Plant-Derived Food Grade Substances (PDFGS) Active Against Respiratory Viruses: A Systematic Review of Non-clinical Studies

Abstract

Human diet comprises several classes of phytochemicals some of which are potentially active against human pathogenic viruses. This study examined available evidence that identifies existing food plants or constituents of edible foods that have been reported to inhibit viral pathogenesis of the human respiratory tract. SCOPUS and PUBMED databases were searched with keywords designed to retrieve articles that investigated the effect of plant-derived food grade substances (PDFGS) on the activities of human pathogenic viruses. Eligible studies for this review were those done on viruses that infect the human respiratory tract. Forty six (46) studies met the specified inclusion criteria from the initial 5,734 hits. The selected studies investigated the effects of different PDFGS on the infectivity, proliferation and cytotoxicity of different respiratory viruses including influenza A virus (IAV), influenza B virus (IBV), Respiratory syncytial virus (RSV), human parainfluenza virus (hPIV), Human coronavirus NL63 (HCoV-NL63), and rhinovirus (RV) in cell lines and mouse models. This review reveals that PDFGS inhibits different stages of the pathological pathways of respiratory viruses including cell entry, replication, viral release and viral-induced dysregulation of cellular homeostasis and functions. These alterations eventually lead to the reduction of virus titer, viral-induced cellular damages and improved survival of host cells. Major food constituents active against respiratory viruses include flavonoids, phenolic acids, tannins, lectins, vitamin D, curcumin, and plant glycosides such as glycyrrhizin, acteoside, geniposide, and iridoid glycosides. Herbal teas such as guava tea, green and black tea, adlay tea, cistanche tea, kuding tea, licorice extracts, and edible bird nest extracts were also effective against respiratory viruses in vitro. The authors of this review recommend an increased consumption of foods rich in these PDFGS including legumes, fruits (e.g berries, citrus), tea, fatty fish and curcumin amongst human populations with high prevalence of respiratory viral infections in order to prevent, manage and/or reduce the severity of respiratory virus infections.

Keywords: Antiviral agent; HCoV; IAV; RSV; Respiratory Tract Infection (RTI); Viral lifecyle; functional foods; polyphenols.

Figure 1

Construction of the search strategy for retrieval of literature on PDFGS with antiviral potentials.

Figure 2

PRISMA flowchart of included studies.

Figure 3

Quality assessment of included in vitro studies.

Figure 4

SYRCLE risk of bias assessment of included animal studies.

Figure 5

Effect of PDFGS on different stages of IAV lifecycle. Infective IAV enters cellular environment following exposure (1). It interacts with the sialic acid residues of host membrane glycoprotein using its HA protein (2). The virus is internalized into the cytoplasm in a clarithin-dependent and independent mechanism (3). Increased acidic ph of the endosome triggers the activation of M1, fusion of viral genome with the endosomal membrane and release of viral genome into the cytoplasm (4). The viral RNA enters the nucleus where it utilizes host enzymes and some viral proteins such as PA, PB1, PB2, and NP for replication and transcription of viral genome (5). This leads to the production of viral mRNA transcripts (6), viral full length negative sense viral RNA (7), and suppression of host mRNA and protein synthesis (8). The viral mRNA is translated with the host protein synthesis apparatus (9). Some of the synthesized viral proteins are exported to the nucleus to facilitate the transcription and replication of viral genome (10). The others are packaged alongside with viral RNA strands into infective IAV particles (11). The infective IAV buds off from the cell into extracellular spaces and perpetuate further viral infections (12). Different PDFGS as shown in the image, are able to reduce IAV cellular titer, inhibit IAV host interaction, IAV cytoplasmic release, IAV transcription and replication, IAV mRNA transcript and protein synthesis, IAV assembly, packaging, and budding. A. melanocarpa, Aronia melanocarpa; DMO-CAP, 6-demethoxy-4′-O-methylcapillarisin; EBN, edible bird nest; EGCG, Epigallocatechin gallate; G. thunbergii, Geranii thunbergii; GSP, Grape seed proanthocyanidin; HA, hemagglutinin; HA2, Fusion peptide; HS, Hibiscus sabdariffa; IAV-P, IAV polymerase; M1, Matrix protein 1; M2, matrix protein 2; NA, Neuraminidase; NP, nucleoprotein; NS1, Non-structural protein 1; NS2, Non-structural protein 2; P. oleracea, Portulaca oleracea; PA, Polymerase acidic protein; PB1, Polymerase basic protein 1; PB2, Polymerase basic protein 2; R. acetosa, Rumex acetosa; vRNP, Viral ribonucleoprotein.

Figure 6

Effect of PDFGS on different stages of RSV lifecycle. Infective RSV gets into the respiratory tract following exposure to RSV viruses (1). RSV interacts with epithelial receptor proteins such as TLR4, CX3CR1 and HSPG using its RSV-F, RSV-G, and RSV-SH proteins (2). Intact RSV enters the host cytosol in an endosome (3). RSV nucleocapsid is released into the cytoplasm (5). Replication and transcription of RSV genome takes place at the inclusion bodies leading to the production of viral mRNA transcript (6) or full length positive sense antigenomes(7) following regulatory control by RSV M2-2. The positive sense antigenome is used as a template to generate the negative sense viral genome (8). The viral mRNA transcript is translated with the host mRNA translation apparatus (9). The negative sense viral RNA genome is packaged alongside with some viral proteins and other host factors required for RSV infectivity (10) this eventually buds off (11) into the pool of infective RSV. PDFGS reduced the cellular pool of infective RSV, suppressed RSV host receptor interaction as well as inhibited RSV internalization, replication, and transcriptional activities. PDFGS also lowered the levels of RSV mRNA transcripts as well as RSV protein. 18β-GA, 18β-glycyrrhetinic acid; CX3CR1, CX3C chemokine receptor 1; GSP, Grape seed proanthocyanidin; HSPG, Heparan sulfate proteoglycan; RSV, Respiratory syncytial virus; RSV-F, RSV fusion protein; RSV-G, Glycoprotein; RSV-L, RSV RNA-dependent RNA polymerase; RSV-M2-1, RSV matrix M2-1; RSV-M2-2, RSV matrix M2-2; RSV-N, RSV nucleoprotein; RSV-NS1, RSV non-structural protein 1; RSV-NS2, RSV non-structural protein 2; RSV-P, RSV phophoprotein; RSV-SH, RSV hydrophobic protein; TLR4, Toll-like receptor 4; Z. officinale, Zingiber officinale.

Figure 7

Hypothetical mechanism of respiratory viruses-induced cellular damages. Activation of TLR receptor by viral RNA leads to the generation of localized inflammation at sites of infection. This inflammation may progress into hyper-inflammation if the virus succeeds in evading host antiviral defenses or if viral infection is prolonged. This consequently leads to the distortion of cellular homeostasis including the upregulation of wnt/b-catenin, AKT, and MAPK signaling. Persistent activation of these signaling cascade may trigger endoplasmic reticulum stress resulting in further oxidative stress and inflammation which eventually leads to tissue damages. AKT, Protein kinase B; MAPK, Mitogen-activated protein kinase; NF-κB, Nuclear factor-κB; ROS, Reactive oxygen species; TLR, Toll-like receptor.

Figure 8

Effect of PDFGS on host antiviral immune responses. Membrane resident immune receptors such as TLR senses viral RNA. This stimulates the expression of transcription factors which subsequently enhance the production of antiviral peptides and other immune mediators. Viruses induced suppression of host protein synthesis can downregulate the synthesis of antiviral immune mediator and can potentially lead to a dysfuntional cellular homeostasis. This could lead to inflammation and consequently, cause damages to tissues. PDFGS suppresses viral proteins, enhances the exepression of antiviral proteins as well as suppress virus-induced inflammations. 18β-GA, 18β-glycyrrhetinic acid; A. digitata, Adansonia digitata; AP-1, Activator protein-1; DC, Dendritic cells; DMO-CAP, 6-demethoxy-4′-O-methylcapillarisin; G. thunbergii, Geranii thunbergii; GSP, Grape seed proanthocyanidin; IAV, Influenza A virus; IAV-NS1, IAV non-structural protein 1; IAV-NS2, IAV non-structural protein 2; IAV-PA-X, transcript product of IAV polymerase; IFITM, IFN-induced transmembrane; IFN, Interferons; IL-1β, Interleukin 1β; IL-6, Interleukin 6; IL-8, Interleukin 8; IRF, Interferon regulatory factor; IRF3, Interferon regulatory factor 3; MDA-5, Melanoma differentiation-associated protein 5; MxA, Myxovirus Resistance Gene A; MxB, Myxovirus Resistance Gene B; NF-κB, Nuclear factor kappa B; NK, Natural Killer cells; OAS, 2'-5' oligoadenylate synthetase; PKR, Protein kinase R; RIG-1, Retinoic acid-inducible gene I; RNase L, Ribonuclease L; ROS, Reactive oxygen species; RSV, Respiratory syncytial virus; RV, Rhinovirus; TLR, Toll-like receptor; TNF-α, Tumor necrosis factor-α; Vit D, Vitamin D; Z. officinale, Zingiber officinale.