Type II Secretion and Legionella pneumophila Infection

Project: Research project

Project Details

Description

Legionella pneumophila
(
Lp
) is the agent of Legionnaires' disease, a common and potentially fatal form of
pneumonia.
Lp
is ubiquitous in natural and man
-
made water systems and infects the lungs after the inhalation
of contamin
ated aerosols. In water and the lungs,
Lp
grows as an intracellular parasite, inf
ecting either aquatic
protozoa or alveolar
macrophages
. Previously, we
demonstrated
that
Lp
expresses
a type II secretion (T2S)
system
that mediates the secretion of >25 pro
teins (substrates) and is required for optimal infection of both
amoebal and mammalian
host cells and the
murine
lung.
During the last grant period, we documented that
secreted PlaC (an acyltransferase), ProA (a metalloprotease), SrnA (a ribonuclease),
Nt
tA, and Lpw18401,
and
two
other
“novel” substrates promote intracellular growth/survival in
Acanthamoeba
,
Hartmannella
, and
Naegleria
amoebae in a
unique
host
-
specific fashion. We also demonstrated that T2S and
a subset of
novel
substrates enhance
intrace
llular growth/survival within lung
macrophages
and likely do
so by helping to retain
host protein Rab1 on the
Legionella
-
containing vacuole. Finally, among other results, we
documented
that
T2S and at lea
st two of its substrates, i.e., ProA and NttA,
damp
en the chemokine and cytokine output of
infected
macrophages
, a process that would
most likely
impede the clearance of
Lp
from the infected lung.
This subversion of cytokine production was due, in part, to dampened signal transduction and cytokine gene
tra
nscription.
In sum,
we have been at the forefront of demonstrating that T2S
is critical
in
all of the major
facets of the
Lp
lifecycle and its associated disease,
elaborating more
substrates
and encoding a wider variety
of activities than is
currently
app
reciated for any other
bacterial
T2S system.
In the current proposal, we will
now
determine i) mechanisms by which PlaC, ProA, SrnA, and NttA and other novel T2S substrates enhance
Lp
growth in
multiple
amoebae, which
are
the
essential links
in
Lp
disease
transmission
from water systems to
humans
, ii)
how
T2S and its novel substrates Lpw02811 and Lpw18401
act to
modulate
Rab1 in
macrophages,
which are
the
critical host cell in the
Lp
-
infected mammalian host, and iii) the mechanisms by which T2S and
its
sub
strates
,
including NttA, modulate cytokine signaling in
Lp
-
infected macrophages
as well as
assess
the
impact of cytokine subversion on the cellular inflammatory response in the
Lp
-
infected lung.
The proposed
studies will i) increase significantly our under
standing of the pathogenesis of
Lp
, which is an important
and
increasing
public health concern within the US and throughout the world, ii) expand our molecular
understanding of both bacterial protein secretion and intracellular infection, iii) have im
plica
tions for other
important
pathogens that utilize or are predicted to use T2S,
iv) have implications for other bacteria that are
pathogenic by virtue of being intracellular parasites of macrophages, and
v) offer potential
new
targets for
disease diagnosis,
treatment, or prevention.
StatusFinished
Effective start/end date9/1/148/31/19

Funding

  • National Institute of Allergy and Infectious Diseases (5R01AI043987-17)

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