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Abstract
Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.
Highlights
Rabies is a zoonotic viral encephalitis responsible for 60,000 reported human deaths annually, the true burden is suspected to be much higher [1]
In this study we investigated if street rabies virus (RABV) can induce antiinflammatory pathways in human monocyte-derived macrophages (MDMs) and if interaction between RABV and macrophages can affect T cell proliferation
We demonstrate that a street RABV strain (SHBRV) has an anti-inflammatory effect on human MDMs by inducing the cholinergic anti-inflammatory pathway (CAP) through binding of RABVG to Nicotinic acetylcholine receptors (nAChr) α7, characterized by cytoplasmic retention of NFκB and a decreased tumor necrosis factor α (TNF-α) response upon LPS stimulation
Summary
Rabies is a zoonotic viral encephalitis responsible for 60,000 reported human deaths annually, the true burden is suspected to be much higher [1]. The virus is able to reach the CNS without triggering a strong local immune response [4, 5]; neither is a systemic immune response induced, as indicated by the low or absent neutralizing antibodies at the end-stage of disease of most patients [6, 7]. This lack of immune activation is caused by limited viral replication at the inoculation site [8, 9], as well as by active immune evasion and suppression, as extensively reviewed [10, 11]. Previous research identified major immune evasive mechanisms, including the blocking of RIG-I activation by the nucleoprotein (N) [12,13,14] and the IFN signal transduction pathway by the phosphoprotein (P) [15,16,17]
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