The Glucose Sensor-Like Protein Hxs1 Is a High-Affinity Glucose Transporter and Required for Virulence in Cryptococcus neoformans

Abstract

Cryptococcus is a major fungal pathogen that frequently causes systemic infection in patients with compromised immunity. Glucose, an important signal molecule and the preferred carbon source for Cryptococcus, plays a critical role in fungal development and virulence. Cryptococcus contains more than 50 genes sharing high sequence homology with hexose transporters in Saccharomyces cerevisiae. However, there is no report on their function in glucose sensing or transport. In this study, we investigated two hexose transporter-like proteins (Hxs1 and Hxs2) in Cryptococcus that share the highest sequence identity with the glucose sensors Snf3 and Rgt2 in S. cerevisiae. The expression of HXS1 is repressed by high glucose, while the HXS2 expression is not regulated by glucose. Functional studies showed that Hxs1 is required for fungal resistance to oxidative stress and fungal virulence. The hxs1Δ mutant exhibited a significant reduction in glucose uptake activity, indicating that Hxs1 is required for glucose uptake. Heterologous expression of Cryptococcus HXS1 rendered the S. cerevisiae mutant lacking all 20 hexose transporters a high glucose uptake activity, demonstrating that Hxs1 functions as a glucose transporter. Heterologous expression of HXS1 in the snf3Δ rgt2Δ double mutant did not complement its growth in YPD medium containing the respiration inhibitor antimycin A, suggesting that Hxs1 may not function as a glucose sensor. Taken together, our results demonstrate that Hxs1 is a high-affinity glucose transporter and required for fungal virulence.

Amino Acid Permeases and Virulence in Cryptococcus neoformans

“…Aap4 and Aap5 are necessary during thermal and oxidative stress, consistent with the role of both physiological responses in host invasion and virulence. Other nutrient transporters, such as glucose, ammonium and iron transporters, have been studied in pathogenic fungi and shown to affect fitness, in vitro survival and to attenuate virulence in some cases [ 8 , 68 – 70 ]. A previous report related the same effects for the glucose transporter in C .…”

“…A previous report related the same effects for the glucose transporter in C . neoformans [ 68 ]. To our knowledge, this is the first time that amino acid transport is reported as important for in vivo virulence in an opportunistic pathogen that affects humans.…”

SNF3 as High Affinity Glucose Sensor and Its Function in Supporting the Viability of Candida glabrata under Glucose-Limited Environment

“…In addition, the loss of Hgt4 also affects the ability of C. albicans to perform the yeast-hyphal morphological switch and therefore compromises its pathogenicity in mouse model of disseminated candidiasis (Brown et al, 2006 ). Apart from that, the ability to transport glucose by Cryptococcus neoformans is also diminished with the loss of Hxs1, a high affinity glucose sensor-like protein (Liu et al, 2013 ). The diminished glucose uptake activity leads to an attenuated strain of C. neoformans in which the strain demonstrated a delay in lethal infection in mice model.…”

Correlation between the invasive fungal infection among and their blood glucose levels

“…Stress can promote the release of various inflammatory factors, such as large quantities of TNF-IL-1 and IL-6 with insulin resistance, leading to the formation of hyperglycemia, which can weaken the defense response of the body, reduce the chemotaxis and phagocytosis of polymorphonuclear leukocytes, and ultimately increase the incidence of infection. The resulting infection can further aggravate the symptoms of stress hyperglycemia, forming a vicious circle and producing poor prognosis [7]. (2) Improved BGL is beneficial for the expression of activated B or T cells, the establishment and maintenance of the immune system, and the reduction of nosocomial infections by accelerating recovery from inflammations.…”