The battle for autophagy between host and influenza A virus

Figures & data

Figure 1. Schematic overview of the autophagic pathway.

Table 1. Different strains of influenza virus regulate autophagy formation in different cell types

Viral Strains	Infected Cells	Multiplicity of infection (MOI)	Reference
A/WSN/33 (H1N1)	MDCK; A549	0.05	36
A/duck/Hubei/Hangmei01/2006(H5N1)	A549	0.1	37
A/swine/HeBei/012/2008 (H9N2)	A549	2	38
A/swine/HeBei/012/2008 (H9N2)	A549	1	39
A/Jilin/9/2004 (H5N1)	MEF	10	40
A/Quail/Hong Kong/G1/97 (H9N2/G1) A/Hong Kong/54/98 (H1N1) A/HongKong/415,742/09 (S-OIV)	Primary blood macrophages	2	41
A/Hong Kong/8/68 (H3N2)	Memory B cells	5	42
A/WSN/33(H1N1)	MDCK	5	43
A/PR/8/34(H1N1)	hiPSCs	5	44
A/mallard/Huadong/S/2005 (H5N1) A/Ck/SH/F/98(H9N2) A/PR8/34(H1N1)	CEF; DF1	0.1	45
A/Aichi/68 (H3N2)	A549; MLE-12; MDAMC; HaCat	0.6 or 0.8	48
A/PR/8/34(H1N1)	A549	1	52
A/WSN/33(H1N1)	A549	0.01	53
A/PR/8/34 (H1N1)	Hela	1	54
A/new.Coledonia/20/1999(H1N1) A/Jilin/9/2004(H5N1)	A549	4	68
A/Zhejiang/2/2009 (H1N1)	BMDCs	4	74
A/Hong Kong/2108/2003 (H9N2) A/Nanjing/108/2009 (H1N1)	A549; Hela; HPMECs; HUVECs	1	92
A3/Beijing/30/95(H3N2)	A549; Ana-1	100TCID50	124

MDCK: Madin-Darby canine kidney; A549: human lung epithelial cells; CEF: primary chick embryo fibroblasts; DF1: chicken fibroblast cells; MLE-12: mouse lung epithelial cells; MDAMC: human breast carcinoma cells; HaCat: human keratinocyte cells; hiPSCs: human-induced pluripotent stem cells; Ana-1: murine macrophage; BMDCs: bone‐marrow‐derived dendritic cells; MEF: mouse embryonic fibroblasts; Hela: human cervical carcinoma cell

Figure 2. Influenza virus induced autophagy to promote its replication.

Figure 3. The working model of the roles of different viral proteins in the regulating of autophagy with IAV.

Figure 4. Host regulates autophagy against influenza virus infection.

Table 2. Antiviral compounds related with autophagy against IAV

Antiviral compounds	Activity (IC50)	Virus subtype	Cell types	Mechanism of action	Literature
Astragaloside IV	50 mg/L	H1N1	A549	Promoting the fusion of autophagosomes with lysosome	111
Aloe vera ethanol extract (AVE)	25 μg/mL, 250 μg/mL	H1N1, H3N2	MDCK	Inhibiting IAV mRNA synthesis and protein expression	113
Catechin	50 μM	H1N1	A549	Decreasing the expression of viral M2 and NP protein	114
Tauroursodeoxycholic acid	3 mmol/L	H1N1, H5N1	A549	Interfering the oligomeric states of influenza viral M2	115
Salinomycin	10 μM	H1N1	MDCK	Inhibiting the proton channel activity of viral M2	116
Thiopurines	10 μM	H1N1	A549	Affecting the synthesis and maturation of IAV glycoproteins hemagglutinin and neuraminidase	117
Baicalin	50 μg/mL	H3N2	A549, Ana-1	Inhibiting the activity of IAV neuraminidase; inhibiting the activity of IAV neuraminidase	121,122,123,124
Punicalagin	10 μM	H1N1, H3N2	MDCK	An inhibitor of influenza neuraminidase and regulating Akt/FOXO3a and P62/Nrf2 signalling pathway to control autophagy activation	118119
Atorvastatin	5 μM	H1N1	MDCK	Inhibiting HMG-CoA reductase activated by autophagy to block the replication of IAV	125
Anthocyanins	10 µg/mL	H1N1	MDCK	Suppressing influenza virus adsorption	126,127
Berberine	16.8 µM	H1N1	murine macrophage cell	Stimulating BNIP3-mediated mitophagy initiation to inhibit IAV-induced excessive inflammasome	133
Oligonol	10 µg/mL	H1N1	A549	Activating SIRT1-AMPK-autophagy pathway to block IAV replication	134, 135
Vitamin D3	100 nM	H1N1	A549	Increasing the expression of Syntaxin-17 (STX17), which may be an inhibitor of membrane fusion and mediate mitophagosome-lysosome fusion	126,137,138,139
Procyanidin	25 µg/mL	H1N1	A549	Leading to the accumulation of LC3II and inhibited the expression of autophagy-related proteins for blocking IAV replication	140
Evodiamine	12.5 µg/mL	H1N1	A549	Suppressing the dissociation of Beclin1-Bcl2 heterodimer	141
Eugenol	5 µg/mL	H1N1	A549	Inhibiting the Dissociation of Beclin1-Bcl2 Heterodimer and the Elevation of Autophagy Induced by IAV	142
Silybin	100 μM	H1N1	A549	Blocking the Atg12-Atg5/Atg16 heterotrimer, autophagosomes accumulation and oxidative stress	142
Edible bird’s nest	5 μg/ml	H1N1	MDCK	Decreasing the RhoA protein expression, reducing LC3-II protein level, and increasing the lysosomal degradation.	131
Hochuekkito	12.5 mg/ml	H1N1	MDCK	Preventing IAV-induced cell death via the induction of autophagy in host cell at the early post-infection stage	132

Zhou Z, Jiang X, Liu D, et al. Autophagy is involved in influenza A virus replication. Autophagy. 2009 Apr;5(3):321–328. DOI:10.4161/auto.5.3.7406.

 PubMed Web of Science ®Google Scholar

Wang R, Zhu Y, Zhao J, et al. Autophagy Promotes Replication of Influenza A Virus In Vitro. J Virol. 2019 Feb 5;93(4):e01984–18. DOI:10.1128/JVI.01984-18.

 PubMed Web of Science ®Google Scholar

Klionsky DJ, Abdalla FC, Abeliovich H, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8(4):445–544.

 PubMed Web of Science ®Google Scholar

Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2016;12(1):1–222. 3rd edition

 PubMed Web of Science ®Google Scholar

Gannagé M, Dormann D, Albrecht R, et al. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe. 2009;6(4):367–380.

 PubMed Web of Science ®Google Scholar

Ampomah PB, Lina HKL. Influenza A virus-induced apoptosis and virus propagation. Apoptosis. 2020;25(1–2):1–11.

 PubMed Web of Science ®Google Scholar

Godbole NM, Sinha RA, Tiwari S, et al. Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated anti-apoptotic signalling. Virus Res. 2020;282:197936.

 PubMed Web of Science ®Google Scholar

Ma J, Sun Q, Mi R, et al. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling. J Genet Genomics. 2011;38(11):533–537.

 PubMed Web of Science ®Google Scholar

Yeganeh B, Ghavami S, Rahim MN, et al. Autophagy activation is required for influenza A virus-induced apoptosis and replication. Biochim Biophys Acta Mol Cell Res. 2018;1865(2):364–378.

 PubMed Web of Science ®Google Scholar

Zhang RH, Zhang HL, Li PY, et al. Autophagy is involved in the replication of H9N2 influenza virus via the regulation of oxidative stress in alveolar epithelial cells. Virol J. 2021 Jan 18;18(1):22. DOI:10.1186/s12985-020-01484-x.

 PubMed Web of Science ®Google Scholar

Chen M, Jeongsoo Hong M, Sun H, et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med. 2014;20(5):503–510.

 PubMed Web of Science ®Google Scholar

Il Jung K, Woong Pyo C, Choi S-Y. Influenza A virus-induced autophagy contributes to enhancement of virus infectivity by SOD1 downregulation in alveolar epithelial cells. Biochem Biophys Res Commun. 2018;498(4):960–966.

 PubMed Web of Science ®Google Scholar

Liu G, Zhong M, Guo C, et al. Autophagy is involved in regulating influenza A virus RNA and protein synthesis associated with both modulation of Hsp90 induction and mTOR/p70S6K signaling pathway. Int J Biochem Cell Biol. 2016;72:100–108.

 PubMed Web of Science ®Google Scholar

Zhang R-H, Zhang H-L, Pei-Yao L, et al. Autophagy is involved in the acute lung injury induced by H9N2 influenza virus. Int Immunopharmacol. 2019Sep;74:105737. DOI:10.1016/j.intimp.2019.105737

 PubMed Web of Science ®Google Scholar

Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection. Sci Signal. 2012;5(212):ra16.

 PubMed Web of Science ®Google Scholar

Zang F, Chen Y, Lin Z, et al. Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection. Immunology. 2016;148(1):56–69.

 PubMed Web of Science ®Google Scholar

Wang L, Jiang H, Shen S-M, et al. Inhibition of autophagy and chemokine induction by sphingosine 1-phosphate receptor 1 through NF-κB signaling in human pulmonary endothelial cells infected with influenza A viruses. PLoS One. 2018;13(10):e0205344.

 PubMed Web of Science ®Google Scholar

Zhu H-Y, Han L, Shi X-L, et al. Baicalin inhibits autophagy induced by influenza A virus H3N2. Antiviral Res. 2015;113:62–70.

 PubMed Web of Science ®Google Scholar

Zhang J, Zhang W, Ren L, et al. Astragaloside IV attenuates IL-1beta secretion by enhancing autophagy in H1N1 infection. FEMS Microbiol Lett. 2020;367(4):fnaa007.

 PubMed Web of Science ®Google Scholar

Choi J-G, Lee H, Soo Kim Y, et al. Kyoung Mi Moon 1, Won-Kyung Cho 1, Jin Yeul Ma. Aloe vera and its Components Inhibit Influenza A Virus-Induced Autophagy and Replication. Am J Chin Med. 2019;47(6):1307–1324.

 PubMed Web of Science ®Google Scholar

Chang C-C, You H-L, Huang S-T. Catechin inhibiting the H1N1 influenza virus associated with the regulation of autophagy. J Chin Med Assoc. 2020;83(4):386–393.

 PubMed Web of Science ®Google Scholar

Li N, Zhang Y, Wu S, et al. Tauroursodeoxycholic acid (TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2. Sci Bull (Beijing). 2019;64(3):180–188.

 Google Scholar

Jang Y, Soo Shin J, Yoon Y-S, et al. Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function. J Virol. 2018;92(24):e01441–18.

 PubMed Web of Science ®Google Scholar

Slaine PD, Kleer M, Duguay BA, et al. Thiopurines activate an antiviral unfolded protein response that blocks influenza A virus glycoprotein accumulation. J Virol. 2021; 641:180–188.

 Google Scholar

Ding Y, Dou J, Teng Z, et al. Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase. Arch Virol. 2014;159(12):3269–3278.

 PubMed Web of Science ®Google Scholar

Li R, Wang L. Baicalin inhibits influenza virus A replication via activation of type I IFN signaling by reducing miR‑146a.Mol Med Rep. 2019;20(6):5041–5049.

 Google Scholar

Nayak MK, Agrawal AS, Bose S, et al. Antiviral activity of baicalin against influenza virus H1N1-pdm09 is due to modulation of NS1-mediated cellular innate immune responses. J Antimicrob Chemother. 2014;69(5):1298–1310.

 PubMed Web of Science ®Google Scholar

Ping L, Ruikun D, Chen Z, et al. Punicalagin is a neuraminidase inhibitor of influenza viruses. J Med Virol. 2020;93(6):3465–3472.

 PubMed Web of Science ®Google Scholar

Luo J, Long Y, Ren G, et al. Punicalagin Reversed the Hepatic Injury of Tetrachloromethane by Antioxidation and Enhancement of Autophagy. J Med Food. 2019;22(12):1271–1279.

 PubMed Web of Science ®Google Scholar

Episcopio D, Aminov S, Benjamin S, et al. Atorvastatin restricts the ability of influenza virus to generate lipid droplets and severely suppresses the replication of the virus. FASEB J. 2019;33(8):9516–9525.

 PubMed Web of Science ®Google Scholar

Knox YM, Hayashi K, Suzutani T, et al. Activity of anthocyanins from fruit extract of Ribes nigrum L. against influenza A and B viruses.Acta Virol. 2001;45(4):209–215.

 Google Scholar

Kim R-J, Hah Y-S, Sung C-M, et al. Hyung Bin Park. Do antioxidants inhibit oxidative-stress-induced autophagy of tenofibroblasts? J Orthop Res. 2014;32(7):937–943.

 PubMed Web of Science ®Google Scholar

Liu H, You L, Jun W, et al. Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS. J Leukoc Biol. 2020;108(1):253–266.

 PubMed Web of Science ®Google Scholar

Koyuncu E, Budayeva HG, Miteva YV, et al. Sirtuins are evolutionarily conserved viral restriction factors. mBio. 2014;5(6):e02249–14.

 PubMed Web of Science ®Google Scholar

Park SK, Seong RK, Kim JA, et al. Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway. Nutr Res Pract. 2016;10(1):3–10.

 PubMed Web of Science ®Google Scholar

Gui B, Chen Q, Chuanxia H, et al. Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice. Virol J. 2017;14(1):10.

 PubMedGoogle Scholar

Ding B, Zhang G, Yang X, et al. Phosphoprotein of human parainfluenza virus type 3 blocks autophagosome-lysosome fusion to increase virus production. Cell Host Microbe. 2014;15(5):564–577.

 PubMed Web of Science ®Google Scholar

Dai J, Wang G, Weizhong L, et al. High-throughput screening for anti-influenza A virus drugs and study of the mechanism of procyanidin on influenza A virus-induced autophagy. J Biomol Screen. 2012;17(5):605–617.

 PubMedGoogle Scholar

Dai JP, Li WZ, Zhao XF, et al. A drug screening method based on the autophagy pathway and studies of the mechanism of evodiamine against influenza A virus.PLoS One. 2012;7(8):e42706.

 Google Scholar

Dai J-P, Zhao X-F, Zeng J, et al. Drug screening for autophagy inhibitors based on the dissociation of Beclin1-Bcl2 complex using BiFC technique and mechanism of eugenol on anti-influenza A virus activity. PLoS One. 2013;8(4):e61026.

 PubMed Web of Science ®Google Scholar

Jian-Ping Dai, Li-Qi Wu, Rui Li, Xiang-Feng Zhao, Qian-Ying Wan, Xiao-Xuan Chen, Wei-Zhong Li, Ge-Fei Wang, Kang-Sheng Li. Identification of 23-(s)-2-amino-3-phenylpropanoyl-silybin as an antiviral agent for influenza A virus infection in vitro and in vivo. Antimicrob Agents Chemother. 2013;57(9):4433–4443.

 PubMed Web of Science ®Google Scholar

Takanashi K, Dan K, Kanzaki S, et al. The Preventive Effect of the Traditional Japanese Herbal Medicine, Hochuekkito, against Influenza A Virus via Autophagy in vitro. Pharmacology. 2017;99(3–4):99–105.

 PubMed Web of Science ®Google Scholar

Haghani A, Mehrbod P, Safi N, et al. Edible bird’s nest modulate intracellular molecular pathways of influenza A virus infected cells. BMC Complement Altern Med. 2017;17(1):22.

 PubMedGoogle Scholar