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Inhibitory Siglec-sialic acid interactions in balancing immunological activation and tolerance during viral infections.

ABSTRACT: Siglecs are a family of emerging glyco-immune checkpoints. Inhibiting them can enhance the functions of several types of immune cells, whereas engaging them can reduce hyper-inflammation and hyper-activation of immune functions. Siglec-sialoglycan interactions play an important role in modulating immunological functions during cancer, however, their roles in regulating immunological equilibrium during viral infections is less clear. In this review, we discuss the documented and potential roles of inhibitory Siglecs in balancing immune activation and tolerance during viral infections and consider how this balance could affect both the desired anti-viral immunological functions and the unwanted hyper- or chronic inflammation. Finally, we discuss the opportunities to target the Siglec immunological switches to reach an immunological balance during viral infections: inhibiting specific Siglec-sialoglycan interactions when maximum anti-viral immune responses are needed, or inducing other interactions when preventing excessive inflammation or reducing chronic immune activation are the goals.

SUBMITTER: Saini P

PROVIDER: S-EPMC9663867 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Inhibitory Siglec-sialic acid interactions in balancing immunological activation and tolerance during viral infections.

Saini Pratima P Adeniji Opeyemi S OS Abdel-Mohsen Mohamed M

EBioMedicine 20221110

Siglecs are a family of emerging glyco-immune checkpoints. Inhibiting them can enhance the functions of several types of immune cells, whereas engaging them can reduce hyper-inflammation and hyper-activation of immune functions. Siglec-sialoglycan interactions play an important role in modulating immunological functions during cancer, however, their roles in regulating immunological equilibrium during viral infections is less clear. In this review, we discuss the documented and potential roles o ...[more]

PMID: 36371982

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Project description:Pseudomonas aeruginosa (PA) is commonly associated with nosocomial and chronic infections of lungs. We have earlier demonstrated that an acidic sugar, sialic acid, is present in PA which is recognized and bound by sialic acid binding immunoglobulin type lectins (siglecs) expressed on neutrophils. Here, we have tried to gain a detailed insight into the immunosuppressive role of sialic acid-siglec interactions in macrophage-mediated clearance of sialylated PA (PA+Sia). We have demonstrated that PA+Sia shows enhanced binding (~1.5-fold) to macrophages due to additional interactions between sialic acids and siglec-E and exhibited more phagocytosis. However, internalization of PA+Sia is associated with a reduction in respiratory burst and increase in anti-inflammatory cytokines secretion which is reversed upon desialylation of the bacteria. Phagocytosis of PA+Sia is also associated with reduced intracellular calcium ion concentrations and altered calcium-dependent signaling which negatively affects phagosome maturation. Consequently, although more PA+Sia was localized in early phagosomes (Rab5 compartment), only fewer bacteria reach into the late phagosomal compartment (Rab7). Possibly, this leads to reduced phagosome lysosome fusion where reduced numbers of PA+Sia are trafficked into lysosomes, compared to PA-Sia. Thus, internalized PA+Sia remain viable and replicates intracellularly in macrophages. We have also demonstrated that such siglec-E-sialic acid interaction recruited SHP-1/SHP-2 phosphatases which modulate MAPK and NF-κB signaling pathways. Disrupting sialic acid-siglec-E interaction by silencing siglec-E in macrophages results in improved bactericidal response against PA+Sia characterized by robust respiratory burst, enhanced intracellular calcium levels and nuclear translocation of p65 component of NF-κB complex leading to increased pro-inflammatory cytokine secretion. Taken together, we have identified that sialic acid-siglec-E interactions is another pathway utilized by PA in order to suppress macrophage antimicrobial responses and inhibit phagosome maturation, thereby persisting as an intracellular pathogen in macrophages.

Dataset Information

Inhibitory Siglec-sialic acid interactions in balancing immunological activation and tolerance during viral infections.

Publications

Inhibitory Siglec-sialic acid interactions in balancing immunological activation and tolerance during viral infections.

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