Human galectin-1 and galectin-3 promote Tropheryma whipplei infection

Abstract

Tropheryma whipplei , is an actinobacterium that causes different infections in humans, including Whipple’s disease. The bacterium infects and replicates in macrophages, leading to a Th2-biased immune response. Previous studies have shown that T. whipplei harbors complex surface glycoproteins with evidence of sialylation. However, the exact contribution of these glycoproteins for infection and survival remains obscure. To address this, we characterized the bacterial glycoprofile and evaluated the involvement of human β-galactoside-binding lectins, Galectin-1 (Gal-1) and Galectin-3 (Gal-3) which are highly expressed by macrophages as receptors for bacterial glycans. Tropheryma whipplei glycoproteins harbor different sugars including glucose, mannose, fucose, β-galactose and sialic acid. Mass spectrometry identification revealed that these glycoproteins were membrane- and virulence-associated glycoproteins. Most of these glycoproteins are highly sialylated and N-glycosylated while some of them are rich in poly-N-acetyllactosamine (Poly-LAcNAc) and bind Gal-1 and Gal-3. In vitro, T. whipplei modulates the expression and cellular distribution of Gal-1 and Gal-3. Although both galectins promote T. whipplei infection by enhancing bacterial cell entry, only Gal-3 is required for optimal bacterial uptake. Finally, we found that serum levels of Gal-1 and Gal-3 were altered in patients with T. whipplei infections as compared to healthy individuals, suggesting that galectins are also involved in vivo . Among T. whipplei membrane-associated proteins, poly-LacNAc rich-glycoproteins promote infection through interaction with galectins. T. whipplei modulates the expression of Gal-1 and Gal-3 both in vitro and in vivo . Drugs interfering with galectin–glycan interactions may provide new avenues for the treatment and diagnosis of T. whipplei infections.

Elevated serum galectin-1 concentrations are associated with increased risks of mortality and acute kidney injury in critically ill patients

“…Sensitivity analyses using different definitions of study exposure were also performed. Gal-1 concentrations was either presented as continuous variable; or divided by the criterion value of ROC curve, or by the Gal-1 value of reported viral [27] or bacterial [28] infection in the sensitivity analyses. To investigate the effect of Gal-1 modified by different conditions, we performed subgroup analyses with the cohort stratified by the presence of diabetes, proteinuria, initial eGFR, pneumonia, and septic shock.…”

Whipple’s disease: etiology, pathogenesis, clinic, diagnosis and treatment

“…Галектины Gal-1 прототипа (14,5 кДа) и Gal-3 химерного типа (26 кДа) высоко экспрессируются и секретируются иммунными клетками, в частности миелоидного ряда, для осуществления миграции, пролифе-рации, адгезии и передачи сигналов [24]. При БУ Gal-1 и Gal-3 связывают бактериальные гликопротеины и усиливают проникновение бактерий в клетки, а дефицит Gal-3 значительно снижает поглощение TW макрофагами [26]. Бактерия фагоцитируется макрофагами СО тонкой кишки, которые мигрируют в подслизистый слой [27].…”

Advancement of anti‐LAG‐3 in cancer therapy

“…63 Because LAG-3 receptors can offer several binding sites for Gal-3 under heady glycosylation, the LAG-3/Gal-3 interaction may have influences on tumor metastatic properties, apoptotic properties, and resistance to chemotherapy. 64,65 A few early stage clinical trials confirmed the enhancement of tumor-specific immune responses through targeting LAG-3/Gal-3 interaction, which makes LAG-3/Gal-3 axis the next promising strategy for certain cancer types. 66 However, the understanding of how LAG-3 participates in cell communication in the tumor microenvironment remains far from comprehensive.…”

“…A change in glycosylation is a hallmark of tumor progression 63 . Because LAG‐3 receptors can offer several binding sites for Gal‐3 under heady glycosylation, the LAG‐3/Gal‐3 interaction may have influences on tumor metastatic properties, apoptotic properties, and resistance to chemotherapy 64,65 . A few early stage clinical trials confirmed the enhancement of tumor‐specific immune responses through targeting LAG‐3/Gal‐3 interaction, which makes LAG‐3/Gal‐3 axis the next promising strategy for certain cancer types 66–68 …”