Surface Glycans Regulate Salmonella Infection-Dependent Directional Switch in Macrophage Galvanotaxis Independent of NanH.

Salmonella invades and disrupts gut epithelium integrity, creating an infection-generated electric field that can drive directional migration of macrophages, a process called galvanotaxis. Phagocytosis of bacteria reverses the direction of macrophage galvanotaxis, implicating a bioelectrical mechanism to initiate life-threatening disseminations. The force that drives direction reversal of macrophage galvanotaxis is not understood. One hypothesis is that Salmonella can alter the electrical properties of the macrophages by modifying host cell surface glycan composition, which is supported by the fact that cleavage of surface-exposed sialic acids with a bacterial neuraminidase severely impairs macrophage galvanotaxis, as well as phagocytosis. Here, we utilize N-glycan profiling by nanoLC-chip QTOF mass cytometry to characterize the bacterial neuraminidase-associated compositional shift of the macrophage glycocalyx, which revealed a decrease in sialylated and an increase in fucosylated and high mannose structures. The Salmonella nanH gene, encoding a putative neuraminidase, is required for invasion and internalization in a human colonic epithelial cell infection model. To determine whether NanH is required for the Salmonella infection-dependent direction reversal, we constructed and characterized a nanH deletion mutant and found that NanH is partially required for Salmonella infection in primary murine macrophages. However, compared to wild type Salmonella, infection with the nanH mutant only marginally reduced the cathode-oriented macrophage galvonotaxis, without canceling direction reversal. Together, these findings strongly suggest that while neuraminidase-mediated N-glycan modification impaired both macrophage phagocytosis and galvanotaxis, yet to be defined mechanisms other than NanH may play a more important role in bioelectrical control of macrophage trafficking, which potentially triggers dissemination.

Immune profiling of lupus miliaris disseminatus faciei and successful management with anti-tumour necrosis factor therapy.

Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory dermatosis of unknown aetiology, most often seen in young adults. Although many treatments for LMDF exist, treatment guidelines have not been developed, and response to therapy is generally unpredictable. We present the results of transcriptomic analysis of LMDF lesional skin, which revealed a variety of differentially expressed genes linking LMDF to alterations in innate and adaptive T helper 1 immunity. Immunohistochemical analysis was also performed, identifying similar changes in T-cell immune responses. Given evidence for increased tumour necrosis factor (TNF) pathway activity, our patient, who had previously been refractory to multiple treatments, was initiated on TNF inhibitor therapy with excellent response. This characterization of the LMDF immune response may lead to improved treatment of this condition.