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Complex adaptive immunity to enteric fevers in humans: lessons learned and the path forward.
[typhoid]
Salmonella
enterica
serovar
Typhi
(
S
.
Typhi
)
,
the
causative
agent
of
typhoid
fever
,
and
S
.
Paratyphi
A
and
B
,
causative
agents
of
paratyphoid
fever
,
are
major
public
health
threats
throughout
the
world
.
Although
two
licensed
typhoid
vaccines
are
currently
available
,
they
are
only
moderately
protective
and
immunogenic
necessitating
the
development
of
novel
vaccines
.
A
major
obstacle
in
the
development
of
improved
typhoid
,
as
well
as
paratyphoid
vaccines
is
the
lack
of
known
immunological
correlates
of
protection
in
humans
.
Considerable
progress
has
been
made
in
recent
years
in
understanding
the
complex
adaptive
host
responses
against
S
.
Typhi
.
Although
the
induction
of
S
.
Typhi-
specific
antibodies
(
including
their
functional
properties
)
and
memory
B
cells
,
as
well
as
their
cross-reactivity
with
S
.
Paratyphi
A
and
S
.
Paratyphi
B
has
been
shown
,
the
role
of
humoral
immunity
in
protection
remains
undefined
.
Cell
mediated
immunity
(
CMI
)
is
likely
to
play
a
dominant
role
in
protection
against
enteric
fever
pathogens
.
Detailed
measurements
of
CMI
performed
in
volunteers
immunized
with
attenuated
strains
of
S
.
Typhi
have
shown
,
among
others
,
the
induction
of
lymphoproliferation
,
multifunctional
type
1
cytokine
production
,
and
CD
8
(
+
)
cytotoxic
T
-
cell
responses
.
In
addition
to
systemic
responses
,
the
local
microenvironment
of
the
gut
is
likely
to
be
of
paramount
importance
in
protection
from
these
infections
.
In
this
review
,
we
will
critically
assess
current
knowledge
regarding
the
role
of
CMI
and
humoral
immunity
following
natural
S
.
Typhi
and
S
.
Paratyphi
infections
,
experimental
challenge
,
and
immunization
in
humans
.
We
will
also
address
recent
advances
regarding
cross-talk
between
the
host
's
gut
microbiota
and
immunization
with
attenuated
S
.
Typhi
,
mechanisms
of
systemic
immune
responses
,
and
the
homing
potential
of
S
.
Typhi-
specific
B-
and
T
-
cells
to
the
gut
and
other
tissues
.
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