Application of Plant Viruses

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1		Srividhya Venkataraman	--	2658	2022-11-03 15:53:58	\|
2	format	Jason Zhu	-3 word(s)	2655	2022-11-04 02:22:56	\|

This entry is adapted from the peer-reviewed paper 10.3390/v13091697

Plant-based nanotechnology programs using virus-like particles (VLPs) and virus nanoparticles (VNPs) are emerging platforms that are increasingly used for a variety of applications in biotechnology and medicine. Tobacco mosaic virus (TMV) and potato virus X (PVX), by virtue of having high aspect ratios, make ideal platforms for drug delivery. TMV and PVX both possess rod-shaped structures and single-stranded RNA genomes encapsidated by their respective capsid proteins and have shown great promise as drug delivery systems. Cowpea mosaic virus (CPMV) has an icosahedral structure, and thus brings unique benefits as a nanoparticle.

expression vectors aspect ratio VLPs VNPs TMV

1. Molecular Characteristics of Tobacco Mosaic Virus (TMV) Advantageous for Biotechnological Use

TMV was initially characterized in the 19th century and has since become a paradigm for the current perspective on the morphogenesis of self-assembling viral particle structures ^[1]. TMV is the most well-studied plant virus, and it is also the most important plant virus both scientifically and economically ^[2]^[3]. In recent times, this knowledge has been translated toward the generation of novel compounds and structures that could be used in nanotechnology and medicine. TMV can be easily produced and purified in bulk amounts, and therefore has become of tremendous importance in molecular biology and virology ^[4]. TMV has been used to detect translational enhancers for the augmented expression of heterologous genes ^[5]^[6], and for the design of effective vectors for virus-induced gene silencing and transient expression in plant systems ^[7], as well as for creating virus-resistant plant lines ^[8]^[9].

TMV is also simple and well-characterized with respect to particle structure and genome organization. Thus, it is well suited as a highly amenable experimental system for different applications. The rod-shaped virus particle measures 300 nm in length and 18 nm in diameter, and contains a 6.7 kb viral RNA genome that is encapsidated by 2130 identical copies of the capsid protein assembled in a helical arrangement. The crystal structure of the 158 amino acid capsid protein has been determined ^[10]. The genomic RNA contains a stretch of 432 nucleotide bases that forms the origin-of-assembly sequence (OAS) sufficient for viral assembly ^[11]. At neutral pH and without its RNA, the coat protein (CP) assembles itself into an 18 nm double disk, a 20S aggregate or nano-ring containing two layers of 17 CP molecules which can serve as a nanoscale scaffold. The amino acid sequence of the CP has many accessible regions for chemical modifications both at the inner and outer surfaces ^[2]. TMV can also assemble into spherical nanoparticles of 100–800 nm, in the absence of its RNA genome, by thermal processing ^[12]. Moreover, the TMV RNA genome can self-assemble with its purified CP in vitro to generate infectious virus particles ^[13], in addition to its ability to self-assemble in vivo. Therefore, TMV has become a model system for RNA-protein recognition.

Different strategies can be used to modify TMV, such as the modification of the interior or exterior surface of the capsid through genetic engineering, chemical conjugation, or a combination of both processes. The interaction and transport of heterologous cargo within the virus inner cavity or generation of multivalent structures by particle integration have thus been adopted. The conformation of the TMV CP facilitates the insertion of foreign peptides at both its N- and C-termini. In addition to this, the loop formed from CP amino acids 59–66 can be used towards surface display of foreign peptides on intact virions or on CP assemblies ^[14].

2. The Use of Genetically Engineered TMV in Biochemistry, Nanotechnology, and Plant Biotechnology

The location of C-terminus of the TMV CP on the exterior surface of assembled TMV virions makes it the most used site for insertion of foreign peptides.

TMV particles have been exploited for active enzyme display, with wide-ranging uses in biodetection, sensor development, medicine, and enzymatic conversion. Enzymes such as penicillinase ^[15]^[16], horseradish peroxidase ^[17], and glucose oxidase ^[18] have been expressed on the TMV surface, as TMV exhibits a strong stabilizing effect on these enzymes. TMV adapter rods have been incorporated on sensor surfaces, which have facilitated bioaffinity-derived presentation of streptavidin conjugates of the above enzymes at surface densities that are not attainable on supports free of TMV. Enhanced reusability and augmented target detection ranges of these high-performance TMV-based biosensors have been reported and present great promise for multiple applications.

TMV membranes have been engineered that could be recruited as tissue engineering frameworks by sequentially altered layering of two TMV variants with different charges. Recently, these TMV-based carrier templates have been used to prepare surfaces that promote cellular attachment and differentiation ^[19]^[20]^[21].

Some cells have been cultivated on TMV-covered culture supports and peptide ligands have been presented in a spatially defined manner over nanometric scales. Arginine–glycine–aspartic acid peptide associated TMV layers have been used for osteogenesis of stem cells from bone marrow ^[20]^[21]. TMV has been employed as a carrier for peptide motifs and is capable of cell-binding that simulates extracellular matrix proteins. TMV-derived nanorod fibers synthesized from complexation with electrospun composite polymers have been used to generate mats for better handling ^[22].

Transgenic plants expressing TMV CP were generated by Powell Abel et al. (1986) ^[9]. These plants showed resistance to TMV challenge and, as a result, initiated the theory of “capsid protein-induced resistance” ^[23]. TMV has also been used to engineer virus-induced gene silencing (VIGS) systems for Colletotrichum acutatum, a phytopathogenic fungus which proved to efficiently assemble virus particles inside hyphal cells ^[24].

3. The Use of TMV in Medicine, Cancer, Imaging, and Theranostics

TMV disks have a flat and round morphology that yields a high aspect ratio. TMV particles, by virtue of their flexuous rod-like structures, marginate toward blood vessel walls, enhancing the likelihood of invading diseased areas of the body, while accumulating inside tumor tissues ^[25]^[26]. In contrast to their spherical equivalents, the helical virus derived VLPs and VNPs transit more efficiently through tissues and membranes ^[27]. As compared with VLPs, VNPs are more effective because their RNA genome cargo functions as a ruler to define the length of the nucleoprotein–virus complex. In addition, the surface characteristics of these viruses can be altered by means of genetic or chemical approaches without compromising virus structural integrity. Consequentially, the positions of functional units such as drugs, contrast agents, or targeting ligands can be spatially controlled which enables the engineering of multifunctional systems that harbor different combinations of these moieties ^[28].

Molecular imaging is an emerging biomedical field which facilitates the visualization, identification, and evaluation of biological mechanisms in vivo. Some of these imaging technologies include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and optical imaging, which enable the monitoring of molecular and cellular processes in normal and diseased conditions in living subjects. Ideally, a given molecular imaging technique should readily afford optimal signal-to-noise ratios within the target site while minimizing toxicity ^[29].

VLPs are more beneficial for molecular imaging technologies than synthetic nanoparticles, due to their short half-life in circulation and their low retention times, which thus reduce probable side effects ^[30]. Furthermore, VLPs can be developed to carry a wide array of contrast agents and fluorescent labels, as they can be modified with antibodies, peptides, and aptamers to enable enhanced targeting to specific tissues and cells.

TMV has been successfully used for imaging, targeting atherosclerosis, and thrombosis ^[31]. Cargo mRNA encoding the green fluorescent protein (GFP) was encapsulated within TMV, which when administered into mice, elicited an immune response against GFP. This provided a proof-of-concept that this technology can be utilized for vaccine development ^[32]. TMV has also been engineered to display the iLOV protein, which acts as a fluorescent probe ^[33]. TMV has also been used in theranostics (drugs and/or techniques combined to both diagnose and treat medical conditions), for enabling photoacoustic imaging and MRI capabilities to photothermal therapy (PTT) treatment.

4. Molecular Characteristics of PVX Advantageous for Biotechnological Use

PVX is a single-stranded, positive-sense RNA virus with a flexuous rod-like morphology. The PVX genome is 6430 bases in length ^[34] and contains a 5′ cap structure and 3′ poly-A tail. There are five open reading frames (ORFs) encoding the ORF1 replicase protein for viral replication, the ORF 2, 3, and 4 triple gene block (TGB) proteins which mediate virus movement and the ORF5 capsid protein for encapsidation and cell-to-cell movement. Protein overexpression systems based on plant viruses are more economical and easier to implement as compared with stable transformation which is more laborious and could take protracted lengths of time ^[35], whereas infecting plants with genetically engineered viruses directly or through Agrobacterium-mediated infiltration enables easy, rapid, highly efficient transient expression of heterologous proteins. Particularly, the sequence between the TGB and the CP can be modified to clone and express foreign genes ^[36]^[37]^[38].

5. PVX as an Expression Vector and Repurposing PVX for Use in Medicine, Cancer, and Theranostics

PVX has been widely explored as an expression vector for several biopharmaceutical applications such as for antigenic epitopes displayed on the virus outer surface, as well as for expressing full-length and fusion proteins ^[39]. Virus-derived biocatalysts have been generated using filamentous PVX that was integrated with the enzyme lipase ^[40]. The major advantage of this scaffold is the ability of the PVX-lipase complex to self-replicate, unlike the equivalent synthetic systems. Such enzymes can be positioned in or on the virus capsid, thus, spatially combining several different enzymes into specific groups that can simulate metabolic cascades.

Of note is the engineering of PVX to serve various biomedical purposes. Uhde-Holzem et al. (2016) ^[41] reported genetically altered PVX which displayed Staphylococcus aureus protein A fragments on its surface, and proved to be easily functionalized with IgG to be used in biosensing plant viruses ^[42]. PVX has also been widely used in biotechnology, disease diagnostics, development of vaccines/antibodies against infectious diseases, as well as cancer research and treatment. The CP of PVX is not capable of forming VLPs on its own ^[43]^[44]. PVX nanoparticles have been shown to inhibit tumor growth in both cell lines and animal models ^[45]. They are increasingly being used for immunotherapy of tumor microenvironments.

PVX-based VLPs and VNPs are ideal tools in molecular imaging and unlike synthetic nanoparticles, they have limited half-lives in circulation as well as diminished retention times, thereby, decreasing the chances of unwanted side effects. Additional studies have reported that PVX has been conjugated to fluorescent reporters that could be applied towards theranostics, nanomedicine, and in vivo imaging ^[46]. The small fluorescent iLOV protein was expressed on PVX through genetic engineering, and the resultant engineered PVX served as a fluorescent probe which could be of potential use in vivo imaging. Shukla et al. (2018) ^[47] reportedly produced PVX VNPs that displayed mCherry or GFP on their N-termini in N. benthamiana plants. Significantly, fluorescent PVX could successfully be used for in vivo particle tracking in an HT-29 murine model, for in vitro imaging of HT-29 cells, and for tracing viral infection within plants.

6. Molecular Characteristics of CPMV Advantageous for Biotechnological Applications

CPMV is the type member of the genus Comovirus, composed of two separately encapsidated positive-strand RNAs. RNA-1 is capable of independent replication in plant cells; however, RNA-2 (encoding the viral movement and structural proteins) depends on RNA-1 for its replication. CPMV virions are icosahedral in shape and are comprised of 60 copies each of a large (L) and a small (S) coat protein ^[48].

7. Applications of Comoviruses CPMV and Cowpea Chlorotic Mottle Virus (CCMV) in Medical Biotechnology and Cancer

CPMV has been developed as an autonomously replicating virus vector for the expression of either peptides or polypeptides in plants. Examples of CPMV used as an epitope presentation system include epitopes from the outer membrane (OM) protein F of Pseudomonas aeruginosa which were shown to protect mice against bacterial challenge, and an epitope expressing the 30 amino acid D2 domain of the fibronectin-binding protein (FnBP) from Staphylococcus aureus, which has been shown to be able to protect rats against endocarditis ^[49].

In addition to the use of CPMV to present peptides, replicating and non-replicating expression vectors based on CPMV have been developed ^[50]. The non-replicating expression system is based on a disabled version of RNA-2 of CPMV. A gene of interest is positioned between the 5′ leader sequence and 3′ untranslated region (UTR) of RNA-2, and the vector is introduced to the plant via Agrobacterium-mediated transient transformation ^[51]. By deleting an in-frame initiation codon located upstream of the main translation initiation site of RNA-2, a massive increase in foreign protein accumulation has been observed. This CPMV non-replicating system generated high quality purified anti-HIV-1 antibody in plants ^[52]. The vector has also been used to express influenza vaccine proteins.

Meshcheriakova et al. (2017) compared the differences between empty virus-like particles (eVLPs) of CPMV and intact virus containing its RNA genome, for their potential use as nanoparticles ^[53]. eVLPs are noninfectious and could be loaded with heterologous material, which has increased the number of possible applications for CPMV-based particles. In addition to this, they have distinct yet overlapping immunostimulatory effects resulting from virus RNA in wild-type particles, and therefore can be used for different immunotherapeutic strategies ^[54].

As described for TMV, CPMV has been explored for its potential to block cancer ^[55]. Steinmetz et al. (2011) found that CPMV nanoparticles could bind to vimentin, a protein found on the surface of most cells ^[56]. Vimentin is upregulated during tumor progression, making it an attractive target for cancer therapy. The fact that surface vimentin expression correlated with CPMV uptake demonstrated the ability of CPMV to detect invasive cancer cells. Soon after this discovery, Lizotte et al. (2016) found that inhaled CPMV nanoparticles could be rapidly taken up by lung cancer cells in a mouse model and activated neutrophils in the tumor microenvironment to initiate an antitumor immune response ^[57]. CPMV nanoparticles also demonstrated antitumor immunity in ovarian, colon, and breast tumor models in mice.

Patel et al. (2018) used CPMV nanoparticles in conjunction with radiotherapy to delay ovarian tumor growth in a mouse model ^[58]. The treatment was able to result in an increase in tumor infiltrating lymphocytes (TILs), suggesting that this combined treatment could act as a future in situ tumor vaccine. Further studies by Wang and Steinmetz (2019) found that a protein known as CD47, which is widely expressed on tumor cells, prevents the action of T cells and phagocytic cells. The authors used a combination therapy of CD47-blocking antibodies and CPMV nanoparticles to act synergistically and elicit an antitumor immune response ^[59]. The same research group also used low doses of cyclophosphamide (CPA) and CPMV nanoparticles as a combination therapy to successfully reduce mouse tumors in vivo ^[60].

Recently, Albakri et al. (2019) explored how CPMV particles could activate human monocytes, dendritic cells (DCs), and macrophages ^[61]. Monocytes, upon incubation with CPMV in vitro, released the chemokines CXCL10, MIP-1α, and MIP-1β into cell culture supernatants. Dendritic cells and monocyte-derived macrophages also were activated after incubation with CPMV. The authors found that activation was part of SYK signaling. Shukla et al. (2020) were able to demonstrate that CPMV outperformed many other types of virus-like particles, and therefore was a particularly strong immune stimulant ^[62].

Plant VLPs based on CCMV have been employed to deliver mRNA. For example, CCMV was used to successfully deliver enhanced yellow fluorescent protein (EYFP) mRNA to mammalian BHK-21 cells, using transfection with lipofectamine. In this case, the mRNA was successfully delivered and released from the VLPs into the cytoplasm of the BHK-21 cells, facilitating EYFP expression ^[63]. Furthermore, CCMV can be used to deliver mRNA vaccines, and a proof of concept has been demonstrated with a variety of reporter genes ^[64].

There are other examples of how icosahedral VLPs can be utilized in medicine. For example, CCMV can be disassembled and reassembled to encapsulate CpG ODNs (oligodeoxynucleotides). CpG ODNs are ligands of the toll-like receptor 9 (TLR9). Upon activation, TLR9 has the capability to induce macrophages. The CpG loaded CCMV VLPs showed significantly enhanced uptake by tumor associated macrophages and inhibited the growth of solid CT26 colon cancer and B16F10 melanoma tumors in Balb/c mice via the macrophage activation ^[65].

As another example, encapsulated drug-activating enzymes within plant VLPs such as CCMV can be utilized for therapeutic purposes ^[66]. Cytochrome P450 family enzymes can convert chemotherapeutic prodrugs into an active format. Using plant VLPs to encapsulate these enzymes can reduce side effects while increasing retention and targeting to the tumor site ^[67]^[68]. CCMV has been used, for example, to encapsulate bacterial cytochrome, CYPBM3, to activate the prodrugs into activated forms of tamoxifen and resveratrol.

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Subjects: Biotechnology & Applied Microbiology

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Srividhya Venkataraman

Kathleen Hefferon

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