Ching-Tai Huang1, Chen-Yiu Hung2, Yu-Chia Hseih3, Chia-Shiang Chang4, Arul Balaji Velu5, Yueh-Chia He4, Yu-Lin Huang4, Ting-An Chen4, Tse-Ching Chen6, Chun-Yen Lin7, Yung-Chang Lin8, Shin-Ru Shih5, Avijit Dutta9. 1. Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan; College of Medicine, Chang Gung University, Guishan-33333, Taoyuan City, Taiwan. 2. Department of Thoracic Medicine, Chang Gung Memorial Hospital, Guishan-33333, Taoyuan City, Taiwan. 3. Division of Pediatric Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. 4. Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. 5. Research Center for Emerging Viral Infections and Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Guishan- 33333, Taoyuan City, Taiwan. 6. College of Medicine, Chang Gung University, Guishan-33333, Taoyuan City, Taiwan; Department of Pathology, Chang Gung Memorial Hospital, Guishan-33333, Taoyuan City, Taiwan. 7. College of Medicine, Chang Gung University, Guishan-33333, Taoyuan City, Taiwan; Division of Hepatogastroenterology, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. 8. College of Medicine, Chang Gung University, Guishan-33333, Taoyuan City, Taiwan; Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. 9. Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. Electronic address: duttijiva@gmail.com.
Abstract
BACKGROUND: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern. PURPOSE: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection. METHODS: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2 influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1 influenza virus infected mice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo. RESULTS: Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC50 value 91.83 ± 18.97 μM. In H1N1 influenza virus infected mice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-β activation. Viral neuraminidase mediated immune suppression with TGF-β was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted. CONCLUSION: Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in human influenza.
BACKGROUND: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern. PURPOSE: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection. METHODS: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1influenza virus infectedmice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo. RESULTS:Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC50 value 91.83 ± 18.97 μM. In H1N1influenza virus infectedmice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-β activation. Viral neuraminidase mediated immune suppression with TGF-β was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted. CONCLUSION:Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in humaninfluenza.
Authors: Mohamed E Abouelela; Hamdy K Assaf; Reda A Abdelhamid; Ehab S Elkhyat; Ahmed M Sayed; Tomasz Oszako; Lassaad Belbahri; Ahmed E El Zowalaty; Mohamed Salaheldin A Abdelkader Journal: Molecules Date: 2021-03-21 Impact factor: 4.411