A Mutant Vesicular Stomatitis Virus with Reduced Cytotoxicity and Enhanced Anterograde Trans-synaptic Efficiency

Kuang, Lin; Zhong, Xin; Ying, Min; Li, Lei; Tao, Sijue; Zhu, Xutao; He, Xiaobin; Xu, Fuqiang

doi:10.21203/rs.2.21708/v1

Cited by 3 publications

(4 citation statements)

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“…MSR1 can be selectively and highly upregulated in the spinal cord following VSV infection. Given that VSV and its pseudotyped viruses have been widely applied to vaccine research and oncolytic therapy (33)(34)(35), it seems plausible to improve VSV-mediated oncolytic efficacy by manipulating MSR1 expression.…”

Section: Discussionmentioning

confidence: 99%

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system

Yang

Lin

Harrison

et al. 2020

Preprint

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21Macrophage scavenger receptor 1 (MSR1) plays an important role in host defense to bacterial 22 infections, M2 macrophage polarization and lipid homeostasis. However, its physiological 23 function in viral pathogenesis remains poorly defined. Herein, we report that MSR1 24 facilitates vesicular stomatitis virus (VSV) infection in the spinal cord. Msr1-deficient 25 (Msr1 -/-) mice presented reduced morbidity and mortality following lethal VSV infection, 26 along with normal viremia and antiviral innate immune responses, compared to Msr1 +/-27 littermates and wild-type mice. Msr1 expression was selectively upregulated in the spinal 28 cord, which was the predominant target of VSV infection. The viral load in the spinal cord 29 was positively correlated with Msr1 expression level and was reduced in Msr1 -/mice.30Through its extracellular domain, MSR1 interacted with VSV surface glycoprotein and 31 facilitated its cellular entry. In conclusion, our results demonstrate that MSR1 serves as a 32 cellular entry receptor for VSV and facilitates its infection specifically in the spinal cord. 33 Key words: vesicular stomatitis virus, MSR1, scavenger receptor. 34 35 36 37 38 39 40 41 3 42 Author Summary 43 As a member of Class A scavenger receptors, macrophage scavenger receptor 1 (MSR1), 44 recognizes various ligands including oxidized low-density lipoproteins (oxLDL), viruses and 45 bacterial lipopolysaccharide (LPS), therefore performs many functions in tissue homeostasis 46 and innate immunity, including pathogen clearance, lipid metabolism, macrophage 47 polarization, and pro-or anti-inflammatory responses in different disease conditions. 48 However, the physiological function of MSR1 during viral infection remains poorly 49 understood. Vesicular stomatitis virus (VSV) is a negative-sense, single-stranded RNA virus, 50 which is common in livestock (e.g. cattle, horses and swine) and produces significant 51 economic losses. VSV is also widely used as an important model virus for fundamental 52 research and vaccine development. But, the mechanism underlying VSV neurotropism is 53 largely unknown. We herein report that MSR1 serves as a cellular receptor facilitating VSV 54 infection specifically in the central nervous system. We demonstrated that MSR1 interacted 55 with VSV virions through its extracellular domain binding to VSV-G protein, and 56 overexpression of the extracellular domain alone was sufficient to promote VSV infection. 57 Our results reveal a novel function for Msr1 as a critical determinant of VSV infection 58 specifically in the spinal cord.59 60 61 62 63 4 64 Introduction 65 Macrophage scavenger receptor 1 (MSR1; also known as CD204, SCARA1 and SR-A1), a 66 member of Class A scavenger receptors, performs many functions in homeostasis and 67 immunity, including pathogen clearance, lipid metabolism and macrophage polarization [1]. 68 MSR1 recognizes a wide range of ligands including oxidized low-density lipoprotein 69 (oxLDL), endogenous proteins, beta-amyloid, lipoteichoic acid (LTA) and bacterial 70 ...

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Section: Discussionmentioning

confidence: 99%

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system

Yang

Lin

Harrison

et al. 2020

Preprint

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“…Compared to the well-developed retrograde tracers, the development of anterograde transneuronal tracers lags behind [ 41 ]. There are only a few choices available for anterograde transneuronal tracing, including AAV [ 42 ], vesicular stomatitis virus (VSV) [ 43 , 44 ], and HSV-1 strain H129 [ 45 , 46 , 47 ]. Although traditionally considered as a non-transmittable tracer, high concentrations of recombinant AAV1 and AAV9 were shown to be able to transport anterogradely in the axon and spread to the post-synaptic neurons, thus serving as an anterograde transneuronal tracer [ 42 ].…”

Section: Viral Tracersmentioning

confidence: 99%

“…VSV pseudotyped with G protein of lymphocytic choriomeningitis virus (LMCV) was reported to spread anterogradely, but it was later found to be due to potential contamination [ 43 ]. Recently, Lin et al reported VSV-NR7A, a recombinant VSV with N gene mutation, as an anterograde tracer with low toxicity [ 44 ], which still requires more time and data to confirm.…”

Section: Viral Tracersmentioning

confidence: 99%

Anterograde Neuronal Circuit Tracers Derived from Herpes Simplex Virus 1: Development, Application, and Perspectives

Liu

Hong

Xiong

et al. 2020

IJMS

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Herpes simplex virus type 1 (HSV-1) has great potential to be applied as a viral tool for gene delivery or oncolysis. The broad infection tropism of HSV-1 makes it a suitable tool for targeting many different cell types, and its 150 kb double-stranded DNA genome provides great capacity for exogenous genes. Moreover, the features of neuron infection and neuron-to-neuron spread also offer special value to neuroscience. HSV-1 strain H129, with its predominant anterograde transneuronal transmission, represents one of the most promising anterograde neuronal circuit tracers to map output neuronal pathways. Decades of development have greatly expanded the H129-derived anterograde tracing toolbox, including polysynaptic and monosynaptic tracers with various fluorescent protein labeling. These tracers have been applied to neuroanatomical studies, and have contributed to revealing multiple important neuronal circuits. However, current H129-derived tracers retain intrinsic drawbacks that limit their broad application, such as yet-to-be improved labeling intensity, potential nonspecific retrograde labeling, and high toxicity. The biological complexity of HSV-1 and its insufficiently characterized virological properties have caused difficulties in its improvement and optimization as a viral tool. In this review, we focus on the current H129-derived viral tracers and highlight strategies in which future technological development can advance its use as a tool.

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“…Analyzing the connection of brain neural networks, including input and output neural pathways, is the basis to reveal the principle of the brain function and elucidate the mechanism of brain diseases [1]. Structural and functional studies of brain connection require anterograde and retrograde viral tracers [2][3][4][5]. The retrograde trans-monosynaptic technology based on rabies virus SAD-B19 strain can label the input network of specific types of neurons [6,7], which has been used to solve a large number of neuroscience problems and has been widely popularized and applied in the field of neuroscience [8,9].…”

Section: Introductionmentioning

confidence: 99%

Improved production and expanded application of CVS-N2c-ΔG virus for retrograde tracing

Kuang

Li²,

Ma³

et al. 2022

Preprint

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Neurotropic virus tracers, particularly those with low toxicity and high efficient tracing, are powerful tools for structural and functional dissections of neural circuits. The retrograde trans-mono-synaptic technology based on rabies virus CVS-N2c strain has reduced cytotoxicity and enhanced efficiency, attains long-term gene manipulation for functional studies, but suffers from difficult preparation and low yield. To overcome these shortcomings, an improved production system was established for rapid rescue and preparation of CVS-N2c-ΔG virus, CVS-N2c-ΔG with the same titer as SAD-B19-ΔG can be prepared within a short time. Meanwhile, we found that N2cG coated CVS-N2c-ΔG allows efficient retrograde access to projection neurons, and further expand its application in VTA/SNc to DLS pathway that unaddressed by rAAV9-Retro, and the efficiency is 6 folds higher than that of rAAV9-Retro. Then the trans-synaptic efficiency of CVS-N2c-ΔG virus was evaluated. Results showed that the trans-mono-synaptic efficiency of oG-mediated CVS-N2c-ΔG was 2-3 folds higher than that of oG-mediated SAD-B19-ΔG, but there was no difference between oG-mediated and N2cG-mediated CVS-N2c-ΔG system. In addition, codon modified N2cG (optiG) did not increase the efficiency of CVS-N2c-ΔG tracing. Finally, we found that the CVS-N2c-ΔG produced by the improved method can be used for monitoring neural activity of projection neurons, and the time window can be maintained for 3 weeks, and it can also express sufficient recombinases for efficient transgene recombination. That is, the virus produced by the improved production system does not affect its own function, paving the way for its further optimization, popularization and application in structural and functional studies of neural circuits.

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A Mutant Vesicular Stomatitis Virus with Reduced Cytotoxicity and Enhanced Anterograde Trans-synaptic Efficiency

Cited by 3 publications

References 28 publications

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system

Anterograde Neuronal Circuit Tracers Derived from Herpes Simplex Virus 1: Development, Application, and Perspectives

Improved production and expanded application of CVS-N2c-ΔG virus for retrograde tracing

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