key: cord-0858712-cnh8ekex authors: Sagaya Jansi, R.; Khusro, Ameer; Agastian, Paul; Alfarhan, Ahmed; Al-Dhabi, Naif Abdullah; Arasu, Mariadhas Valan; Rajagopal, Rajakrishnan; Barcelo, Damia; Al-Tamimi, Amal title: Emerging paradigms of viral diseases and paramount role of natural resources as antiviral agents date: 2021-03-10 journal: Sci Total Environ DOI: 10.1016/j.scitotenv.2020.143539 sha: 17b04dab905c729f3aaefae8e0dba4d6b1aba9f6 doc_id: 858712 cord_uid: cnh8ekex In the current scenario, the increasing prevalence of diverse microbial infections as well as emergence and re-emergence of viral epidemics with high morbidity and mortality rates are major public health threat. Despite the persistent production of antiviral drugs and vaccines in the global market, viruses still remain as one of the leading causes of deadly human diseases. Effective control of viral diseases, particularly Zika virus disease, Nipah virus disease, Severe acute respiratory syndrome, Coronavirus disease, Herpes simplex virus infection, Acquired immunodeficiency syndrome, and Ebola virus disease remain promising goal amidst the mutating viral strains. Current trends in the development of antiviral drugs focus solely on testing novel drugs or repurposing drugs against potential targets of the viruses. Compared to synthetic drugs, medicines from natural resources offer less side-effect to humans and are often cost-effective in the productivity approaches. This review intends not only to emphasize on the major viral disease outbreaks in the past few decades and but also explores the potentialities of natural substances as antiviral traits to combat viral pathogens. Here, we spotlighted a comprehensive overview of antiviral components present in varied natural sources, including plants, fungi, and microorganisms in order to identify potent antiviral agents for developing alternative therapy in future. • Viral diseases with high mortality rates are major public health threat globally. • Antiviral drugs and vaccines against deadly diseases are of urgent demand. • Medicines from natural resources have shown low side-effect to human. • Plants, fungi, and microorganisms are recognized as potent antiviral agents. • Drugs from natural resources as future antiviral therapy are suggested. In the current scenario, the increasing prevalence of diverse microbial infections as well as emergence and reemergence of viral epidemics with high morbidity and mortality rates are major public health threat. Despite the persistent production of antiviral drugs and vaccines in the global market, viruses still remain as one of the leading causes of deadly human diseases. Effective control of viral diseases, particularly Zika virus disease, Nipah virus disease, Severe acute respiratory syndrome, Coronavirus disease, Herpes simplex virus infection, Acquired immunodeficiency syndrome, and Ebola virus disease remain promising goal amidst the mutating viral strains. Current trends in the development of antiviral drugs focus solely on testing novel drugs or repurposing drugs against potential targets of the viruses. Compared to synthetic drugs, medicines from natural resources offer less side-effect to humans and are often cost-effective in the productivity approaches. This review intends not only to emphasize on the major viral disease outbreaks in the past few decades and but also explores the potentialities of natural substances as antiviral traits to combat viral pathogens. Here, we spotlighted a Viral diseases are colossal threat to human and animal population. Emerging viral disease outbreaks have grown rapidly in the recent years and it has created great impact on human life, leading to the sudden increase in mortality rates. Over the past two decades, there have been seven disease epidemics that resulted in huge economic losses in the world, of which Coronavirus disease 2019 , Severe acute respiratory syndrome (SARS), Nipah virus (NIV) disease, West Nile virus disease, Avian Influenza, and Rift Valley fever are caused by viruses. Three modes of viral disease occurrence have been identified such as a) infection to a new host with no transmission, b) spread out to local populations, and c) epidemic or constant host-to-host transmission (Parrish et al., 2008) . Viruses generally consist of DNA or RNA (single/double stranded or positive/negative stranded) as their genetic material which is surrounded by a lipoprotein/glycoprotein covering. Table 1 shows the classification of selected animal viruses with DNA/RNA genomes. Viruses invade host and employ the host metabolic processes as well as generate many copies of viral proteins that produce individual virus. The viral strains eventually get adapted to the host's immune systems. Pre-vaccination was found to be more effective approach. The transmission of virus also depends on the contact of people in a population. Since the viral strains are mutated and are getting adapted, it is difficult to develop the vaccines (Alexander and Kobes, 2011) . The antiviral drugs play a very important role in today's life by suppressing the viral transmission and helps in host surviving. Analyzing and understanding the kinetics and dynamics of antiviral drugs aid in controlling the virus during pandemics because the hosts may expose to the infection again. Antivirals are effective in cases where there are no vaccines available for viruses like Influenza virus (Pepin et al., 2013) . The degree of virus infection depends on the immunity of human. The immunocompromised hosts are at higher risk of viral infection, thereby creating the situation worse for those people (Ye et al., 2013) . The drug usage should be studied properly to analyze the results. Administration of drugs is taken into consideration for predicting the dynamics during epidemic waves. The emergence of pandemic has made every country to contain stockpile of antiviral drugs. These drugs are important because studies showed that these drugs can help in controlling future pandemic. Though it might not cure it, the rate of transmission can be controlled (Becker and Wang, 2011) . Antivirals in combination with other antimicrobials help to combat resistant strains (Villa et al., 2017) . Similarly, direct acting antiviral agents (DAA) was very effective in treating hepatitis C virus (HCV) infection. The DAAs constitute a combination of simeprevir, paritaprevir, ritonavir, daclatasvir, ledipasvir, ombitasvir, sofosbuvir, and dasabuvir. The proper intake of food along with the drugs had a great effect (Talavera Pons et al., 2017) . Antiviral drugs perform targeted therapy by interacting with viruses' target proteins and the host's immune system (Thomasy and Maggs, 2016) . Despite the availability of plethora of antiviral drugs in the market, there is continuous effort by worldwide researchers to identify new therapeutic agents from un/less exploited resources. Those bioactive agents have revealed in vitro and in vivo antiviral potentialities against various groups of viruses. Bioactive agents from natural resources have established a great foundation for designing new therapeutic drugs. It is certainly essential to understand the nature, source of origin, and role of identified active agents as therapeutics. Considering this, the present comprehensive review overviews the effectiveness of antiviral components present in various natural sources (plants, fungi, and prokaryotes) in order to identify potential antiviral agents for developing alternative therapy in future. Zika virus belongs to family Flaviviridae. The virus is transmitted through the bite of infected female mosquitoes, Aedes aegypti and Aedes albopictus. Flaviviruses in human can also lead to many diseases that include West Nile, dengue, yellow fever, tick-borne, and Japanese encephalitis. The route of transmission of ZIKV is through arthropod vectors, central nervous system injury, and hemorrhagic fevers. The infection of ZIKV during pregnancy results in birth defects in new born babies, a condition called microcephaly. In adults, it leads to temporary paralysis. In Flaviviridae family, all members have enveloped virus with single stranded RNA genome and possesses 3 structural proteins envelope, capsid, precursor membrane, and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Patients in phase I and II clinical trials are vaccinated with DNA/mRNA vaccine. Symptoms of this infection include skin rashes, headache, joint pain, muscle pain, and fever. The major outbreak took place in Yap Island (2007), South America (2015 America ( -2016 , and French Polynesia (2013 . Guillian-Barre`syndrome and microcephaly are common neurological manifestations of this disease (Lin et al., 2018) . Nipah virus can be transmitted to humans from animals like bats or pigs. It can also transmit through contaminated food or directly from people to people. It was first recognized in Malaysia (1999) , the people who were in contact with sick pigs or contaminations of tissues. Transmission is through unprotective contact or secretions from pigs, and fruits contaminated with secretions of urine by infected fruit bats. Symptoms include fever, headache, myalgia, and acute encephalitis. Incubation period ranges from 4 to 14 days. The diagnosis includes reverse transcription-polymerase chain reaction (RT-PCR) from body fluids and enzyme-linked immunosorbent assay (ELISA). The fruit bats belonging to the family Pteropodidae are the host of NIV. It has also been reported in other animals such as horse, sheep, goats, cats, and dogs. It is a single stranded and non-segmented enveloped RNA virus. The NIV is second member of genus Henipavius belonging to the family Paramyxoviridae. Prevention can be done by reducing overcrowding between animals and avoiding consumption of contaminating foods (Singh et al., 2019) . Severe acute respiratory syndrome coronavirus (SARS-COV) belongs to family Coronaviride and order Nidovirales. It causes respiratory or intestinal infections in humans and animals. It is positive sense single stranded RNA virus which has genome size about 30 kb with 14 functional open reading frames (ORFs). Their genome size is larger with respect to all other RNA viruses. Symptoms of this infection include cough, chillness, myalgia, sore throat, rhinorrhea, breathlessness, and diarrhea. Serum test, RT-PCR, and ELISA are the most common tests performed for diagnosing the infected patients. There is no effective antiviral agent identified till date to control SARS-COV (Cheng et al., 2007) . Herpes genitalis is a sexually transmitted infection caused by herpes simplex virus type-1 (HSV-1) or herpes simplex virus type-2 (HSV-2). They are enveloped DNA virus. The primary mode of transmission is by direct contact. There are some similarities between HSV-1 and HSV-2 based on type of epitopes and antigenic cross reactions. HSV-1 occurs in childhood and HSV-2 occurs during sexual contact. HSV-2 is commonly seen in females. Primary infection results in papular skin, lesion in mucous membrane, swelling in inflammatory regions in vulva, and dysuria. The recurrent infection includes fever, menstruation stress, abortion, and eye lesion. The diagnosis is done by swabbing the infected mucous membrane and then analyzed using polymerase chain reaction (PCR). Another diagnosis includes antibody detection of HSV infection. Acyclovir, valacyclovir, and famciclovir are the first line drugs used for its treatment (Sauerbrei, 2016) . Measles is caused by Rubella virus. It mainly affects children and pregnant women. The virus belongs to the family Paramyxoviridae and holds single stranded negative sense RNA, encodes 6 structural proteins, and 2 non-structural proteins. Measles occurs only in humans and is transmitted by respiratory droplets, saliva, skin to skin contact, and touching contaminated surface. Incubation period of the virus is 14-18 days. Symptoms include maculopapular rashes, cough, conjunctivitis, fever, and diarrhea. Samples from throat, nasal, and urine are used for analyzing using PCR. Attenuated measles strain is used as a vaccine in the beginning stage of the infection (Kondamudi and Waymack, 2020) . Human papilloma virus disease is a sexually transmitted infection which causes cervical cancer and genital warts. Among various types of HPV, type 16 and 18 are responsible for causing cervical cancer and HPV 6 and 11 cause genital warts. It mostly affects woman and is transmitted through skin to skin contact and infects vagina or anal intercourse. Cervical cancer can be detected by papanicolaou testing; hence changes in squamous epithelium cells should be noted. The changes observed on the abnormal cells are referred as cervical intraepithelial neoplasia (CIN). Depending on the depth of the abnormal cells, it can be classified into 3 types (CIN-1, CIN-2, and CIN-3). CIN-1, CIN-2, and CIN-3 show mild, moderate, and severe dysplasia, respectively. For human papilloma virus, vaccine was developed against the type 6, 11, 16, and 18. It is prophylactic quadrivalent vaccine named gardasil. Another type of vaccine is bivalent vaccine, developed against HPV 16 and 18 (Braaten and Laufer, 2008) . AIDS is caused by human immunodeficiency virus (HIV). The virus infects the CD4+ T lymphocytes cells and results in catastrophic effect in the host. When the virus replication is increased it results in cardiovascular disease and infects other organs, resulting in kidney and liver damage. In some cases, tuberculosis plays the major role in activating the disease. Vaccines are developed using X-ray crystallography, cryo electron microscopy, and other technologies including probing the Bcell lineage and genome sequencing (Schwetz and Fauci, 2019) . Ebola virus belongs to family Filoviridae and is transmitted by fruit bats. It is transmitted by infected blood, airborne, and infection through droplet. The EVD can be diagnosed using blood samples, saliva, breast milk, semen, sweat, tears, stool, skin, vaginal, and rectal swabs. The transmission can also be oral such as by consuming uncooked animal food. The production of disease can be through tear, mucous membrane, and skin; which infects immune system and reaches lymph nodes, causing lymphadenopathy and hematogenous spread through liver and spleen resulting in failure of organs. Symptoms can be headache, dysphagia, malaise, dry cough, sore throat, nausea, vomiting, diarrhea, and conjuctival bleeding. Diagnosis is done by RT-PCR and ELISA test by the samples taken from infected persons. Currently, there is no antiviral drug for this virus (Hasan et al., 2019) . Chicken pox is caused by varicella zoster virus (VZV) which is also responsible in causing herpes zoster or shingles. It is transmitted by inhaling aerosol droplets from infected patient. Symptoms include small itchy blister that spreads over chest, back, and then spreads through face, resulting in fatigue, fever, headache, and pharyngitis lasy for seven days. It is diagnosed by PCR by the blister fluid samples. Vaccine was introduced in 1995 and it helps in the prevention of the infection (Ayoade and Kumar, 2020) . Hanta virus causes hemorrhagic fever. It is also called as hanta virus cardio pulmonary syndrome, renal syndrome, and non-pathogenic prospects hill virus. It affects the function of kidney. The virus enters the host by interacting with cell surface integrin receptors and also uses alpha 5 beta 1 receptors to enter into the cell. The infection occurs by direct contact with infected rodents and inhaling virus through lungs. Hanta virus can be differentiated into many types such as Seoul virus from domestic rat, others are black creek canal virus, bayou virus etc. Symptoms include chillness, dizziness, headache, nausea, cough, vomiting, malaise, diarrhea, back pain, abdominal pain, and tachycardia. Diagnosis is based on positive serological test, blood samples detecting viral antigen, viral RNA sequences, serological assays, immunohistochemistry, and PCR. There is no antiviral drug for hanta virus but antipyretics and analgesic are used to control the disease (Mir, 2010) . Recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family Coronaviridae. It has created a great impact throughout the world by its pathogenic nature and named COVID-19 by World Health Organization. The infection was acquired from seafood market in Wuhan, China. The genome of coronavirus consists of positive single stranded RNA of approximately 27-32 kb. The virus has Nsp1-16 (non-structural proteins) genes and others that code for four structural proteins including the envelope protein (E), membrane protein (M), spike protein (S), and the nucleocapsid protein (N) (Schoeman and Fielding, 2019) . Symptoms include cough, mild fever, breathlessness, and throat congestion. Detection of the SARS-CoV-2 can be done by RT-PCR. Although few drugs and traditional remedies have been reported to alleviate mild symptoms of COVID-19, there are no medicines or vaccines approved to cure the disease till date. Nevertheless, there are several clinical trials undertaken including antibiotics, vaccines, and natural products proposed for treatment purpose (Bimonte et al., 2020) . Dengue and dengue hemorrhagic fever are caused by the virus that belongs to Flaviviridae family. Flaviviruses infect host by the intermediate vectors like mosquitoes (Aedes aegypti) or ticks. There are four distinct serotypes of dengue viruses (DEN-1, DEN-2, DEN-3, and DEN-4) (Gubler and Clark, 1995) . Approximately 2.5 billion people are susceptible at risk for this epidemic disease. Clinically, this disease has an incubation period of 2-7 days and symptoms include rashes, anorexia, cold, flu, nausea, vomiting, and respiratory illness. Laboratory diagnosis includes immunoassay tests and PCR amplification. No vaccines or specific antiviral drugs are available for this disease. Chikungunya, an epidemic threat in the recent years is a mosquitoborne disease in the tropical regions. It is caused by Chikungunya virus (CHIKV), a pathogen of the genus Alphavirus and the family Togaviridae. These are otherwise known as arboviruses as they are arthropod-borne viruses. CHIKV is similar to other alphaviruses including Sindbis viruses and Ross River viruses. Three distinct genotypes including Asian, West African, and East Central South African have been observed so far. CHIKV holds a positive sense single stranded RNA of 12 kb genome length. The genome analysis revealed that the viral comprise two ORFs. The 5′ORF encodes the nsP1, nsP2, nsP3, and nsP4 non-structural proteins, and the 3′ORF encodes capsid (C), envelope (E1 and E2), and two peptides (E3 and 6K) (Nunes et al., 2015) . The acute stage lasts for a week whereas the chronic stage lasts from months to years. The symptoms include fever, arthralgia, rarely causing cardiac, ophthalmic, and neurological disorders. Diagnostic assays include ELISA, IgM antibody levels, and PCR. Treatment includes anti-rheumatic drugs but no vaccines have been discovered yet. Influenza viruses are significant due to its unavailing presence in the past centuries. The virus belongs to the family Orthomyxoviridae. Three forms namely A, B, and C infect human. Influenza A and B viruses cause relatively high morbidity and mortality compared to the C type. These are enveloped viruses that encompass segmented negative-sense single-stranded RNA. The gene structure contains surface glycoproteins, hemagglutinin (HA), and neuraminidase (NA). Based on the types of HA and NA, a total of 16 HA (H1-16) and 9 NA (N1-9) subtypes are identified in birds. Recent outbreaks in humans contain subtypes H1N1 and H3N2 that are reported to be endemic. The zoonotic spread from birds and swine includes H5N1, H7N9, and H9N2. These have the capabilities to mutate into new forms and produce severe pathological effects (Harris et al., 2017) . Symptoms include rapid onset of fever, dry cough, headache, muscle and joint pain, and severe malaise. The diagnostic method comprises influenza-specific RNA by RT-PCR. Treatment includes NA and HA inhibitors with monoclonal antibodies (Nachbagauer and Krammer, 2017) and antiviral drugs. MERS-CoV is a zoonotic viral respiratory disease that has infected people with a high mortality rate of nearly 50% in the Middle East (first identified in Saudi Arabia in 2012). The disease is alleged to be contracted from infected camels. Coronaviruses possess enveloped single stranded RNA that is spherical in shape with glycoprotein projections. The genome shows presence of two ORFs namely ORF 1a and 1b coding for non-structural proteins. Structural proteins encode the spike (S), envelope (E), membrane (M), and nucleocapsid (N). Symptoms include mild respiratory disease to severe acute respiratory disease and death. Severe illness can lead to the respiratory failure and may weaken the immune systems, especially with those with renal diseases, cancer, lung diseases, and diabetes. RT-PCR assay has been used as a diagnostic tool to detect the virus. At present, no vaccine or precise treatment is available (Alagaili et al., 2014) . Hepatitis viruses are hepaciviruses that belong to Flaviviridae. These viruses possess a linear and positive sense single stranded RNA genome coding for nearly 10 proteins. There are 7 genotypes encountered till date (genotype 1 to 7). Hepatitis A virus (HAV), a member of hepatovirus is an endemic spread by fecal-oral route. Symptoms include necrosis and inflammation of the liver cells. It includes a positive sense RNA and the genome comprise of about 7500 (nucleotides). The incubation period is approximately 3-5 weeks. Hepatitis B virus (HBV) belongs to Hepadnaviridae family and includes dsDNA virus that replicates via reverse transcription (Stuyver et al., 2000) . HCV is transmitted by blood-to-blood contacts and other blood/body fluid contaminants. This is an enveloped single-stranded RNA virus similar to flavivirus. It leads to complications such as liver cirrhosis, liver failure, and liver cancers such as hepatocellular carcinoma. Currently, no treatment is available for HCV infections. Immune system is a complex network of defence mechanism present in living organisms to fight the invading foreign microorganisms and provides protection from diseases. The immune system confers immunity to the organism by eliciting immune responses mediated by specialized immune cells and organs. Once the virus enters the host cells (cytopathic and non-cytopathic), it replicates, kills the infected cells, and invades other cells by releasing cellular contents (Münz et al., 2009) . Innate mechanism in human acts by the interaction of the virus particles with various receptors like endosomal Toll-like receptors, C-type lectin receptors, cytoplasmic retinoic acid-inducible gene I receptors, and Nod-like receptors. Once induced, these receptors produce cytokines and interferons. Following the action encountered by the innate cells like neutrophils and release of pro-inflammatory cytokines, special T cells get induced to respond to the invaders. These cells also persuade B cells to secrete antibodies, which form immune complexes. They further invoke cytotoxic T lymphocytes CD8+ to transfer to the infection site and kill infected cells. Antibody mediated immune responses ie. antigen-antibody complexes induce activation of complement cascade. HIV-1, human cytomegalovirus, and certain other viruses use the host complement control proteins into their virions that create cell lysis (Mengshol et al., 2010) . The complement system of the innate immunity includes several factors and cell surface proteins that invoke immune response to the pathogens (Carroll, 2004) . Three pathways of complement system are i) classical pathway (viral antigens bound with IgM and IgG interact with C1q and activates 2 serine proteases C1r and C1s, that further cleaves C4 into C4a and C4b to form the C3 convertase-C4bC2a) ii) alternate pathway (triggered by the hydrolysis of C3 that binds to protease factor B. This is cleaved by Factor D to form Bb in order to end the formation of C3 convertase-C4bC2a), and iii) lectin pathway (antigenic substances initiate mannose-binding lectin (MBL) and the ficolins. It forms a complex with MBL-associated serine proteases and cleaves C4 and C2 proteins to form C3 convertase-C4bC2a). These pathways regulate and activate complement factors and unite to form the major C3 component involved in virus pathogenesis (Ricklin et al., 2010) . The innate, complement, and the adaptive immune responses are interlinked and are activated by the varying mechanisms, depending on the type of infecting viral particles leading to reduced pathogenesis, regulate inflammatory conditions, and modulating adaptive responses ( Fig. 1 ). Recent researches in etiology have made better understanding of viral diseases. There is a continuous search of natural drugs to target viral proteins. Only limited chemicals are available for treating emerging viral diseases which is a major disadvantage. Therefore, there is an urgent need to unravel the potential antiviral metabolites from varying natural sources. Medicinal plants produce a variety of bioactive constituents that have the abilities to inhibit the replication cycle of various types of DNA or RNA viruses like HIV, HSV, Influenza virus, Human rhinovirus, Hepatitis B and C virus (HBV and HCV), and Dengue virus. Throughout the globe, medicinal plants act as important components to relieve from various ailments like bacterial, viral, and other infections. To mention a few, bioflavonoids such as Naringin (grape), daidzein (soybean), quercetin (foods and fruits such as green and black tea, apple, onion, citrus, tomato, and some other plants), and hesperetin (citrus) have been reported to fight dengue virus replication (Zandi et al., 2011) . Extracts of plants like Rosa nutkana and Amelanchier alnifolia were found active against enteric coronavirus (Jassim and Naji, 2003) . Significant compound glycyrrhizin, found in Glycyrrhiza glabra, has antiviral activity against many viruses such as HBV, HCV, HIV, and HSV infections. Lycorine isolated from Lycoris radiate showed strong anti-SARS-CoV activity. The hot water extracts of Stevia rebaudiana blocked entry of various infectious serotypes of Human Rhinovirus into the permissive cells by an anionic polysaccharide with uronic acid as a major sugar constituent (Mishra et al., 2013) . Essential oils (eucalyptus oil, tea tree oil, and thyme oil) and monoterpenes like isoborneol proved antiviral activities against HSV-1 by inhibiting glycosylation of viral proteins (Astani et al., 2010) . Silymarin (from the seeds of Silybum marianum) and catechin (present in green tea extract) inhibited HCV and also displayed anti-inflammatory and immunomodulatory actions (Calland et al., 2012) . Table 2 illustrates antiviral properties of various plants associated metabolites against deadly viruses. Fungi are excellent sources of bioactive metabolites, possessing antiviral properties (Table 3 ). The first antiviral metabolite from fungi Stachybotrys sp. was tested against H1N1 Influenza virus . Compounds isolated from Penicillium sp. were tested for antiviral properties. Trypilepyrazinol acted as an inhibitor against HIV-1 and HCV. (+)-neocitreoviridin showed anti-influenza A virus activity. 3-β-hydroxyergosta-8,14,24(28)-trien-7-one expressed anti-HIV and anti-influenza A activities (Li et al., 2019) . Fungi associated compounds such as physcion, neoechinulin D, and dihydroauroglaucin inhibited replication of Influenza A virus (Bovio et al., 2019) . A sulphated polysaccharide from Agaricus brasiliensis against HSV-1 and 2, two proteins namely neutral protein bound polysaccharide, acidic protein bound polysaccharide, and triterpenes and laccases of Ganoderma lucidum exhibited anti-HIV-1 protease activity and anti-HIV-1 reverse transcriptase activity (Bishop et al., 2015) . GFAHP, a protein from Grifola frondosa inhibited replication of HSV-1 (Hassan et al., 2015) . Alternaria sp. ZJ-2008003, extracted from Sarcophyton sp. produced tetrahydroaltersolanols C-F and dihydrosolanol A and alterporriols N-R. Tetrahydroaltersolanol C and alterporriol Q showed antiviral activities against the porcine reproductive and respiratory syndrome virus. 11a-Dehydroxyisoterreulactone A from Aspergillus terreus possessed weak antiviral activity against HSV-1 virus. Aspergilli peptides D and E showed inhibitory activities towards HSV-1. Asperterrestide A displayed antiviral activity against H1N1 and H3N2 Influenza virus. Aspergillus sp. derived from Muricellaabnormalis, on fermentation yielded 22-O-(N-methyl-L-valyl)-21-epiaflaquinolone B. It exhibited antiviral activity against human respiratory syncytial virus. Isobutyrolactone II, obtained from another strain of Aspergillus sp. expressed strong antiviral activity towards HSV-1 (Liu et al., 2020) . The metabolites halovirs A-E isolated from the marine fungus Scytalidium sp. demonstrated antiviral activity against HSV type-1 and Anagallis arvensis HSV 1 and poliovirus Amoros and Girre (1987) Gymnemic acid Gymnema sylvestre Anti-influenzal activity Rao and Cochran (1974) Table 4 shows antiviral attributes of algal metabolites and polysaccharides. Griffithsin and Scytovirin isolated from red and blue-green algae, respectively inhibited HCV (Takebe et al., 2013) . The former is also a prominent HIV inhibitor (Besednova et al., 2019) . Group I diterpenes like 8α,11-dihydroxy-pachydictyol A, 8β-hydroxy pachydictyol A from Dictyota sp. and diterpenes of Group II including Acetoxypachydiol, 3β-actoxydilophol obtained from Dictyota plectens showed weak antiviral activity. Dolabelladienols A-B extracted from Dictyota pfaffii displayed strong antiviral properties. Bicyclic diterpenes, Crenulidanes from Da-1, and AcDa-1 obtained from D. menstrualis inhibited HIV replication process . Fucoidan, a polysaccharide from the marine alga, Cladosiphon okamuranus prevented dengue virus infection (Teixeira et al., 2014) . The effect is specific on retroviruses by using heparan sulphate as primary viral receptors (Besednova et al., 2019) . Carrageenan, from Gigartina skottsbergii inhibited Influenza virus, HIV, HPV, HSV-1, HSV-2, and dengue virus. Galactan from red algae like Callophyllis variegate and Agardhiella tenera possessed antiviral properties against HIV, HSV-1, -2, Dengue virus, and Hepatitis A virus. Alginate from brown algae inhibited Hepatitis B, Influenza A, and HIV. Fucan from brown algae like Adenocytis utricularis and Undaria pinnatifida expressed antiviral activities against HIV, HSV, Sindbis virus, and Vesicular Stomatitis Indiana virus. The extract of red alga, Schizymenia pacifica exhibited antiviral properties against HIV (Ahmadi et al., 2015) . Calcium spirulan, isolated from Spirulina platensis blocked replication of HSV-1, HIV-1, Influenza A, measles, and mumps virus. Extract of Spirulina maxima reduced HSV-2 infection. Cyanovirin-N, a protein produced by blue-green alga Nostoc ellipsosporum stopped HSV-1 entry into cells by preventing fusion with HSV-1 glycoproteins (Kim et al., 2011) . Nostoflan, extracted from Nostoc flagelliforme showed antiviral activities against HSV-1, HSV-2, and Influenza A virus (Thuan et al., 2019) . Dieckol isolated from Ecklonia cava prevented cleavage of SARS-CoV 3CL protein and stopped viral replication (Koirala et al., 2017) . Ulvan, from Ulva armoricana has been identified to have antiviral properties (Xu et al., 2017) . Laminarans or laminarins have been found to play the role of HIV reverse transcriptase and avoid absorption of HIV onto human lymphocytes (Besednova et al., 2019) . Therapeutic agents from natural resources, particularly bacteria are considered pivotal alternatives of commercially available synthetic drugs. Advancements in genomic technology (identify secondary metabolite gene clusters) and analytical techniques (isolation and purification of compounds) have led the drug discovery approaches to identify novel compounds with antiviral ability. Few noteworthy antiviral drugs isolated so far include surfactins from Bacillus subtilis which display antiviral activities against HSV (Ongena and Jacques, 2008) . Representatives of exopolysaccharides (EPS) producing strains of the genera Streptococcus, Lactococcus, Lactobacillus, Leuconostoc, Pediococcus, and Weissella have been well studied for immunostimulating properties. The EPSs extracted from lactic acid bacteria of the genera Pediococcus, Leuconostoc, and Lactobacillus significantly proved to produce antiadenovirus effects in cell line studies (Biliavska et al., 2019) . Other microbial metabolites like spongouridine, spongothymidine, statins, myriocin, NA255, and cyclosporine were reported to have antiviral activities against HSV1,2, HBV, HIV, influenza virus, HCV, and coronaviruses (Nkongolo et al., 2014) . Antiviral attributes of bacteria associated bioactive compounds are summarized in Table 5 . Actinomycetes are present in various environments and are active in the microbial communities. The secondary metabolites of these organisms are potential antiviral agents (Table 6 ). Xiamycin and its methyl ester of Streptomyces sp. GT2002/1503 showed selective anti-HIV-1 activity . The compound (4S)-4-hydroxy-10-methyl-11oxo-dodec-2-en-1,4-olide, identified from Streptomyces sp. Smu03 possessed antiviral property over a broad range of Influenza A virus . Antimycin A from Streptomyces kaviengensis inhibited RNA virus families like Togaviridae, Picornaviridae, Bunyaviridae, and western equine encephalitis virus. AhmpatininiBu from Streptomyces sp. CPCC 202950 and 4862F from Streptomyces albosporus I03A-04862 inhibited HIV-1 protease. Narasin from Streptomyces aureofaciens prohibited postentry stages of viral replication during Dengue virus infection (Teixeira et al., 2014) . Other antivirals include daptomycin from Streptomyces roseosporus (Jakubiec-Krzesniak et al., 2018), diffusomycin from Streptomyces sp. KBFP-2025 (Vil et al., 2019) , and Sinefungin from Streptomyces griseolus and Streptomyces incarnatus NRRL 8089 (Chen et al., 2017) . Endophytes are a group of bacteria and fungi which live inside the host without damaging them. Metabolites obtained from endophytes possess antiviral properties (Table 7) . Xiamycin A, a distinguished compound extracted from Bruguiera gymnorrhiza mangrove plant, demonstrated selective anti-HIV activity (Christina et al., 2013) . Lichens are symbiotic organisms between fungi and algae. Nearly 1100 bioactive metabolites have been isolated from 18,500 lichens, but still numerous organisms are yet to be discovered from different environments. These metabolites generally belong to the classes of polyketides, phenols, terpenoids or quinines. Several research studies indicated the antiviral activities of metabolites (Table 8) , such as (+)usnic acid, sekikaic acid, and anthraquinones against arenaviruses, respiratory syncytial virus, and HSV type 1 (Boustie and Grube, 2005; Stocker-Wörgötter, 2008; Zambare and Christopher, 2012; Lai et al., 2013) . Plants are a potential source of antiviral agents. In India, herbal medicines have proved to intensify therapeutic effects against several viral infections like Dengue virus, HBV, HCV, HSV, HIV, and Influenza virus. These natural agents inhibit viral replication and synthesis. These indigenous plants stand alone in Indian tradition and have been recognized worldwide for its beneficial healing effects (Ballabh and Chaurasia, 2007; Pandey et al., 2008) .. Some of the common medicinal plants used are shown in Fig. 2 . An Indian Government initiative, Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH) held by the Ministry of Health and Family Welfare, 2014 provides education, awareness, and enhances research to use natural resources that can fight several life threatening diseases. Ayurvedic medicine has been in use since two thousand years. Over 700 herbal drugs were recorded in Ayurveda with reported clinical effects categorised into 50 drug classifications. Also, Unani is recognized as traditional medicine producer, showing therapeutic effects against many infectious diseases. Both the Ayurvedic and Unani systems of medicine have recorded several preparations like decoctions, powders, and liquids of potential plants with immunomodulatory and antiviral properties (Subhose et al., 2005; Patwardhan et al., 2005; Weeks, 2020) . Due to changing lifestyles and requirements for nutrition and immunity to overcome growing infections complementary and herbal medicine can act as best alternatives for chemical drugs. Nutraceutical components and ethnopharmacological preparations play a very important role to fight against viral infections (Kamboj, 2000) . India is the largest manufacturer of traditional health products and formulations from medicinal plants. Herbal medicines and other nutrients from food are provided as dietary supplements in the form of pills, capsules, powders, solids or liquid (processed forms). They act as antioxidants, vitamin, and mineral supplements, also alleviate health against respiratory diseases, strengthen the immune system, and protect against the common cold (Mukherjee and Wahile, 2006) . CHMs contain several plant products and preparations which play a tremendous role in treating various ailments (Fig. 3) . They help to regulate body temperature and detoxify chemical substances in our body. Xiaoqinglong decoction mixture is used in China for respiratory ailments such as asthma, cough, and chronic obstructive pulmonary disease. The mixture consists of wild ginger (Xixin, Asari Radix et Rhizoma), Pinellia ternata (Banxia, Pinelliae Rhizoma), Liquorice root (Gancao, Glycyrrhizae Radix et Rhizoma), Chinese Magnoliavine Fruit (Wuweizi, Schisandrae Chinensis Fructus), dried ginger (Ganjiang, Zingiberis Rhizoma), Cassia Twig (Guizhi, Ramulus Cinnamomi), Chinese Ephedra herb (mahuang, Ephedrae Herba), and white peony root (Baishao, Paeoniae Radix Alba). This herbal extract exhibited antiviral activity against drug-resistant H1N1 virus (Zhen et al., 2018) . Extracts of Scutellaria baicalensis contain flavonoids such as 5,7,4′-trihydroxy-8-methoxyflavone, baicalein, and 5,7,8,4′-tetrahydroxyflavone. These extracts showed antiviral properties that inhibited the neuraminidase activity of Sendai virus and Infuenza A H5N1 (Hou and Lu, 2009) . Houttuynia cordata Thunb is a traditional Chinese medicine used for treating pneumonia and lung-related ailments. It is also found active against SARS-CoV (Lau et al., 2018) . Maoto is a Japanese herbal medicine used for upper respiratory tract infection. Maoto constitutes extracts obtained from Ephedra herb, Apricot kernel, Cinnamon bark, and Glycyrrhiza root. Maoto expressed antiviral effect against Influenza virus PR8 and H1N1 by inhibiting the V-ATPase present in the endosome and lysosome membranes, thereby preventing the uncoating of the virus and its entry into the cytoplasm (Masui et al., 2017) . Korean Red Ginseng is used as traditional medicine in East Asian countries as it has enhanced pharmacological properties as compared with fresh ginseng (the root of Panax ginseng) because of the steaming process against Respiratory syncytial virus, Rhinovirus, Influenza virus, HIV, Hepatitis virus, Norovirus, Rotavirus, Enterovirus, and Coxsackievirus (Im et al., 2016) . A healthy immune system is the necessity in today's world to combat emerging pathogenic infections. Fig. 4 enlists common nutraceuticals to improve immunity against viral pathogens. Vitamins are the best source of nutrient supplements readily available in plants, fresh fruits, and vegetables. Vitamin C and D hamper speedy recovery of common cold, cough, sore throats, etc., while other vitamins like A, B6, K, and E strengthen the immune system by enhancing inflammatory responses and speed up the biochemical pathways involved in viral destruction. Minerals like zinc, copper, iron, and potassium inhibit pro-inflammatory cytokines and enable the differentiation of T-lymphocytes (Patel et al., 2019) . In addition to micronutrients, probiotics not only metabolize food but also wipe out pathogens from the hosts. Herbal home remedies like preparation of decoctions with garlic, ginger, turmeric, pepper, and onions increase flu fighting responses and boost the immune system Curtis et al., 2017) . Newly emerging viral diseases are serious threat to human health. Recent impact of viral disease outbreaks like COVID-19, SARS, EVD, ZIKV disease, NIV disease, and Influenza viruses have emphasized new drug designing and vaccine development. Though synthetic molecules are available for viral infections, traditional medicines or novel drug formulations from different natural sources benefit better with low complications. Natural resources viz. medicinal plants, bacteria, and fungi have been identified as promising producers of plethora of alkaloids, coumarins, phenolics, flavonoids, lignans, terpenoids, tannins, and ailments. These evidences led to investigate further the field of pharmacology in order to strengthen the constant warning of emerging and re-emerging viral infections and develop a state of preparedness in the world. However, plethora of natural resources still requires in depth pharmacological investigations in terms of suggesting their profound roles as therapeutics. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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