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2016 ; 126
(6
): 2280-94
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Bicarbonate correction of ketoacidosis alters host-pathogen interactions and
alleviates mucormycosis
#MMPMID27159390
Gebremariam T
; Lin L
; Liu M
; Kontoyiannis DP
; French S
; Edwards JE Jr
; Filler SG
; Ibrahim AS
J Clin Invest
2016[Jun]; 126
(6
): 2280-94
PMID27159390
show ga
Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to
mucormycosis, an angioinvasive fungal infection with high mortality. Previously,
we demonstrated that Rhizopus invades the endothelium via binding of fungal CotH
proteins to the host receptor GRP78. Here, we report that surface expression of
GRP78 is increased in endothelial cells exposed to physiological concentrations
of ?-hydroxy butyrate (BHB), glucose, and iron that are similar to those found in
DKA patients. Additionally, expression of R. oryzae CotH was increased within
hours of incubation with DKA-associated concentrations of BHB, glucose, and iron,
augmenting the ability of R. oryzae to invade and subsequently damage endothelial
cells in vitro. BHB exposure also increased fungal growth and attenuated R.
oryzae neutrophil-mediated damage. Further, mice given BHB developed clinical
acidosis and became extremely susceptible to mucormycosis, but not aspergillosis,
while sodium bicarbonate reversed this susceptibility. BHB-related acidosis
exerted a direct effect on both GRP78 and CotH expression, an effect not seen
with lactic acidosis. However, BHB also indirectly compromised the ability of
transferrin to chelate iron, as iron chelation combined with sodium bicarbonate
completely protected endothelial cells from Rhizopus-mediated invasion and
damage. Our results dissect the pathogenesis of mucormycosis during ketoacidosis
and reinforce the importance of careful metabolic control of the acidosis to
prevent and manage this infection.
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