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Development
of
anti-­-Leishmania
vaccines…

of
the
L.
infantum
histone
H2A
was
made
using
sera
from
infected
dogs
that
were

recognizing
this
basic
protein
(50).
The
rest
of
the
nucleosome
forming
histones

(H3,
H2B
and
H4)
was
described
as
antigens
in
serologic
assays
employing
canine

VCL
sera
(51,
52).
Antigenicity
is
not
only
related
to
the
VL
canine
infection,
since

the
four
core
histones
were
also
recognized
by
sera
from
CL
and
MCL
human

patients,
being
the
H2A
the
most
antigenic
core
histone
(53).
This
protein
is
also

recognized
by
sera
from
VL
patients
infected
with
L.
chagasi
(34).
The
antigenicity

of
the
H1
linker
histone
in
patients
infected
by
L.
braziliensis
has
been

demonstrated
by
Dr.
Valladares
research
group
(Facultad
de
Farmacia,

Universidad
de
La
Laguna)
(54,
55).
Remarkably,
the
anti-­-histone
humoral

response
elicited
during
infection
is
specific
for
the
parasite
antigens
and
does
not

show
cross-­-reactivity
with
the
host
histone,
since
B
cell
epitopes
are
mainly

located
in
the
most
divergent
regions
of
the
parasite
histones
(52,
55-­-57).
The

presence
of
IFN-­-gamma
mediated
specific
T
cell
responses
has
been
demonstrated

for
the
H2B
protein
in
human
patients
of

CL
and

VL
(49,
58)
and
for
H2A
and
H3

in
CL
patients
(59).

The
prophylactic
value
of
the
Leishmania
histones
was
evaluated
in

different
experimental
models
with
the
implication
of
different
Spanish

researchers.
Induction
of
Th1
responses
against
the
four
L.
infantum
nucleosomal

histones
were
able
to
protect
BALB/c
mice
against
a
virulent
challenge
with
L.

major
(60,
61),
L.
braziliensis
(62)
and
L.
infantum
(63).
Beside
data
reporting
the

protective
capacities
of
the
H1
histone
in
murine
(64)
and
monkey
(65)
models,
a

vaccine
based
on
this
protein
was
tested
with
success
(62.5%

of
infected
animals

without
clinical
symptoms)
in
a
vaccine
trial
against
experimental
canine
VL
(66).

Taking
into
account
the
high
degree
of
immunogenicity
of
the
parasite

histones
and
their
value
as
immuno-­-prophylactic
molecules
tools
against

leishmaniasis
in
different
experimental
models,
parasite
histones
emerge
as
a

powerful
tool
against
Leishmania
infection.
In
this
sense
and
as
it
is
indicated
in

section
4,
different
combination
molecules
designed
as
anti-­-Leishmania
vaccines

include
Leishmania
histone-­-genes
or
proteins.

3.2.
Leishmania
ribosomes
as
vaccines

Leishmania
ribosomes
have
emerged
as
immunodominant
particles
during

parasite
infection.
Many
ribosomal
proteins
are
recognized
by
the
sera
from
VL

dogs
(67-­-70)
or
are
antigenic
in
human
MCL
and
VL
patients
(68,
71).
Leishmania

acidic
ribosomal
P
proteins
(namely
P0,
P2a
and
P2b)
are
good
examples
of

Leishmania
intracellular
antigens.
Strong
humoral
responses
are
elicited
against

them
during
infection
(mainly
in
the
VL
forms
of
human
and
canine
disease).

Interestingly,
anti-­-P
antibodies
are
specifically
directed
against
parasite
P
proteins

without
cross-­-reactivity
with
the
host
orthologs
(reviewed
in
(48))
although
these

proteins
are
antigenic
in
patients
with
autoimmune
diseases
(72).
The
location
of
B

255