Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis
Teclegiorgis Gebremariam, … , Scott G. Filler, Ashraf S. Ibrahim
Teclegiorgis Gebremariam, … , Scott G. Filler, Ashraf S. Ibrahim
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2280-2294. https://doi.org/10.1172/JCI82744.
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Research Article Infectious disease

Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis

Abstract

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 β-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.

Authors

Teclegiorgis Gebremariam, Lin Lin, Mingfu Liu, Dimitrios P. Kontoyiannis, Samuel French, John E. Edwards Jr., Scott G. Filler, Ashraf S. Ibrahim

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Figure 6

BHB augments growth of R. oryzae and attenuates neutrophil functions.

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BHB augments growth of R. oryzae and attenuates neutrophil functions. (...
(A) R. oryzae spores (5 × 105/ml) were grown in RPMI-1640 without phenol red supplemented with 10 mM BHB, 26 mM NaHCO3, or both, which resulted in modulation of the media pH. (B) Growth of R. oryzae was measured spectrophotometrically at 600 nm over time (n = 12 for each time point per each group). (C) R. oryzae spores (105 per 10 μl) were plated on RPMI-1640 without phenol red supplemented with BHB or BHB + NaHCO3 agar plates (n = 12 per arm), and the diameter of the colony was measured 24 hours after incubation at 37°C. (D) The effects of BHB or BHB + NaHCO3 on human neutrophil inhibition of R. oryzae (1:10, effector/target ratio) were analyzed using XTT assay (n = 4 per arm). (E) The effects of BHB or BHB + NaHCO3 on the ability of human neutrophils to produce ROS were analyzed using flow cytometry after addition of DHR123. *P < 0.015 vs. all other groups; **P < 0.001 vs. all other groups; ‡P < 0.002 vs. all other groups; #P < 0.05 vs. the 2 other treatments.