Salmonella enterica serovar Typhimurium is an intracellular pathogen that grows within a modified endomembrane compartment, the Salmonella-containing vacuole (SCV). Maturation of nascent SCVs ...involves the recruitment of early endosome markers and the remodelling of phosphoinositides at the membrane of the vacuole, in particular the production of phosphatidylinositol 3-phosphate PI(3)P. Sorting nexins (SNXs) are a family of proteins characterized by the presence of a phox homology (PX) domain that binds to phosphoinositides and are involved in intracellular trafficking in eukaryotic cells. We therefore studied whether sorting nexins, particularly sorting nexin 3 (SNX3), play a role in Salmonella infection. We found that SNX3 transiently localized to SCVs at early times post invasion (10 min) and presented a striking tubulation phenotype in the vicinity of SCVs at later times (30-60 min). The bacterial effector SopB, which is known to promote PI(3)P production on SCVs, was required for the formation of SNX3 tubules. In addition, RAB5 was also required for the formation of SNX3 tubules. Depletion of SNX3 by siRNA impaired RAB7 and LAMP1 recruitment to the SCV. Moreover, the formation of Salmonella-induced filaments (Sifs) was altered by SNX3 knock-down. Therefore, SNX3 plays a significant role in regulating the maturation of SCVs.
Summary
CARD9 deficiency (CANDF2; OMIM# 212050) is an autosomal‐recessive monogenic inborn error of immunity conferring susceptibility to invasive fungal diseases, including the very distinct ...syndrome of spontaneous central nervous system candidiasis, in which opportunistic yeast of the genus Candida infect the central nervous system (either brain parenchyma and/or meninges) in the absence of trauma, chemotherapy or underlying systemic disease. We present a patient with spontaneous endophthalmitis of the right eye due to Candida albicans; further investigations revealed concomitant cerebral abscess. She had a history of left endophthalmitis due to the dematiaceous mould, Aureobasidium pullulans, 15 years earlier. Targeted sequencing of the CARD9 gene revealed 2 novel variants (c.184G>A and c.288C>T). Analysis in silico predicted each variant altered splicing, which was confirmed by sequencing of cDNA from proband and carrier offsprings: c.184G>A results in a 4‐base pair frameshift deletion with loss of allelic expression; c.288C>T results in an in‐frame 36‐bp pair deletion with detectable protein. CARD9 deficiency can present with a phenotype of spontaneous candidal endophthalmitis. We report 2 novel mutations in CARD9, both affecting splicing, expanding the range of morbid variants causing CARD9 deficiency, emphasising the importance of both genomic and cDNA sequencing for this condition.
Summary
CARD
9 deficiency (
CANDF
2;
OMIM
# 212050) is an autosomal‐recessive monogenic inborn error of immunity conferring susceptibility to invasive fungal diseases, including the very distinct ...syndrome of spontaneous central nervous system candidiasis, in which opportunistic yeast of the genus
Candida
infect the central nervous system (either brain parenchyma and/or meninges) in the absence of trauma, chemotherapy or underlying systemic disease. We present a patient with spontaneous endophthalmitis of the right eye due to
Candida albicans
; further investigations revealed concomitant cerebral abscess. She had a history of left endophthalmitis due to the dematiaceous mould,
Aureobasidium pullulans
, 15 years earlier. Targeted sequencing of the
CARD
9
gene revealed 2 novel variants (c.184G>A and c.288C>T). Analysis in silico predicted each variant altered splicing, which was confirmed by sequencing of
cDNA
from proband and carrier offsprings: c.184G>A results in a 4‐base pair frameshift deletion with loss of allelic expression; c.288C>T results in an in‐frame 36‐bp pair deletion with detectable protein.
CARD
9 deficiency can present with a phenotype of spontaneous candidal endophthalmitis. We report 2 novel mutations in
CARD
9
, both affecting splicing, expanding the range of morbid variants causing
CARD
9 deficiency, emphasising the importance of both genomic and
cDNA
sequencing for this condition.
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