii Rocky Mountain Ticks Small mammals, North & South
spotted fever dogs, rabbits, birds America
R. conorii Boutonneuse fever Ticks Rodents, dogs Africa, Southern
Europe, India
R. sibirica North Asia tick Ticks Rodents Eurasia, Asia
typhus
R. japonica Japanese spotted Ticks Rodents, dogs Japan
fever
R. australis Queensland tick Ticks Rodents Australia
typhus
R. akari Rickettsialpox Mites House mice, rats Worldwide
Ehrlichioses group:
Ehrlichia chaffeensis Human monocytic Ticks Humans, deer USA, Europe
ehrlichiosis
Ehrlichia Sp Human granulocytic Ticks Humans, deer, USA, Europe
ehrlichiosis rodents
Others:
Coxiella burnetii Q fever Ticks Small mammals, Worldwide
sheep, goats, cattle,
dogs
Orientia tsutsugamushi Scrub typhus Mites Rodents Asia, Indian
subcontinent, Australia
aNot listed are R. helvetica, R. honei, and R. slovaca (6).
bEvidence for arthropod serving as a vector or vertebrate serving as a host is based on the rickettsial isolation from field-
collected specimens, experimental studies, and indirect evidence for rickettsial presence or exposure to rickettsiae
(hemolymph test and serosurveys).

louse-borne rickettsiae are transmitted to Tick-borne Rickettsial Pathogens

humans through contamination of broken skin The development and extensive use of the
and mucosal surfaces by infected vector feces. hemolymph test (which has been fundamental to
Although rickettsiae have common features tick and rickettsial surveys), improved isolation
with their vertebrate and invertebrate hosts, methods, and the application of molecular
they differ considerably in terms of arthropod techniques have helped identify 14 valid,
vectors, geographic distribution, and virulence relatively distinct SFG rickettsiae (Tables 1, 2).
(Table 1). In this article, we focus on the Except for mite-borne R. akari, all SFG
members of the typhus group (TG) and spotted rickettsiae are transmitted by ixodid ticks
fever group (SFG) rickettsiae to construct a (Tables 1, 2). In addition to R. rickettsii, the
conceptual framework of the natural history of etiologic agent of RMSF, eight other tick-borne
human rickettsioses and evaluate feeding rickettsial species are human pathogens (Table 1;
behavior of the vectors with regard to 6). The remaining SFG rickettsiae are isolated
rickettsial maintenance and transmission. only from ticks and have low or no pathogenicity

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 Perspectives

to humans or certain laboratory animals (7).

However, some of these rickettsiae could be
etiologic agents of as-yet-undiscovered, less
severe rickettsioses.
Distribution of SFG rickettsiae is limited to
that of their tick vectors. In the United States, a
high prevalence of SFG species in ticks cannot be
explained without the extensive contributions of
transovarial transmission. The transovarial and
transstadial passage of SFG rickettsiae within
tick vectors in nature ensures rickettsial survival
without requiring the complexity inherent in an
obligate multihost reservoir system. Although
many genera and species of ixodid ticks are
naturally infected with rickettsiae, Dermacentor
andersoni and D. variabilis are the major vectors
of R. rickettsii. SFG infection rates vary
considerably by state. For example, the infection
rate for adult D. variabilis collected from
vegetation and mammalian hosts was 2% to 9% in
Connecticut, 5% in New York, 6% in Kentucky-
Tennessee and Maryland, 8.8% in Arkansas, and
10% in Alabama (5,8,9). Rickettsia and tick
surveys indicate that R. rickettsii is less
prevalent in vector ticks than some other SFG
rickettsiae. In most cases, the SFG-positive ticks,
including D. andersoni and D. variabilis, are
infected with nonpathogenic rickettsiae rather
than with R. rickettsii (Table 2). The low
prevalence of R. rickettsii in SFG-positive ticks is
intriguing. Interspecific competition among ticks
may result in stable maintenance of SFG
rickettsiae through transovarial transmission and Figure. Composite diagram of the life cycle of Rocky
may cause the gradual replacement of R. rickettsii Mountain spotted fever, rickettsialpox, and murine
in the tick population. Very little is known about typhus. A. Life cycle of Rickettsia rickettsii in its tick
the process of interspecific competition between and mammalian hosts (7); B. Rickettsia akari life
prokaryotic microorganisms in ticks. Burgdorfer cycle; and C. Rickettsia typhi life cycle.
et al. (10) reported that D. andersoni from the
east side of Bitterroot Valley in western Montana
contained a nonpathogenic SFG-rickettsia, which transmitted rickettsiae horizontally (10,11).
they named East Side agent. East Side agent has Thus, ticks constitutively infected with R.
recently been described as a new species, R. peacockii and infected experimentally with R.
peacockii (11). This rickettsia is rarely present in rickettsii were unable to transmit R. rickettsii to
tick hemolymph and is readily missed by the their progeny. In effect, infection of D. andersoni
standard hemolymph test. The rickettsiae are with R. peacockii blocked the subsequent ability
confined primarily to the tick posterior of the ticks to transmit R. rickettsii transovarially
diverticulae of the midgut, the small intestine, (10,11). The phenomenon of transovarial inter-
and most importantly, the ovaries. R. peacockii is ference provided an explanation for the curious
maintained in the tick population through long-standing disease focus in Bitterroot Valley.
transovarial transmission, and the infected ticks Most cases of RMSF have occurred among
were shown to be refractory to ovarian infection residents on the west side of the valley where D.
with R. rickettsii. However, these ticks acquired andersoni were abundant; on the east side, D.
experimental infection with R. rickettsii and andersoni were also abundant and were reported

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 Perspectives

Table 2. Epidemiologic characteristics of the North American tick-borne rickettsiaa

Rickettsia Natural cycle
species Disease Vectors Hosts
Rickettsia rickettsii Rocky Mountain Dermacentor, Amblyomma, Small mammals,
spotted fever Rhipicephalus, Haemaphysalis dogs, rabbits, birds
R. akari Rickettsialpox Liponyssoides House mice, rats
R. amblyommii A. americanum Small mammals
R. bellii D. andersoni, D. variabilis, Rodents, dogs
D. occidentalis, D. albopictus,
H. leporispalustris
R. canada Haemaphysalis Rabbits, hares, birds
R. montana D. andersoni, D. variabilis Rodents, dogs
R. parkeri A. americanum, A. maculatum Domestic animals,
birds, rodents
R. peacockii D. andersoni Rodents, deer
R. rhipicephali R. sanguineus, D. andersoni, Small mammals
D. variabilis, D. occidentalis
aExcluding four as yet undescribed species of SFG rickettsiae (WB-8-2, 364-D, Tillamook, and the D. parumapertus agent).

to feed on residents, yet few (if any) locally enters a quiescent period before emerging as a
acquired cases of RMSF occurred there (8,10). In questing nymph the following year. How
the presence of R. peacockii, R. rickettsii could not rickettsiae survive within the tick during this
be maintained transovarially—it could only be quiescent period and regain infectivity during the
transmitted horizontally, and thus long-term nymphal feeding is poorly understood. Although
maintenance could not be sustained. Transovarial the precise mechanisms of rickettsial reactiva-
interference by tick-associated symbionts such as tion are not known, temperature shift and blood
R. peacockii is unlikely to be confined only to D. intake are believed to reactivate rickettsiae. As in
andersoni ticks on the east side of Bitterroot the Borrelia burgdorferi-Ixodes scapularis model,
Valley, Montana. Burgdorfer et al. (10) stated transmission of rickettsiae probably cannot occur
that transovarial interference of R. rickettsii in D. until after 24 hours of tick attachment, which
andersoni ticks may be mediated by other allows time for rickettsial growth.
nonpathogenic SFG rickettsiae—R. montana and
R. rhiphicephali. Tick surveys for SFG rickettsiae Insect-Borne Rickettsial Pathogens
generally report finding R. rickettsii only in a Unlike SFG, TG rickettsiae are associated
minority of ticks with rickettsiae (Table 3). Most with insects (Table 1). Their association with
infected ticks harbor nonpathogenic species. Thus, blood-sucking insects such as human body lice
transovarial interference may have epidemiologic (Pediculus humanus) and fleas (Xenopsylla
significance: it may explain why ticks collected from cheopis and other rodent fleas [13-15]) provides
various geographic regions are not infected with rickettsiae the potential to spread rapidly among
two or more species of SFG rickettsiae. susceptible populations. Both fleas and human
The tick-rickettsia interrelationships are body lice, intermittent feeders, are capable of
complex, and the mechanisms used by rickettsiae multiple feeding and thus of transmitting
to survive in unfed overwintering ticks or during rickettsiae to several hosts. Outbreaks of
molting are poorly understood. How changes epidemic typhus thereby can result from rapid
(e.g., before and after blood meal) in tick gut transmission of R. prowazekii from human to
physiology influence rickettsial growth, cell human by infected lice. Unlike ticks that
division, and differential expression of rickettsial transmit SFG rickettsiae, lice infected with R.
surface protein is not well understood. Although prowazekii die within 2 weeks after imbibing
experiments (8,10) have deciphered the phenom- infected blood. R. typhi, the etiologic agent of
enon of reactivation of rickettsial virulence after murine typhus, does not shorten the life span of
infected ticks take a blood meal, the underlying fleas (15). Although R. typhi and R. felis are
molecular events have yet to be elucidated. Other maintained transovarially in fleas (15-18), there
aspects of rickettsia-tick interactions need to be is no evidence that R. prowazekii is maintained in
studied. For example, after feeding, a tick larva human body lice vertically. Since lice die of R.

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 Perspectives

prowazekii infection, the role of the reservoir in with many rats and fleas. Murine typhus occurs
maintaining the rickettsiae in nature becomes in epidemics or has a high prevalence, is often
essential. R. prowazekii sequesters in its human unrecognized and substantially underreported,
host; persistence of rickettsiae occurs despite the and although it may be clinically mild, can cause
strong, long-lasting immunity after infection severe and even fatal cases (19). Thousands of
with R. prowazekii. Patients with recrudescent human cases used to occur annually in the United
typhus (Brill-Zinsser disease) serve as potential States (13,14). Outbreaks have been reported in
reservoirs capable of infecting lice. Although a Australia and recently in China, Kuwait, and
search for a zoonotic cycle of R. prowazekii in Thailand (13-15). The classic cycle of R. typhi
areas with louse-borne typhus epidemics (e.g., involves rats (Rattus rattus and R. norvegicus)
Ethiopia and Burundi) proved to be unsuccessful, and primarily the rat flea, X. cheopis (13,14). X.
flying squirrels (Glaucomys volans) in the cheopis is the main vector, and transmission is
eastern United States are naturally infected with affected by contact with rickettsia-containing flea
this organism. Flying squirrel ectoparasites (lice feces or tissue during or after blood feeding.
and fleas) were implicated in the transmission of Reported cases of murine typhus in the United
R. prowazekii between the squirrels and from States are from south and central Texas and the
squirrels to humans (5). Although the distribu- Los Angeles and Orange County area of
tion of G. volans extends to the entire eastern California (21-25). However, most of the cases are
United States as well as to isolated areas of attributed to opossum-cat flea cycles. Both
Mexico and Guatemala, the search for an opossums and domestic cats collected from the
extrareservoir of R. prowazekii was not pursued case areas were seropositive for R. typhi
further. Consequently, the importance of the R. antibodies. The cat flea, Ctencephalides felis,
prowazekii and squirrel system remains unclear. which is a competent vector of murine typhus, is
In the absence of a zoonotic cycle, conditions such as the most prevalent flea species (97%) collected
widespread lice infestations, active human infec- from opossums, cats, and dogs in southern Texas;
tion, reactivation of latent infection in patients with no fleas were recovered from rats in this area. In
recrudescent typhus could easily ignite a resur- addition to R. typhi, R. felis was also found in
gence of louse-borne typhus. Louse-borne typhus opossums and their fleas (15). This finding,
continues to occur in epidemics following the consistent with surveys in other areas of the
breakdown of social, economic, or political systems, country (14,20), further documents the reduced
as exemplified by recent outbreaks in Burundi and role of rat and X. cheopis in the maintenance of
remote parts of South America. Therefore, active murine typhus within endemic-disease areas of
surveillance to monitor louse-borne typhus and the United States. The maintenance of R. typhi in
prevent its spread is indicated. the cat flea and opossum cycle is therefore of
In contrast to louse-borne typhus, murine potential public health importance since C. felis
typhus is prevalent throughout the world and is a prevalent and widespread pest that avidly
accounts for widespread illness in areas infested bites humans (12,15).

Table 3. Species composition of tick-borne rickettsiae isolated from hemolymph-positive Dermacentor ticksa
California Montana Ohio Long Island Maryland
D. occidentalis D. andersoni D. variabilis D. variabilis D. variabilis
Rickettsial sp. (No. isolates) (No. isolates) (No. isolates) (No. isolates) (No. isolates)
R. rickettsii 0 (0) 9 (10) 18 (4) 0 (0) 8 (2)
R. rhipicephali 96 (79) 44 (47) 0 (0) 0 (0) 0 (0)
R. montana - 7 (8) 59 (13) 100 (100) 0 (0)
Other SFGb - - 5 (1)c - 88 (23)d
R. bellii 4 (3) 39 (41) 18 (4) 0 (0) 4 (1)
Total number
isolates 82 106 22 100 26
aShows a compilation of various statewide surveys, comparing the species composition of SFG rickettsiae in Dermacentor spp.

ticks that tested positive by immunofluorescence assay.

bSFG, spotted fever group.
cR. amblyommii.
dMouse anti-sera made against Maryland isolates reacted with WB-8-2 (unnamed SFG rickettsiae).

Vol. 4, No. 2, April–June 1998 183 Emerging Infectious Diseases

 Perspectives

In many parts of the world, murine typhus which suggests an interference phenomenon.
infection is intimately associated with introduced Such a precedent exists—several tick species
commensal rodents (R. rattus, R. norvegicus, and carry nonpathogenic rickettsiae (e.g., D. andersoni
Mus musculus) and their ectoparasites, particu- in east side Bitterroot Valley of western
larly fleas. Although R. typhi have been isolated Montana, A. americanum in Maryland) fre-
from other commensal rodents and even shrews, quently encountered in tick samples from
they do not seem to play a role in the transmission different parts of the United States (8,9).
of murine typhus to humans (13,14). In Rangoon Recent work in our laboratory with TG
(Myanmar), of four species of murines and one rickettsiae suggests that interspecific competi-
shrew commonly found in buildings, 7% (M. tion between closely related rickettsiae may
musculus) to 30% (R. rattus) and 38% (Bandicota control rickettsial establishment in arthropods.
bengalensis) of those tested were seropositive to Studies have identified both R. typhi and R. felis
R. typhi. In contrast, 62% of R. rattus collected in opossums and in their cat fleas in endemic-
from buildings in Addis Ababa (Ethiopia) and disease regions in Texas and California (21-25).
49% of those collected in Sarawak (Nepal) were However, infection with both rickettsiae has not
seropositive for murine typhus (Azad et al., been observed in individual fleas (20-24). The
unpub. data). Infection rates in X. cheopis fleas intermittent feeding behavior of cat fleas
collected from rats were 7% to 18%. While associates them with various hosts, which
infection rates vary considerably among indoor increases the likelihood of infection with more
rats and their fleas, murine typhus infection than one pathogenic organism. Cat fleas
seems clearly associated with indoor rat constitutively infected with R. felis and experi-
populations throughout the world. However, in mentally infected with R. typhi contained both
the absence of indoor rats, murine typhus rickettsial species. While the R. felis infection
infection is maintained in suburban and rural rate in the infected flea population was 86% to
cycles when native animals seek shelter in 94%, prevalence of dually infected fleas was 13%
human habitations where food and hospitable and 26% (25). While no other relationships
environments are plentiful. involving multiple bacterial infections in
arthropods have been studied as thoroughly, the
Pathogen-Arthropod Interaction results from the few available studies show that
The process of displacement of pathogenic dual infections in arthropod vectors are rare (e.g.,
rickettsiae with nonpathogenic endosymbionts in human granulocytic ehrlichia was recently
ticks through transovarial interference is of identified in 2.2% and 4% of I. scapularis ticks
potential epidemiologic importance. The dis- coinfected with B. burgdorferi) (26).
placement might occur only if transovarial Whether infection with nonpathogenic rick-
maintenance of pathogenic rickettsiae harms the ettsiae presents an advantage to the tick
host or the maintenance of nonpathogenic population is difficult to ascertain because of lack
organisms confers important advantages to the of experimental data. There is no experimental
tick progeny. Burgdorfer et al. (10), in evidence for rickettsial-induced postzygotic
experimental studies with the D. andersoni-R. reproductive incompatibility, parthenogenesis,
rickettsii model, observed that maintenance of and feminization of genetic males as observed for
this pathogen in ticks over several generations members of the genus Wolbachia (4,27). Although
resulted in unusually high death rates among a rickettsial relative is associated with male
engorged females and reduced numbers and killing in the ladybird beetle (27), we do not know
fertility of deposited eggs. If tick infection with whether any nonpathogenic members of the SFG
pathogenic rickettsiae in nature adversely rickettsiae can induce reproductive incompatibil-
affected egg maturation, oviposition, and em- ity or sex distortion in ticks. A compilation of data
bryogenesis, the balance would favor a tick from various laboratories that maintain cat flea
population infected with the nonpathogenic colonies indicate that after several generations R.
rickettsiae, and over time such tick populations felis infection in fleas approaches 100% (28).
would displace those infected with R. rickettsii. Whether the high infection rate is the result of
Also, ticks infected experimentally with R. selection through reproductive incompatibility
montana and R. rhipicephali could not maintain remains to be elucidated. Flea samples from
R. rickettsii through transovarial transmission, opossums, cats, and dogs in different parts of the

Emerging Infectious Diseases 184 Vol. 4, No. 2, April–June 1998

 Perspectives

United States were infected with R. felis. Since it rickettsiae interact. These intracellular organ-
is maintained transovarially, R. felis could be isms have long been associated with arthropods,
used as a marker to follow changes in the and yet we know very little about their
infection rates over time. relationship with arthropod vectors.
Several questions remain: 1) why does
infection with nonpathogenic rickettsiae prevent This work was supported by grants R37 AI 17828 and
R01 AI 43006 from the National Institutes of Health.
establishment of virulent species in the ovaries of
infected ticks; 2) what are the molecular bases for
Dr. Abdu Azad is professor of microbiology and
transovarial interference; 3) are nonpathogenic immunology, University of Maryland School of
rickettsiae selected favorably by their arthropod Medicine, Baltimore. His laboratory research focuses
hosts through reproductive incompatibility; and on host parasite interactions with particular interest
4) why are nonpathogenic rickettsiae found more in the molecular aspects of rickettsial pathogenesis.
often in ticks than a virulent species. Dr. Charles Ben Beard is research entomologist and
chief, Vector Biology Activity, Entomology Branch,
Summary and Conclusions Division of Parasitic Diseases, NCID, CDC. Research in
Ixodid ticks, fleas, and lice are temporary his laboratory focuses on the molecular biology of insect
disease vectors and the molecular epidemiology of
obligate ectoparasites often found on the same
opportunistic infections in persons with AIDS.
vertebrate hosts. They differ substantially with
respect to feeding behavior and digestion of blood
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Emerging Infectious Diseases 186 Vol. 4, No. 2, April–June 1998