Allicin Alleviates Reticuloendotheliosis Virus-Induced Immunosuppression via ERK/Mitogen-Activated Protein Kinase Pathway in Specific Pathogen-Free Chickens

Abstract

Reticuloendotheliosis virus (REV), a gammaretrovirus in the Retroviridae family, causes an immunosuppressive, oncogenic, and runting–stunting syndrome in multiple avian hosts. Allicin, the main effective component of garlic, has a broad spectrum of pharmacological properties. The hypothesis that allicin could relieve REV-induced immune dysfunction was investigated in vivo and in vitro in the present study. The results showed that dietary allicin supplementation ameliorated REV-induced dysplasia and immune dysfunction in REV-infected chickens. Compared with the control groups, REV infection promoted the expression of inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor-α (TNF-α), whereas, allicin reversed these changes induced by REV infection. The decreased levels of IFN-α, IFN-β, and IL-2 were observed in REV-infected chickens, which were significantly improved by allicin. Allicin suppressed the REV-induced high expression of toll-like receptors (TLRs) as well as melanoma differentiation-associated gene 5 (MDA5) and the activation of mitogen-activated protein kinase (MAPK) and the nuclear factor kappa B p65. REV stimulated the phosphorylation of JNK, ERK, and p38, the downstream key signaling molecules of MAPK pathway, while allicin retarded the augmented phosphorylation level induced by REV infection. The decreased phosphorylation level of ERK was associated with REV replication, suggesting that ERK signaling is involved in REV replication, and allicin can alleviate the REV-induced immune dysfunction by inhibiting the activation of ERK. In addition, REV infection induced oxidative damage in thymus and spleen, whereas allicin treatment significantly decreased the oxidative stress induced by REV infection, suggesting that the antioxidant effect of allicin should be at least partially responsible for the harmful effect of REV infection. In conclusion, the findings suggest that allicin alleviates the inflammation and oxidative damage caused by REV infection and exerts the potential anti-REV effect by blocking the ERK/MAPK pathway.

Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data

“…2 ) ( Weber et al, 1992 ). It is well stablished that OSCs, and allicin and its derivatives contribute significantly to garlics antiviral properties ( Bayan et al, 2014 ; Sharma, 2019 ; Wang et al, 2017 ). The OSCs are highly reactive to the thiol group present in various active viral proteins or enzymes that are crucial for microbial surveillance and fusion ( Ankri & Mirelman, 1999 ; Jain et al, 2007 ).…”

“…The mechanism by which garlicin inhibits the replication of HIV-1 is not clear but it has been proposed that garlicin, being a thiol compound, inhibits phorbol ester stimulated HIV-1 replication or inhibits ‘HIV-1 tat’, a transactivator protein of HIV-1 replication, similar to other thiol compounds (N-acetyl- l -cysteine and 2,3-dimercapto-1-propanol) ( Kubota et al, 1990 ; Roederer et al, 1990 ; Shoji et al, 1993 ). There was no report found on allicin ability to inhibit HIV, but a recent study reported that allicin can inhibit replication of reticuloendotheliosis virus (REV) and alleviates the infection in chicken ( Wang et al, 2017 ). REV is a retrovirus in the Retroviridae family and causes an immunosuppressive syndrome in different avian hosts.…”

“…Garlic also contains non-sulfur constituents including lectins, flavonoids (kaempferol, quercetin and myricetin), polysaccharides (fructan), steroids, saponins, fatty acids (lauric and linoleic acid), several enzymes, vitamins (e.g., A, B 1 and C), allixin, minerals (e.g., Ca, Cu, Fe, K, Mg, Zn and Se) and amino acids which are likely having additive or synergistic effects with OSCs ( Amagase, 2006 ; Josling, 2005 ; Keyaerts et al, 2007 ; Li et al, 2017 ; Sharma, 2019 ). Allicin was reported as one of the main OSCs that was considered one of the principle compounds responsible for antiviral activity ( Wang et al, 2017 ; Weber et al, 1992 ), immunomodulatory ( Arreola et al, 2015 ), anti-inflammatory ( Metwally et al, 2018 ), antioxidant ( Prasad et al, 1995 ) and other pharmacological properties ( Borlinghaus et al, 2014 ). Pre-clinical studies, both in-vitro and in-vivo, showed that allicin-derived OSCs such as ajoene, allitridin, garlicin and DAS also possess potential antiviral ( Fang et al, 1999 ; Keyaerts et al, 2007 ; Liu et al, 2004 ; Terrasson et al, 2007 ; Walder et al, 1997 ), immune enhancing ( Hall et al, 2017 ; Li et al, 2013 ; Yi et al, 2005 ) and other therapeutic activities ( El-Saber et al, 2020 ; Kaschula et al, 2010 ; Yi, L. & Su, 2013 ).…”

“…Pre-clinical investigations ( in-vitro and in-vivo ) of garlic extract (GE) and its OSCs have shown antiviral activity against a wide range of viral infections including flu and respiratory infections ( Chavan et al, 2016 ; Chen et al, 2011 ; Choi, 2018 ; Liu et al, 2013 ; Mehmood et al, 2018 ; Mehrbod et al, 2009 ; Mehrbod et al, 2013 ; Mohajer Shojai et al, 2016 ; Rasool et al, 2017 ; Tsai et al, 1985 ; Weber et al, 1992 ), immunosuppression (“ Garlic extract for HIV? ", 1998 ; Kun Silprasit et al, 2011 ; Shoji et al, 1993 ; Tatarintsev et al, 1992 ; Walder et al, 1997 ), genital herpes ( Romeilah et al, 2010 ; Weber et al, 1992 ), neurological infections ( Luo et al, 2001 ; Meléndez-Villanueva et al, 2019 ; Wang et al, 2016 ), gastrointestinal infections ( Al-Ballawi et al, 2017 ; Weber et al, 1992 ), plant infections ( Mohamed, 2010 ; Shyam & Ashish, 2011 ; Wang et al, 2020 ) and others ( Liu et al, 2013 ; Seo et al, 2017 ; Wang et al, 2017 Weber et al, 1992 ) ( Table 3 , Table 4 ). Further, randomized clinical trials on different commercial garlic preparations also showed that garlic plays a significant therapeutic role in various viral infections such as cold and flu, viral-induced hepatitis, viral-associated warts, as well as immune enhancing activity in viral infected patients ( Table 5 ).…”

Dietary Allicin Improved the Survival and Growth of Large Yellow Croaker (Larimichthys crocea) Larvae via Promoting Intestinal Development, Alleviating Inflammation and Enhancing Appetite

“…High mortality was one of the important limiting factors during fish larvae culture, and more attention has been paid to enhance larval health to improve the survival rate ( Rojo-Cebreros et al, 2018 ). Allicin has been used as immunostimulants to enhance the immune response in mice ( Bruck et al, 2005 ), chicken ( Wang et al, 2017 ), pig ( Lan et al, 2017 ) and many fish species ( Nya and Austin, 2011 ; Abdel-Daim et al, 2015 ; Xu et al, 2020 ). NO is a key molecule in the immune-neuroendocrine integration cooperating with other molecules in vertebrates ( Pederzoli and Mola, 2016 ), and showed protective roles of immuno-protection against pathogenic infection via regulating Akt and ERK pathway ( Zhou et al, 2014 ).…”