Frontiers in Cellular and Infection Microbiology,
Journal Year:
2024,
Volume and Issue:
14
Published: Nov. 12, 2024
Objective
The
fungal
unfolded
protein
response
consists
of
a
two-component
relay
in
which
the
ER-bound
sensor,
IreA,
splices
and
activates
mRNA
transcription
factor,
HacA.
Previously,
we
demonstrated
that
hacA
is
essential
for
Aspergillus
fumigatus
virulence
murine
model
keratitis
(FK),
suggesting
pathway
could
serve
as
therapeutic
target.
Here
investigate
antifungal
properties
known
inhibitors
mammalian
Ire1
both
vitro
treatment
FK.
Methods
activity
was
tested
against
conidia
several
A.
isolates
by
broth
microdilution
assay
biofilm
XTT
reduction.
influence
4μ8C
on
splicing
assessed
through
gel
electrophoresis
qRT-PCR
UPR
regulatory
genes.
toxicity
profile
cornea
applying
drops
to
uninfected
or
-infected
corneas
3
times
daily
starting
4
hours
post-inoculation.
Corneas
were
evaluated
slit-lamp
imaging
optical
coherence
tomography,
at
endpoint
histology
burden
quantification
via
colony
forming
units.
Results
Among
six
screened,
endonuclease
inhibitor
displayed
strongest
with
an
apparent
fungicidal
action.
compound
blocked
conidial
germination
hyphal
metabolism
Af293
same
concentration
range
gene
induction
(60-120
µM).
Topical
sham-inoculated
0.5
2.5
mM
did
not
impact
corneal
clarity,
but
transiently
inhibit
epithelialization
ulcers.
Relative
vehicle-treated
Af293-infected
corneas,
drug
resulted
50%
>90%
reduction
load,
respectively,
latter
corresponded
absence
clinical
signs
infection
pathology.
Conclusion
data
suggest
displays
specific
inhibition
IreA.
application
can
furthermore
block
establishment
infection,
this
class
drugs
be
developed
novel
antifungals
improve
visual
outcomes
FK
patients.
Genes,
Journal Year:
2024,
Volume and Issue:
15(12), P. 1584 - 1584
Published: Dec. 9, 2024
Background/Objectives:
Biallelic
pathogenic
variants
in
the
CEP290
gene
are
typically
associated
with
severe,
early-onset
inherited
retinal
dystrophies
(IRDs)
both
syndromic
and
non-syndromic
forms.
This
study
explores
phenotypic
variability
of
IRDs
variants,
focusing
on
two
siblings
biallelic
one
whom
exhibits
a
remarkably
mild
phenotype,
thereby
expanding
clinical
spectrum.
Methods:
Whole-exome
sequencing
(WES)
mRNA
analysis
were
performed
to
identify
characterize
siblings.
Comprehensive
ophthalmologic
evaluations
assessed
function
disease
progression.
Results:
Two
frameshift
(c.955del,
p.(Ser319LeufsTer16))
missense
(c.5777G>C,
p.(Arg1926Pro)),
identified
trans
Despite
sharing
same
genetic
sister
exhibited
significantly
preserved
function,
while
brother
presented
more
progressive
dystrophy.
Conclusions:
broadens
spectrum
CEP290-related
IRDs,
demonstrating
severity
ranging
from
severe.
These
findings
highlight
importance
personalized
monitoring
tailored
management
strategies
based
individual
presentations
IRDs.
