A
malaria
vaccine
that
prevents
infection
will
be
an
important
new
tool
in
continued
efforts
of
elimination,
and
such
vaccines
are
under
intense
development
for
the
major
human
parasite
Plasmodium
falciparum
(Pf).
Antibodies
elicited
by
can
block
initial
phases
when
sporozoites
deposited
into
skin
mosquito
bite
then
target
liver
further
development.
However,
there
currently
no
standardized
vivo
preclinical
models
measure
inhibitory
activity
antibody
specificities
against
Pf
sporozoite
via
bite.
Here,
we
use
liver-chimeric
mice
as
a
challenge
model
to
assess
prevention
natural
antibodies.
We
demonstrate
these
consistently
infected
with
this
combined
passive
transfer
either
monoclonal
antibodies
or
polyclonal
IgG
from
immune
serum
antibody-mediated
blocking
using
bioluminescent
imaging.
This
methodology
is
useful
down-select
functional
investigate
mechanisms
correlates
protection
clinical
trials,
thereby
informing
rational
optimization.
PLoS neglected tropical diseases,
Год журнала:
2017,
Номер
11(7), С. e0005791 - e0005791
Опубликована: Июль 31, 2017
Plasmodium
falciparum
and
vivax
cause
the
majority
of
human
malaria
cases.
Research
efforts
predominantly
focus
on
P.
because
clinical
severity
infection
associated
mortality
rates.
However,
affects
more
people
in
a
wider
global
range.
Furthermore,
unlike
falciparum,
can
persist
liver
as
dormant
hypnozoites
that
be
activated
weeks
to
years
after
primary
infection,
causing
relapse
symptomatic
blood
stages.
This
feature
makes
unique
difficult
eliminate
with
standard
tools
vector
control
treatment
stage
antimalarial
drugs.
Infection
by
is
initiated
mosquito-transmitted
sporozoite
stage,
highly
motile
invasive
cell
targets
hepatocytes
liver.
The
most
advanced
vaccine
for
(RTS,S,
subunit
containing
portion
major
surface
protein)
conferred
limited
protection
Phase
III
trials,
falling
short
WHO-established
efficacy
goals.
blocking
vivax,
before
establishment
chronic
might
an
effective
strategy
reduce
occurrence
relapsing
It
also
thought
multivalent
comprising
multiple
antigens
will
provide
better
protection,
but
comprehensive
analysis
proteins
sporozoites
not
available.
To
inform
sporozoite-based
development,
we
employed
mass
spectrometry-based
proteomics
identify
nearly
2,000
present
salivary
gland
sporozoites.
Analysis
protein
post-translational
modifications
revealed
extensive
phosphorylation
glideosome
well
regulators
transcription
translation.
Additionally,
CSP
TRAP,
which
were
recently
discovered
glycosylated
sporozoites,
observed
similarly
modified
Quantitative
comparison
proteomes
high
degree
similarity
expression
levels,
including
among
invasion-related
proteins.
Nevertheless,
orthologs
significantly
different
levels
between
two
species
could
identified,
abundant,
species-specific
no
known
orthologs.
Finally,
chemical
labeling
live
isolate
36
are
putatively
surface-exposed
In
addition
identifying
conserved
identified
similar
analyses
other
species,
our
several
as-yet
uncharacterized
proteins,
putative
6-Cys
ortholog
falciparum.
Plasmodium
sporozoites,
the
mosquito-transmitted
forms
of
malaria
parasite,
first
infect
liver
for
an
initial
round
replication
before
emergence
pathogenic
blood
stages.
Sporozoites
represent
attractive
targets
antimalarial
preventive
strategies,
yet
mechanisms
parasite
entry
into
hepatocytes
remain
poorly
understood.
Here
we
show
that
two
main
species
causing
in
humans,
falciparum
and
vivax,
rely
on
distinct
host
cell
surface
proteins,
CD81
Scavenger
Receptor
BI
(SR-BI),
respectively,
to
hepatocytes.
By
contrast,
SR-BI
fulfil
redundant
functions
during
infection
by
rodent
P.
berghei.
Genetic
analysis
sporozoite
factors
reveals
6-cysteine
domain
protein
P36
as
a
major
determinant
receptor
usage.
Our
data
provide
molecular
insights
invasion
pathways
used
different
parasites
hepatocytes,
establish
functional
link
between
putative
ligand
receptors.
The
circumsporozoite
protein
(CSP)
of
Plasmodium
is
a
key
surface
antigen
that
induces
antibodies
and
T-cells,
conferring
immune
protection
in
animal
models
humans.
However,
much
the
work
on
CSP
immunity
has
been
developed
based
studies
using
rodent
or
non-human
primate
antigens,
which
may
not
be
entirely
translatable
to
expressed
by
human
malaria
parasites,
especially
considering
host
specificity
different
species.Using
genetically
engineered
strain
berghei
expresses
luciferase,
GFP
falciparum
orthologue
CSP,
effect
laboratory
preparation,
mosquito
treatment
mouse
factors
sporozoite
infectivity
was
assessed
an
vivo
bioluminescence
assay
mice.
This
compared
with
PCR-based
already
described
monoclonal
antibody
can
provide
sterile
against
challenge.Bioluminescence
demonstrated
similar
detection
levels
quantity
kinetics
liver-stage
infection,
detection.
used
evaluate
delivery
method
infectivity,
as
well
effects
age,
sex
Finally,
this
test
protective
capacity
AB317;
results
strongly
recapitulate
findings
previous
antibody.The
PbGFP-Luc
line
imaging
highly
sensitive
read-outs
infection
mice,
useful
reliably
potency
pre-erythrocytic
interventions.
Nature Communications,
Год журнала:
2017,
Номер
8(1)
Опубликована: Сен. 11, 2017
Abstract
O-glycosylation
of
the
Plasmodium
sporozoite
surface
proteins
CSP
and
TRAP
was
recently
identified,
but
role
this
modification
in
parasite
life
cycle
its
relevance
to
vaccine
design
remain
unclear.
Here,
we
identify
protein
O-fucosyltransferase
(POFUT2)
responsible
for
O-glycosylating
TRAP.
Genetic
disruption
POFUT2
falciparum
results
ookinetes
that
are
attenuated
colonizing
mosquito
midgut,
an
essential
step
malaria
transmission.
Some
POFUT2-deficient
parasites
mature
into
salivary
gland
sporozoites
although
they
impaired
gliding
motility,
cell
traversal,
hepatocyte
invasion,
production
exoerythrocytic
forms
humanized
chimeric
liver
mice.
These
defects
can
be
attributed
destabilization
incorrect
trafficking
bearing
thrombospondin
repeats
(TSRs).
Therefore,
plays
a
similar
metazoans:
it
ensures
TSR
as
part
non-canonical
glycosylation-dependent
endoplasmic
reticulum
quality
control
mechanism.
Nature Communications,
Год журнала:
2018,
Номер
9(1)
Опубликована: Окт. 22, 2018
Interventions
that
can
block
the
transmission
of
malaria-causing
Plasmodium
falciparum
(Pf)
between
human
host
and
Anopheles
vector
have
potential
to
reduce
incidence
malaria.
Pfs48/45
is
a
gametocyte
surface
protein
critical
for
parasite
development
transmission,
its
targeting
by
monoclonal
antibody
(mAb)
85RF45.1
leads
potent
reduction
transmission.
Here,
we
reveal
how
6C
domain
adopts
(SAG1)-related-sequence
(SRS)
fold.
We
structurally
delineate
epitope
I
show
mAb
recognizes
an
electronegative
with
nanomolar
affinity.
Analysis
sequences
reveals
polymorphisms
are
rare
residues
involved
at
binding
interface.
Humanization
rat-derived
conserved
mode
recognition
activity
parental
antibody,
while
also
improving
thermostability.
Our
work
has
implications
transmission-blocking
interventions,
both
through
vaccine
designs
testing
passive
delivery
mAbs
in
humans.
Malaria
resurgence
in
2022
saw
249
million
clinical
cases
and
608,000
deaths,
mostly
children
under
five.
The
WHO-approved
circumsporozoite
protein
(CSP)-targeting
vaccines,
RTS,S
R21,
remain
limited
availability.
Strong
humoral
responses
are
crucial
for
sporozoite
neutralization
before
hepatocyte
infection,
yet
first-generation
vaccines
provide
suboptimal
protection,
necessitating
improved
strategies.
With
the
success
of
mRNA-LNP
against
COVID-19,
there
is
interest
leveraging
this
approach
to
malaria.
Here,
we
developed
a
novel
chemokine
fusion
mRNA
vaccine
targeting
immature
dendritic
cells
(iDC)
enhance
immunity
P.
falciparum
CSP
(PfCSP).
Mice
immunized
with
MIP3α-CSP
exhibited
stronger
CD4
+
T
cell
higher
anti-NANP6
antibody
titers
than
conventional
mRNA-LNP.
Importantly,
upon
berghei
PfCSP
transgenic
challenge,
provided
significantly
greater
protection
from
liver
strongly
associated
multifunctional
titers.
This
study
underscores
iDC
as
promising
strategy
malaria
efficacy.
PLoS Pathogens,
Год журнала:
2016,
Номер
12(7), С. e1005734 - e1005734
Опубликована: Июль 18, 2016
Regulated
protein
secretion
is
required
for
malaria
parasite
life
cycle
progression
and
transmission
between
the
mammalian
host
mosquito
vector.
During
from
to
vector,
exocytosis
of
highly
specialised
secretory
vesicles,
such
as
osmiophilic
bodies,
key
dissolution
red
blood
cell
parasitophorous
vacuole
membranes
enabling
gamete
egress.
The
positioning
adhesins
TRAP
family,
micronemes
sporozoite
surface,
essential
gliding
motility
host.
Here
we
identify
a
conserved
role
putative
pantothenate
transporter
PAT
in
Plasmodium
berghei
vesicle
fusion
two
distinct
classes
vesicles
gametocytes
sporozoites.
membrane
component
bodies
Despite
normal
formation
trafficking
surface
upon
activation,
PAT-deficient
gametes
fail
discharge
their
contents,
remain
intraerythrocytic
unavailable
fertilisation
further
development
mosquito.
Sporozoites
lacking
secrete
TRAP,
are
immotile
thus
unable
infect
subsequent
rodent
Thus,
P.
appears
regulate
populations
different
forms
rather
than
acting
pantothenic
during
transmission.