A view and overview on the control of avian influenza outbreaks in poultry: (4-6) The use of herbal antivirals and probiotics

Unlimited herbs products contain polyphenols, flavonoids, alkaloids or lignans, mostly from traditional Chinese medicine, offer promise as adjuncts or alternatives to the current anti-influenza chemotherapy [21, 36]. Generally, complementary medicine for treating or preventing influenza or influenza-like illness in human seems to be cultural practice differs from nation to nation [6, 20, 82]. Innumerable herbs species with potential inhibitory effects on replication of influenza viruses using in-vitro cell culture methods and embryonated eggs or in-vivo mouse models were frequently described [9, 15, 16, 18, 27, 31, 34, 38, 40, 42, 49, 52-56, 58, 59, 64, 66, 69, 73, 74, 77, 78, 84, 89].

In poultry, antiviral and immunoadjuvant effects of several plants and/or its derivatives have been investigated. Sood et al. [76] found that Eugenia jambolana extracts had 100% virucidal activity against HPAIV H5N1 in tissue culture and in-ovo inoculated chicken embryonated eggs (ECE). Menthol, eucalyptol and ormosinine probably have inhibitory effect on H5 viruses due to strong interactions ability with the viral HA protein [13]. NAS preparation, a Chinese herbal medicine, prevented H9N2 virus-induced clinical signs in treated chickens; however transmission of the virus to untreated chickens was not interrupted [72]. Likewise, eucalyptus and peppermint essential oils preparations protected broilers against H9N2 virus infections [2, 3]. Moreover, application of lyophilized green tea by-product extracts namely catechins in feed or drinking water reduced H9N2 virus replication and excretion in experimentally infected chickens in a dose-dependent manner [44]. In addition, green tea extract was comparable to amantadine in protection of chicken embryos against H7N3 subtype [73]. Catechins alter the infectivity of influenza viruses probably not only by direct interaction with viral HA but also by inhibition of viral RNA synthesis in cell culture [75]. Furthermore, Liu et al. [50] found that statin/caffeine combination was as effective as oseltamivir in reduction HPAIV H5N1-induced lung damage and viral replication in mice. Conversely, Kumaki and colleagues [39] showed that statin had little antiviral activity against H5N1, H3N2 and H1N1 viruses in mouse-model. Stachyflin showed antiviral activity against H1N1, H5N1, H5N2, and H6 viruses in cell cultures as well as in experimentally infected mice [57]. A leave-extract of the wild black currant (Ribes nigrum folium) interfered with virus internalization of H1N1 and H7N7 viruses in cell cultures and impaired their replication in mice without evidence for generation of resistant variants [11]. Also, reduced titer of H5N1 viruses in cell culture or ECE was recently described using extracts of Capparis sinaica Veill [25], Aloe hijazensis [1] and Red Sea grass Thallasodendron ciliatum [26]. Extracts from Phellinus igniarius inhibited replication of H1N1, H3N2 and H9N2 viruses in cell culture probably by preventing virus attachment to the host cells [45]. Likewise, roots of Isatis indigotica inhibited different subtypes of influenza viruses including H6N2, H7N3 and H9N2 viruses in MDCK cells [85]. Similar mode of action has been described for a derivative from andrographolide, a bioactive component of the medicinal plant Andrographis paniculata, which showed significant inhibitory activity against H9N2 and H5N1 in MDCK cells and in mice by blocking the virus binding to SA receptors [5]. Moreover, some alkaloids isolated from the bulbs of Lycoris radiata had anti-influenza activities against HPAIV H5N1 through inhibition of the nuclear-to-cytoplasmic export of the ribonucleoprotein (RNP) complex in MDCK cells [10]. On the contrary, neolignans from leaves of Miliusa mollis Pierre (Annonaceae) had no effect on the HPAIV H5N1 in in-vitro [70]. Chickens injected with different doses of Astragalus polysaccharide (APS) at 7 days post hatch for five successive days were protected against H9N2 infection and showed enhanced humoral immune response after vaccination with the same virus [32].

The immunoadjuvant effect of some herbal extracts as feed additives on the humoral immune response induced by inactivated AIV vaccination in poultry has been studied. Oral administration of ginseng stem-and-leaf saponins in drinking water or Hypericum perforatum L. as a dietary supplement significantly enhanced serum antibody response to inactivated H5N1 or H9N2 vaccines in chickens [30, 43, 88]. The Cochinchina momordica seed extract, Chinese medicine plant, when combined with an inactivated H5N1 vaccine as adjuvant increased significantly the immune response and daily weight gain of two weeks old chickens [67]. On the contrary, herbal extracts of Radix astragali, Radix codonopis, Herba epimedii and Radix glycyrrizae in drinking water did not improve chicken immune response to H5-AIV vaccination [48], likewise diet supplementation with fresh garlic powder had no effect on the humoral immune response of chickens vaccinated with an inactivated H9N2 vaccine [29]. 

As reviewed above, many herbs and/or their extracts have direct inhibitory effects on the replication of different AIV subtypes both in-vitro and in-vivo. In addition to its antiviral activity, these extracts often have immunoadjuvant effect, anti-bacterial, anti-fungal, anti-inflammatory, anti-oxidant and/or analgesic properties which may provide alternative natural broad-spectrum therapy for control of AIV in poultry farms [14, 24, 37, 76].  To date, no adverse effects on body weight or egg production have been described.

Some derivatives (i.e., ginseng saponins) require four to six years to harvest and is very expensive on the market [88]. Methods of the extraction and preparation of the crude extracts and its purity greatly influence the inhibition activity of some herbs against AIV [44, 75]. Moreover, batch-to-batch variations due to variable growth conditions at the plantations have been considered a limiting factor for treatment of influenza [14]. Evident that mutation in the H5 gene probably affects inhibitor binding of some herbs was reported [13]. In addition, in-vitro experiments and animal models to confirm the direct antiviral activities against influenza virus are limited [41]. Moreover, comprehensive investigations of herb-drug interactions, potential toxicity, heterogeneity of herbs species, plant parts (i.e., aerial versus root) and biochemical data identifying the active components are inadequately described [12]. To the best of our knowledge, neither field application nor commercial herbal products have been recorded specifically against avian influenza in poultry although some commercial products for human are available [80]. 

Although probiotics are widely used in poultry to improve innate and adaptive immunity [51, 60, 63], there is a paucity of information on its ability to ameliorate AIV infections. A number of studies have reported the efficacy of probiotic lactic acid bacteria such as Streptococcus thermophiles, several Lactobacillus and Bifidobacterium species to enhance the immune response and to protect mice against different influenza strains/subtypes [4, 8, 19, 22, 23, 28, 33, 35, 46, 61, 62, 68, 79, 81, 86]. In poultry, Lactobacillus plantarum KFCC11389P was as effective as oseltamivir to neutralize the H9N2 virus in ECE and slightly reduced amount of tracheal virus excretion in oral-fed experimentally infected chickens [7]. Out of 220 screened bacterial strains, Seo et al. [71] found that Leuconostoc mesenteroides YML003 had highly anti-H9N2 activity in cell culture and ECE. Decrease cloacal excretion of the virus and a significant increase in the cytokine IFN-gamma in experimentally infected chickens were observed. In another study, administration of Lactobacillus fermentum via nasal route significantly decreased the viral excretion and chicken-to-chicken transmission of H9N2 virus [87]. Likewise, oral administration of Lactobacillus acidophilus increased immune response to H9N2 vaccination, decreased fecal virus excretion and protected broiler chickens against intranasal challenge with a high dose of H9N2 virus [65]. Ghafoor and co-workers [17] showed that multi-strains commercial probiotic protexin® (various Lactobacillus spp., Enterococcus faecium, Bifidobacterium bifidum, Candida pintolepesii and Aspergillus oryzae) improved immune response of broiler chickens to H9N2 vaccination and prevented the mortality and morbidity. On the other hand, dual use of Lactobacillus spp. or Lactococcus lactis as a vector for vaccine production and immunomodulation bacteria has been successfully constructed and protected mice against HPAIV H5N1 [47, 83], such experiments had not been be evaluated in poultry, yet.

Together, direct and indirect antiviral and the immune-stimulation effect in addition to dual use as a vaccine-vector and immunomodulator of the probiotics are promising in the control of AIV in poultry; however their efficacy against HPAIV in poultry is still unknown.

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