Clinical & Medical Biochemistry

Virus Engineered Immune Circuit Possibly Gates Neuro-Excitability Outcomes in Brains

Priyanka Mishra^1,2* and Frederic Pio^{2 1}Department of Biology, University of Texas, Texas, USA
²Department of Molecular Biology and Biochemistry, Simon Fraser University, Columbia, Canada
^*Correspondence: Priyanka Mishra, Department of Biology, University of Texas, Texas, USA, Email:

Received: 11-Aug-2020, Manuscript No. CMBO-24-5986; Editor assigned: 14-Aug-2020, Pre QC No. CMBO-24-5986 (PQ); Reviewed: 28-Aug-2020, QC No. CMBO-24-5986; Revised: 15-Jul-2024, Manuscript No. CMBO-24-5986 (R); Published: 12-Aug-2024, DOI: 10.35841/2471-2663.24.10.223

Introduction

The increasing interest to identify the key features of the gutbrain axis signals a striking hypothesis connecting viral infectionchange in microbial diversity and behavior outcomes that plausibly acts through the neurotransmitter modulation. To understand this association in our lab, a proof-of-concept study using the worm-virus model system C. elegans. Orsay virus revealed an eye-opening clue to the virus’s likely role behind this mechanism in worms. However, the question remains how virus reengineers the immune circuit through gut microbiota to bring potential outcomes in brain behavior [1].

The nematode C. elegans is a living animal model with a gene complement that is remarkably conserved in vertebrates (38% with human). The worm biology is much less complex than that of higher level vertebrates and the developmental systems, organ types and tissue-specific genes are being studied extensively. Since this organism is optically transparent, molecular candidates can be easily labeled with fluorescence and thus the influence of the viral infection can be directly observed in the body and behavior of the worms [2]. Discovered almost a decade ago, Orsay virus is the only known virus capable of naturally infecting the model organism C. elegans.

Description

Orsay is a bipartite positive-sense single stranded RNA virus related to family Nodaviridae that expresses a total of four polypeptides, including an RNA-dependent RNA Polymerase (RdRP), a Capsid Protein-alpha (CP-α), a non-structural protein delta (δ) and a fusion protein capsid-delta (CP-δ/α-δ) produced by ribosomal frameshift [3]. The Orsay virus infection in C. elegans initiates a variety of abnormalities, including intestinal damages. While the functions of RdRP in viral transcription and replication, CP-α role during virus maturation, CP-δ likely function during the virus infection are well recognized; potential characterization of CPs during Orsay infection in the worm remains to be explored [4]. Towards this effort, an approach socalled PROtein FEeding in C. elegans (PROFECE), a not yet available experimental system developed in our lab that can deliver any recombinant protein of interest directly to the worm gut through genetically engineered microbiota environment as a food source, allowed us to investigate the undocumented functions if any of viral capsid proteins to host response in worms [5]. However, since C. elegans feeds on Escherichia coli (E. coli) OP50; engineered bacterial lawn expressing recombinant viral proteins were used as a food source to deliver them to the worm gut and survival and behavioral assays by assessing worm mobility were performed. Our approach considers the bacterial lawn of C. elegans not only as a food source, but also as a genetically engineered microbiota environment to study hostpathogen interaction in the gut of the nematode. The results show that worm fed with protein α-δ survived longer while δ contributes to worm intestinal defects. Morphological analysis in the gut of the worm suggests that protein α limits food absorption in the intestine while α-δ plays a role in food digestion. Moreover, experiments tracking worm mobility showed hyperactive behavior [6]. This indicates that Orsay virus capsid proteins extend life span and causes a hyperactive behavior in C. elegans in response to capsid protein ingestion. It offers a convincing and novel finding showing that viral proteins can affect behavior and lifespan through gut interactions and play an important role in virus pathogenicity as virulent factors. Our interpretation is that viral proteins plausibly affect the serotonin level in the worm gut by dysregulating one of the routes of serotonin biosynthesis, which yet requires to be quantified experimentally [7]. Pertinent to this, a study has also shown that virus infection in C. elegans shifts the microbiota in the gut of the nematode. Since Orsay in C. elegans alters gut bacterial composition and dysregulation of the kynurenine pathway affects behavior and lifespan in a similar manner as are shown in our study, our future hypothesis it that Orsay virus, possibly through microbiota shift, alters the production of serotonin or kynurenine, which induces behavioral modifications. But there is no information available on how virus governs this behavioral change and are currently under thoroughgoing investigation in our lab. However, in our study, comparative modeling of capsid proteins shows that viral protein delta has a high degree of structural similarity with the ratelimiting enzyme (TDO-2) of the kynurenine pathway. Since TDO-2 controls serotonin production and produces metabolites causing brain excitability, it is also plausible that δ mimics and/ or interferes with the host TDO-2 activity. Chiming this information may allow us to develop a novel system in C. elegans to study the virus-gut-brain axis and further unravel the molecular mechanism by which virus modulates host gut microbiota or target intestinal cells to increase those metabolites products and to assess the contribution of the neurotransmitter serotonin in this change of behavior [8].

Conclusion

Hyperactivity after viral infection has been previously reported to occur in many other virus-human systems, including HIV and Zika, but this is the first time that this behavior is reported in C. elegans. Given that C. elegans gene repertoire is very similar to humans and since this change of behavior induced by viruses has been observed in other vertebrates and human, it suggests an evolutionarily conserved mechanism to evade the host immune system. With more information is becoming available on the pathogenesis of virus and the associated immune response, significant gaps remain in our understanding of the impact of virus on the nervous system. Impending findings from this continuing work in our lab, would perhaps gate the onset of many neuro-behavioral disorders triggered by an initial viral infection creating neuronal damage being increasingly reported yet with limited knowledge, including the much debated hot research’s in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID19, that endorses the neuro-invasive and neuro-inflammatory capacity of virus with devastating consequences of neurological and neuropsychiatric complications in patients.

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