Week 4 Discussion- RICKETTSIA RICKETTSIAE -APA format, -300 words minimum      answer these question   -what type of microbe it is    -what disease doe

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Week 4 Discussion- RICKETTSIA RICKETTSIAE -APA format,

-300 words minimum 

    answer these question

  -what type of microbe it is 

  -what disease does it causes

  -where and when it was discovered the signs and symptoms of disease, transmission, course of the disease, virulence factors, laboratory diagnosis,treatments, [prevention and sequelae.

   references are from 

  -microbiology- a system approach-sixth edition 

   – the article is uploaded from keiserlib Pathogenic members of the Rickettsia genus are Gram-
negative, obligate, intracellular bacteria that have a life
cycle which involves both an arthropod vector and a
vertebrate host1–3 (FIG. 1). Rickettsiae are classified into
four groups based on their biological, genetic and anti-
genic characteristics4: the spotted fever group (SFG),
typhus group, transitional group and ancestral group.
SFG rickettsiae include highly pathogenic organisms,
such as tick-transmitted Rickettsia rickettsii (Rocky
Mountain spotted fever (RMSF))5,6, Rickettsia conorii
(Mediterranean spotted fever)1,2,7, Rickettsia africae
(African tick-bite fever)8,9, Rickettsia parkeri (mild-
to-moderate spotted fever rickettsiosis, found in
North and South America)10,11, Rickettsia slovaca
(tick-borne lymphadenopathy)12,13, Rickettsia sibirica
(North Asian tick typhus and lymphangitis-associated
rickettsiosis)14, Rickettsia honei (found in Australia
and Southeast Asia)15, Rickettsia japonica (found
in Japan and Korea)16,17 and the apparently harmless
Rickettsia montanensis, Rickettsia peacockii and Rickettsia
rhipicephali2,18,19. The typhus group includes the highly
pathogenic Rickettsia prowazekii (epidemic typhus) and
Rickettsia typhi (murine typhus)20–23. The ancestral group
includes Rickettsia bellii24 and Rickettsia canadensis25;
whether these species are pathogens is unknown. The
transitional group comprises Rickettsia akari (rickett-
sialpox)26, Rickettsia australis (Queensland tick typhus)27
and Rickettsia felis (flea-borne spotted fever)28 (TABLE 1).
Rickettsia phylogeny has been addressed by sequence
analyses of different genes, varying from housekeeping 
genes, which are useful for distinguishing distinct strains,
to genes that are under evolutionary pressure, such as

those that encode variable immunodominant outer-
membrane proteins. This phylogenetic analysis has sub-
stantially affected the proposed taxonomy of rickettsiae.
However, rickettsial taxonomy remains a controversial
subject, owing to the absence of a universal consensus
on those criteria that should be used for the designation
of species (Box 1).

Rickettsiosis can present with an array of clinical signs
and symptoms6–9,11–16,29–31. Highly lethal RMSF29,30,32,33 is
characterized by headache, fever, myalgia, nausea and
vomiting early in the illness; however, if untreated,
severe injury can develop that sometimes progress to
multi-organ failure. Systemic vascular infection in RMSF
results in encephalitis, which leads to stupor, coma and
seizures, interstitial pneumonia, non-cardiogenic pul-
monary oedema and adult respiratory distress syndrome.
In severe cases, hypovolaemia and hypotensive  shock
result in acute renal failure. Infection of a network of
endothelial cells at the site of tick or mite inoculation
of most SFG rickettsiae is followed by local dermal and
epidermal necrosis that forms an eschar31. Disseminated
infection, further injury to the vascular endothelium and
infiltration of perivascular mononuclear cells leads to
vasodilation, an increase in fluid leakage into the inter-
stitial space and a characteristic rash. Epidemic typhus,
which moulded world history for five centuries, is char-
acterized by fever, headaches, mental confusion and a
rash22,34 (Box 2). Similar to RMSF, epidemic typhus can
develop into life-threatening conditions in previously
healthy, immunocompetent individuals, unless they are
treated early with an appropriate antibiotic. However,
unlike RMSF, R. prowazekii causes latent infection in

Department of Pathology,
University of Texas,
Medical Branch, Galveston,
77555-0609 Texas, USA.
Correspondence to D.H.W.
e-mail: dwalker@utmb.edu
doi:10.1038/nrmicro1866

Housekeeping gene
A gene that is involved in the 
basic functions that are 
required for normal cell 
metabolism and is 
constitutively expressed.

Hypovolaemia
Decreased blood volume — 
more specifically, a decrease in 
the volume of blood plasma.

Hypotensive shock
Shock in which blood pressure 
is lower than normal and does 
not supply blood to the organs.

Emerging and re-emerging
rickettsioses: endothelial cell
infection and early disease events
David H. Walker and Nahed Ismail

Abstract | Rickettsiae cause some of the most severe human infections, including epidemic
typhus and Rocky Mountain spotted fever. Substantial progress has been made in research
into the genomics, vector relationships, pathogenesis and immunity of these obligate,
intracellular, arthropod-transmitted bacteria. This Review summarizes our understanding of
the early and late events in pathogenesis and immunity, modulation of the host response to
rickettsial infection by the vector, host defence, virulence mechanisms and rickettsial
manipulation of host cells.

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http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia conorii

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia africae

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia slovaca

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia sibirica

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=19845

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=10679

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=17469

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia canadensis

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia akari

http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=Rickettsia felis

mailto:dwalker@utmb.edu

Nature Reviews | Microbiology

Infected
human

Infected
eggs

Infected
nymphal tick

Uninfected ticks

Infected female,
adult tick

Tick moults; trans-stadial maintenance

Infected
larval tick

Transovarial
transmission

Infected rodents

Uninfected rodents

Nature Reviews | Microbiology

convalescent individuals, and recrudescence of latent
R. prowazekii infection results in Brill–Zinsser disease,
which is characterized by fever, rash and less-severe ill-
ness that nevertheless can infect feeding lice and ignite
an epidemic35,36.

Interest in the pathogenesis of R. prowazekii and
R. rickettsii has increased following their classifica-
tion as select agents and as category B and C agents
of potential bioterrorism, respectively, by the united
States Centers for Disease Control and Prevention37
(see Further information). These pathogens are highly
infectious agents that are easily disseminated and cause
high morbidity and fatal disease, and thus require
specific improvement in diagnostic tests and disease
surveillance1,6 — the use of R. prowazekii as a biological
weapon was initiated by the Soviet union in the 1930s
and Japan during the Second world war21,38.

The body of knowledge of rickettsial pathogenesis
and immunity is based on disseminated infection of
endothelial cells, the principal target host cells for rick-
ettsiae. Human infections have rarely been investigated
until the middle or late, and often fatal, stages of the ill-
ness. The best animal models for SFG rickettsioses use
R. conorii and R. australis or typhus group rickettsiosis
(using R. typhi) in susceptible mice that are inoculated
intravenously: these manifest systemic endothelial-cell
infection and characteristic pulmonary and cerebral
lesions that recapitulate the clinical and pathological
manifestations of the disease in humans. Infections of
guinea pigs with R. rickettsii and R. prowazekii provide
models of RMSF and epidemic typhus, respectively.

This Review highlights how the arthropod host
acquires, maintains and transmits rickettsiae, the initial
steps in pathogenesis and the subsequent interaction
of the bacteria with cells in the endothelium, the main
target cells. These events include: rickettsial entry,
phagosomal escape, actin-based motility, cell-to-cell
spread and the induction of cell injury. Regarding the
host immune response to rickettsial infection, we will
address innate and acquired immunity, with emphasis

on recent data that illustrate the interaction of rick-
ettsiae with dendritic cells (DCs). we also highlight
some of the potential immunomodulatory effects of
tick saliva on host defences and the immune response
against Rickettsia spp.

Acquisition, interference and immunomodulation
Acquisition. vertebrate hosts are infected with rick-
ettsiae via direct inoculation by a feeding tick or mite
or by scratching infected louse or flea faeces into their
skin. Ticks with hard exoskeletal chitin are vectors and
reservoirs for SFG rickettsiae. The principal vectors of
RMSF in the united States are Dermacentor variabilis
and Dermacentor andersoni (TABLE 1), which are most
active during the late spring and summer, when RMSF
peaks. Epidemic typhus (Box 2) caused by R. prowazekii
is associated with cold weather and lack of hygiene22,
and has re-emerged in louse-infested populations.
Humans in endemic regions, as well as the eastern
flying squirrel Glaucomys volans volans20,39, and its flea
and louse in the united States, and ticks in Mexico and
Africa are the known reservoirs of R. prowazekii40,41.

Interference. Infection of a tick with one SFG rick-
ettsial species seems to interfere with infection by a
second SFG rickettsial species. It was suggested that
rickettsial infection of tick ovaries might alter the
molecular-expression profiles of the oocytes and cause
interference or blocking of the second infection42,43.
This process of rickettsial ‘interference’ might affect
the frequency and distribution of different pathogenic
rickettsiae, and could explain the limited distribution of
virulent R. rickettsii in the eastern part of the Bitterroot
valley, Montana, uSA, where they infect less than 1%
of wood ticks42,44. The low infection rate of R. rickettsii
is attributed to the high infection rate of female wood
ticks (D. andersoni) in the eastern, but not western,
Bitterroot valley with non-virulent rickettsiae, particu-
larly R. peacockii (70% in the eastern compared with
4% in the western side of Bitterroot valley)19,44. In most

Figure 1 | The life cycle of tick-borne rickettsiae. Spotted-fever-group rickettsiae are maintained in nature by
transovarial and trans-stadial transmission in ticks and horizontal transmission to uninfected ticks that feed on
rickettsemic rodents and other animals.

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Superinfection
Infection by a microorganism 
of a cell that is already infected 
by another microorganism.

Transovarial
Passage of parasites or 
infective agents from the 
maternal body to eggs within 
the ovaries and subsequently 
to the larvae that hatch from 
the eggs.

geographic locations, fewer than 0.1% of Dermacentor
spp. ticks carry R. rickettsii45. These data correspond to
the focality of RMSF in the west side of the valley, where
most human cases result from exposure to west-side
ticks (D. andersoni). unlike pathogenic R. rickettsii,
which is lethal for ticks46 and highly virulent in guinea
pigs47, infection with R. peacockii does not cause a
reduction in tick viability, and might even be beneficial
for tick hosts by antagonizing superinfection of ovarian
tissues by R. rickettsii.

Ticks acquire SFG rickettsial species through trans­
ovarial transmission (adult female to egg) and trans­stadial

passage (egg to larva to nymph to adult), and by hori-
zontal acquisition during feeding on a rickettsemic host.
Most SFG rickettsiae are probably maintained in nature
by all these mechanisms (FIG. 1). Therefore, the adverse
effect of virulent R. rickettsii on the viability of adult
ticks and maintenance of Rickettsia spp. in nature are
probably balanced by the feeding of susceptible ticks on
a rickettsemic host, which functions as an amplifying
reservoir for rickettsiae. In fact, it has been shown that
despite the high mortality of experimentally infected
ticks, many larvae that acquire rickettsiae during feeding
survive and are capable of transmitting the infection as

Table 1 | Rickettsial diseases in humans

Disease organism Arthropod
vector

life cycle geographic
area

Eschar rash regional
lymph-
adenopathy

Symptoms
or fever

mortality
rate*

Tick-transmitted spotted fevers

Rocky
Mountain
spotted fever

Rickettsia
rickettsii

Dermacentor
variabilis,
Dermacentor
andersoni,
Rhipicephalus
sanguineus,
Amblyomma
cajennense and
Amblyomma
aureolatum

Transovarian
in ticks and
rodent ticks

Western
hemisphere

Rare Yes No Yes High

Boutonneuse
fever

Rickettsia
conorii

R. sanguineus and
Rhipicephalus
pumilio

Transovarian
in ticks

Southern
Europe,
Africa and
southern
Asia

Frequent Maculo-
papular

No Yes Mild to
moderate

African tick-
bite fever

Rickettsia
africae

Amblyomma
hebraeum and
Amblyomma
variegatum

Transovarian
in ticks

Africa and
the West
Indies

Frequent
and often
multiple

Papular or
vesicular;
often
sparse or
absent

Yes Yes None
reported

Maculatum
disease

Rickettsia
parkeri

Amblyomma
maculatum and
Amblyomma
triste

Ticks Western
hemisphere

Yes Often Yes Yes None
reported

Flea-transmitted diseases

Flea-borne
spotted fever

Rickettsia
felis

Ctenocephalides
felis

Transovarian
in the cat flea

Worldwide Sometimes Sometimes No Yes None
reported

Murine
typhus

Rickettsia
typhi

Xenopsylla
cheopis and
Ctenocephalides
felis

Rat-flea for
X. cheopis
and
Opossumflea
for C. felis

Worldwide No Yes No Yes Low

Louse-transmitted disease

Epidemic
typhus

Rickettsia
prowazekii

Pediculus
humanus
humanus

Human louse Worldwide No Yes No Yes High

Epidemic
typhus

R. prowazekii Fleas and lice of
flying squirrels
and Glaucomys
volans volans

Flying-
squirrel flea
and louse
ectoparasite

United
States

No Yes No Yes Low

Mite-transmitted diseases

Rickettsialpox Rickettsia
akari

Liponyssoides
sanguinus

Transovarian
in mites

Worldwide Yes Yes Yes Yes None
reported

*High mortality is >15%; moderate mortality is 7–15%; mild-to-moderate mortality is 2–7% and low mortality is ≤1%.

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Trans-stadial
Passage of a microorganism 
from one developmental stage 
(stadium) of the host to a 
subsequent stage (or stages).

Haemostatic
Stops blood flow.

nymphs. This suggests that nymphs are a crucial link for
R. rickettsii maintenance and transmission between ver-
tebrates. Importantly, colonies of R. rickettsii-infected
ticks have been observed to maintain the infection with-
out overt deleterious effects for several generations. The
pathological effect of rickettsiae on ticks would explain
the occurrence of RMSF in endemic regions, despite the
low prevalence of naturally infected adult ticks45,46.

Immune modulation. Studies of the virulence of rickett-
siae within their tick vector revealed that feeding ticks
or incubating them at 37°C for 24–48 hours before their
inoculation onto non-immune guinea pigs results in
severe disease, compared with asymptomatic infection
following inoculation of guinea pigs with infected ticks
that were maintained at 4°C or starved for a prolonged
period48. This observation, described as the reactivation
phenomenon by Parker and Spencer44, refers to changes
in the virulence of rickettsiae that are linked to the
physiological status of the ticks.

As an immune evasion or modulation mechanism
that allows the ticks to feed for several days or weeks,
ticks inoculate their saliva with anti-haemostatic com-
ponents that are crucial for the enhancement of blood
feeding and salivary immunomodulatory components
that enhance pathogen transmission and prevent the
host from rejecting the ticks49–53. For example, the saliva
of ticks inhibits neutrophil function52, interferes with the
complement system49–51, natural killer (NK) cell and mac-
rophage activity54, decreases the production of cytokines,
such as interleukin-12 (Il-12) and interferon-γ (IFN-γ),
and decreases T-cell proliferation55,56. Tick-infested mice
do not develop resistance to further infestations with
Rhipicephalus sanguineus, and the immune response in
infested mice exhibits a T helper 2 (TH2)-type pattern

56,57.
Tick saliva might influence T-cell-effector functions
through its initial interaction with professional antigen-
presenting cells, namely DCs58. Such initial interactions
can subsequently influence the differentiation towards
either a TH2-cell phenotype (an ineffective acquired
immune response against intracellular pathogens such as
Rickettsia spp.) or an immunosuppressive phenotype58,59.
Indeed, the addition of tick saliva to bone-marrow-
derived DCs inhibits their maturation by decreasing the
expression of co-stimulatory (CD40, CD80 and CD86)

and adhesion (CD54) molecules58,59. Furthermore, the
maturation of DCs that is stimulated by lipopolysac-
charide in the presence of tick saliva results in reduced
expression of co-stimulatory molecules and reduced
production of Il-12, but not immunosuppressive Il-10.
More importantly, DCs cultured with tick saliva are
inefficient in the induction and activation of antigen-
specific, cytokine-producing T cells58,59. As discussed
below, fully mature DCs are crucial for induction of an
effective TH1 response against Rickettsia spp. Therefore,
it is possible that suppression of DC maturation by tick
saliva during the initial stages of rickettsial infection
could interfere with their co-stimulatory and antigen-
presentation functions. Such suppression of DC matu-
ration would adversely influence the acquired immune
response against tick-transmitted Rickettsia spp., thereby
leading to increased host susceptibility to severe and fatal
rickettsial disease. However, because the tick host is an
important component in the life cycle of rickettsiae, fur-
ther studies are required to address important questions
related to vector biology and disease pathogenesis, such
as whether tick saliva enhances Rickettsia spp. infectivity
during natural transmission and whether pre-exposure
to saliva from uninfected ticks that generates immunity
to saliva protects the vertebrate host, particularly in
endemic areas, from natural tick-transmitted rickett-
sial infection. If immunity to salivary components can

Box 1 | Rickettsial taxonomy

Despite the major advances in serotyping and molecular genotyping of rickettsial isolates from defined geographic
locations, Rickettsia taxonomy is still an evolving field. Novel Rickettsia isolates have been described in recent years, with
the overenthusiastic designation of many new species, which vary much less from one another than the species of other
bacterial genera107. The issue is not whether the isolates can be distinguished from one another, but rather whether the
differences merit designation at the taxonomic level of species or even subspecies. Historically, different species of
prokaryotic pathogens were defined based on the diseases that they caused, regardless of other ecological or
evolutionary considerations. However, the clinical manifestations of most rickettsioses are neither specific to a particular
agent nor to a geographic distribution. Thus, a consensus of taxonomic criteria has yet to be achieved for Rickettsia. A
proposal to adopt the genetic-diversity limits of previously named Rickettsia species for several convenient, but not
uniformly appropriate, genes is an approach that has been specifically rejected by experts in prokaryotic taxonomy108. In
our opinion, if the classification of Rickettsia were congruent with other intracellular bacteria, many of the current species
names would be designated as subspecies and scientists would recognize important new isolates as distinct strains
without needing a new species name.

Box 2 | Epidemic typhus

Epidemic typhus determined the outcome of European
wars from the sixteenth century to the twentieth
century. In Russia, during the First World War, the
revolution and its aftermath, 30 million people suffered
from typhus fever and 3 million of them died. The first
description of typhus originated from the siege of
Naples in 1528, but the role of the human body louse as a
vector was not recognized until 1909, for which Charles
Nicolle was awarded a Nobel Prize. Among the enigmas
of typhus, two of the most intriguing questions are:
in what cells and organs of the body does latent
Rickettsia prowazekii reside during the period after
recovery from the acute infection; and what factors and
mechanisms are responsible for the reactivation of
infection that leads to rickettsemia and potential
louse-borne spread of another epidemic?

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Nature Reviews | Microbiology

d

b

a

e

Endothelial cells

Actin
filaments

Actin
monomers

Cdc42

Phagosome

Rickettsia OmpB

Lysis of phagosome

Cbl

Ku70

Ub

PI3-K

Cbl

N-WASP

RickA

Arp2/3

c

Vasoactive
Causes constriction or dilation 
of blood vessels.

protect against natural rickettsial infection, an effective
anti-rickettsial vaccine could be designed that contains
tick salivary proteins that act as an adjuvant with specific
rickettsial antigens.

Rickettsia–endothelial cell interactions
Rickettsial entry. R. conorii ompB binds specifically to
Ku70 (FIG. 2), a component of the DNA-dependent pro-
tein kinase60. The binding and recruitment of Ku70 to
the plasma membrane are important events in the entry
of R. conorii into non-phagocytic mammalian cells60.
Although nuclear Ku70 is translocated to the cytoplasm
and plasma membrane, where it inhibits apoptosis and
mediates homologous and heterologous cell adhesion
and fibronectin binding, it has been proposed that the
presence of Ku70 within lipid rafts might have an impor-
tant role in the signal transduction that leads to induced
phagocytosis. The role of cholesterol as an essential
component of the membrane receptor that binds to
R. prowazekii was described previously61. Similar to other
intracellular pathogens, such as Listeria monocytogenes,
the entry of R. conorii into non-phagocytic cells is
dependent on membrane cholesterol. Ku70 is present
within lipid microdomains that are enriched in lipid-raft
components. The association of Ku70 with lipid micro-
domains and its binding to R. conorii suggest that Ku70
has an important role in cholesterol-dependent bacterial
entry60. Although the exact mechanism by which Ku70
supports the entry of R. conorii into non-phagocytic cells
remains unclear, the binding of R. conorii ompB to Ku70
might activate membrane Ku70, which is postulated to
lead to the activation of a cascade of signalling events,
including the small GTPase, Cdc42, phosphoinositidyl-
3-kinase, src-family tyrosine kinases and the tyrosine
phosphorylation of focal adhesion kinase62. These
signalling events are known to be strongly associated
with β1-integrin activation and bacterial entry63 (FIG. 2).
Similar to the entry of L. monocytogenes into its host
cells, R. conorii infection stimulates the ubiquitination

of Ku70. In addition, the ubiquitin ligase c-Cbl is
recruited to R. conorii-entry foci, and downregulation
of endogenous c-Cbl blocks bacterial invasion and
Ku70 ubiquitination60,62. The binding of Ku70 to ompB
and the role of Ku70 in bacterial entry into host cells
correlate with the decreased expression of ompB that
is associated with reduced virulence of R. rickettsii str.
Iowa64 and the observation that anti-ompB antibodies
protect animals from an otherwise lethal challenge of
R. conorii65–67. However, it is possible that SFG rick-
ettsial ompA or other unidentified rickettsial outer-
membrane proteins also mediate adhesion by binding
to unknown receptors68.

Rickettsial diseases and endothelial pathogenesis. Most
of the clinical characteristics of rickettsial diseases are
attributed to disseminated infection of the endothelium,
where they grow and stimulate oxidative stress, thereby
causing injury to the endothelial cells. Severe morbidity
and mortality of RMSF are due to effects such as cerebral
oedema and non-cardiogenic pulmonary oedema. The
most prominent pathophysiological effects of rickettsial
infection of endothelial cells include: an increase in vas-
cular permeability; generalized vascular inflammation;
oedema; increased leukocyte–endothelium interactions;
and release of powerful vasoactive mediators that pro-
mote coagulation and pro-inflammatory cytokines69,70.
Evidence that supports a pro-coagulant and pro-inflam-
matory phenotype of the host response is provided by
studies of cultured endothelial cells in which rickettsial
infection causes increased expression of tissue factor,
thrombomodulin plasminogen-activator inhibitor 1,
Il-1, Il-6, Il-8 and E-selectin70–73. Increased plasma
levels of von willebrand factor that are associated with
increased levels of inflammatory cytokines, such as Il-6,
have also been detected in patients with African tick-bite
fever and Mediterranean spotted fever69,74. Prostaglandins
and leukotrienes are crucial vasoactive modulators of vas-
cular tone and permeability that are potential mediators

Figure 2 | Host cell interactions of rickettsiae. a | Spotted-fever-group rickettsiae attach to Ku70 on the surface of
human target cells (the endothelium) via outer-membrane-protein B (OmpB) and to an unknown receptor via outer-
membrane-protein A. b | Cbl ubiquitinates Ku70 (REF. 61), and signal-transduction events that involve Cdc42, protein
tyrosine kinase, phosphatidylinositol 3′-kinase (PI3-K) and Src-family kinases activate the Arp 2/3 complex to induce
cytoskeletal actin to phagocytose the rickettsia62. c | Membranolytic phospholipase D and haemolysin C mediate
rickettsial phagosomal escape83. d | RickA-stimulated activation of Arp2/3-mediated polymerization of host actin propels
the bacterium through the cytosol and into filopodia. e | Rickettsiae are then either released from filopodia
extracellularly or spread into the adjacent cell84–88. Cbl, family of ubiquitin ligases; N-WASP, neural Wiskott–Aldrich
syndrome protein; Ub, ubiquitin.

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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=19943

of microvascular injury and vasculitis in rickettsial
infection75,76. These vasoactive substances are generally
generated by an inducible isoenzyme cyclooxygenase
(CoX)75. Transcriptional activation of host endothe-
lial cells in response to stimulation with R. rickettsii or
R. conorii involves rapid regulation of CoX2 expression
and inhibition of CoX2 activity during infection, which
leads to decreased levels of secreted prostaglandins. As
a regulatory mechanism that prevents the development
of extensive vascular injury, endothelial cells that are
infected with R. rickettsii produce haem oxygenase,
an antioxidant, anti-inflammatory and vasoprotective
enzyme that controls CoX2 activity77. The production of
this antioxidant mechanism by R. rickettsii-infected cells
seems to be dependent on several factors, including: dose
and kinetics of rickettsial infection; viability of the host
cells; de novo protein synthesis by host cells; adhesion
and entry of Rickettsia spp. to the host cell membrane;
rickettsial replication; and viability77. viability is prob-
ably influenced by the host immune status, as well as
whether patients are treated with doxycycline at an early
stage of infection. Nevertheless, the balance between
the production of vasoprotective, anti-inflammatory
and antioxidant haem oxygenase and the generation of
vasoactive substances by CoX2 in Rickettsia-infected
endothelial cells might determine the outcome of rick-
ettsial infection and thus the susceptibility or resistance
to severe, and sometimes fatal, disease.

In an in vitro model of human microvascular
endothelium, R. rickettsii causes early-dose-dependent
increased vascular permeability. Furthermore, pro-
inflammatory cytokines, such as Il-1β and tumour
necrosis factor (TNF), which are probably produced …

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