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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
"human pathogenic strain"
symptom
scrub typhus
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