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Dissemination of Orientia tsutsugamushi and inflammatory responses in a murine model of scrub typhus.
[scrub typhus]
Central
aspects
in
the
pathogenesis
of
scrub
typhus
,
an
infection
caused
by
Orientia
(
O
.
)
tsutsugamushi
,
have
remained
obscure
.
Its
organ
and
cellular
tropism
are
poorly
understood
.
The
purpose
of
this
study
was
to
analyze
the
kinetics
of
bacterial
dissemination
and
associated
inflammatory
responses
in
infected
tissues
in
an
experimental
scrub
typhus
mouse
model
,
following
infection
with
the
human
pathogenic
strain
Karp
.
We
provide
a
thorough
analysis
of
O
.
tsutsugamushi
infection
in
inbred
Balb
/
c
mice
using
footpad
inoculation
,
which
is
close
to
the
natural
way
of
infection
.
By
a
novel
,
highly
sensitive
qPCR
targeting
the
multi
copy
traD
genes
,
we
quantitatively
monitored
the
spread
of
O
.
tsutsugamushi
Karp
from
the
skin
inoculation
site
via
the
regional
lymph
node
to
the
internal
target
organs
.
The
highest
bacterial
loads
were
measured
in
the
lung
.
Using
confocal
imaging
,
we
also
detected
O
.
tsutsugamushi
at
the
single
cell
level
in
the
lung
and
found
a
predominant
macrophage
rather
than
endothelial
localization
.
Immunohistochemical
analysis
of
infiltrates
in
lung
and
brain
revealed
differently
composed
lesions
with
specific
localizations
:
iNOS-expressing
macrophages
were
frequent
in
infiltrative
parenchymal
noduli
,
but
uncommon
in
perivascular
lesions
within
these
organs
.
Quantitative
analysis
of
the
macrophage
response
by
immunohistochemistry
in
liver
,
heart
,
lung
and
brain
demonstrated
an
early
onset
of
macrophage
activation
in
the
liver
.
Serum
levels
of
interferon
(
IFN
)
-
γ
were
increased
during
the
acute
infection
,
and
we
showed
that
IFN-γ
contributed
to
iNOS-dependent
bacterial
growth
control
.
Our
data
show
that
upon
inoculation
to
the
skin
,
O
.
tsutsugamushi
spreads
systemically
to
a
large
number
of
organs
and
gives
rise
to
organ-
specific
inflammation
patterns
.
The
findings
suggest
an
essential
role
for
the
lung
in
the
pathogenesis
of
scrub
typhus
.
The
model
will
allow
detailed
studies
on
host-pathogen
interaction
and
provide
further
insight
into
the
pathogenesis
of
O
.
tsutsugamushi
infection
.
Diseases
Validation
Diseases presenting
"large number"
symptom
acute rheumatic fever
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
canavan disease
coats disease
cowden syndrome
dedifferentiated liposarcoma
dracunculiasis
epidermolysis bullosa simplex
fabry disease
familial mediterranean fever
gm1 gangliosidosis
heparin-induced thrombocytopenia
hereditary cerebral hemorrhage with amyloidosis
hirschsprung disease
kindler syndrome
legionellosis
malignant atrophic papulosis
neuralgic amyotrophy
phenylketonuria
pleomorphic liposarcoma
primary effusion lymphoma
scrub typhus
severe combined immunodeficiency
triple a syndrome
waldenström macroglobulinemia
well-differentiated liposarcoma
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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