Autophagy is an Essential Component of Drosophila Immunity Against Vesicular Stomatitis Virus

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2009 Apr 14

PMID 19362021

Citations 268

Authors

Spencer Shelly

Nina Lukinova

Shelly Bambina

Allison Berman

Sara Cherry

Affiliations

Soon will be listed here.

Abstract

Intrinsic innate immune mechanisms are the first line of defense against pathogens and exist to control infection autonomously in infected cells. Here, we showed that autophagy, an intrinsic mechanism that can degrade cytoplasmic components, played a direct antiviral role against the mammalian viral pathogen vesicular stomatitis virus (VSV) in the model organism Drosophila. We found that the surface glycoprotein, VSV-G, was likely the pathogen-associated molecular pattern (PAMP) that initiated this cell-autonomous response. Once activated, autophagy decreased viral replication, and repression of autophagy led to increased viral replication and pathogenesis in cells and animals. Lastly, we showed that the antiviral response was controlled by the phosphatidylinositol 3-kinase (PI3K)-Akt-signaling pathway, which normally regulates autophagy in response to nutrient availability. Altogether, these data uncover an intrinsic antiviral program that links viral recognition to the evolutionarily conserved nutrient-signaling and autophagy pathways.

Citing Articles

A self-adjuvant multiantigenic nanovaccines simultaneously activate the antiviral and antitumor immunity for the treatment of cancers.

Wang Z, Chen H, Ming R, Wang W, Liu S, Jing Y J Nanobiotechnology. 2025; 23(1):150.

PMID: 40016753 PMC: 11866856. DOI: 10.1186/s12951-025-03208-1.

Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis.

Lin L, Lin Y, Han Z, Wang K, Zhou S, Wang Z Front Immunol. 2024; 15:1460023.

PMID: 39544928 PMC: 11560454. DOI: 10.3389/fimmu.2024.1460023.

AFM41a: A Novel PAD2 Inhibitor for Sepsis Treatment-Efficacy and Mechanism.

Dong T, Barasa L, Yu X, Ouyang W, Shao L, Quan C Int J Biol Sci. 2024; 20(13):5043-5055.

PMID: 39430255 PMC: 11488583. DOI: 10.7150/ijbs.97166.

Maintenance of persistent transmission of a plant arbovirus in its insect vector mediated by the Toll-Dorsal immune pathway.

He Y, Lu G, Xu B, Mao Q, Qi Y, Jiao G Proc Natl Acad Sci U S A. 2024; 121(14):e2315982121.

PMID: 38536757 PMC: 10998634. DOI: 10.1073/pnas.2315982121.

Evolutionary immunology to explore original antiviral strategies.

Imler J, Cai H, Meignin C, Martins N Philos Trans R Soc Lond B Biol Sci. 2024; 379(1901):20230068.

PMID: 38497262 PMC: 10945398. DOI: 10.1098/rstb.2023.0068.

References

Lee H, Lund J, Ramanathan B, Mizushima N, Iwasaki A . Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007; 315(5817):1398-401. DOI: 10.1126/science.1136880. View

Kirkegaard K, Taylor M, Jackson W . Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol. 2004; 2(4):301-14. PMC: 7097095. DOI: 10.1038/nrmicro865. View

Yano T, Mita S, Ohmori H, Oshima Y, Fujimoto Y, Ueda R . Autophagic control of listeria through intracellular innate immune recognition in drosophila. Nat Immunol. 2008; 9(8):908-16. PMC: 2562576. DOI: 10.1038/ni.1634. View

Letchworth G, Rodriguez L, Del cbarrera J . Vesicular stomatitis. Vet J. 1999; 157(3):239-60. DOI: 10.1053/tvjl.1998.0303. View

Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y . In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2003; 15(3):1101-11. PMC: 363084. DOI: 10.1091/mbc.e03-09-0704. View

Ling Y, Shaw M, Ayala C, Coppens I, Taylor G, Ferguson D . Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med. 2006; 203(9):2063-71. PMC: 2118399. DOI: 10.1084/jem.20061318. View

Rich K, Burkett C, Webster P . Cytoplasmic bacteria can be targets for autophagy. Cell Microbiol. 2003; 5(7):455-68. DOI: 10.1046/j.1462-5822.2003.00292.x. View

Liang X, Kleeman L, Jiang H, Gordon G, Goldman J, Berry G . Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998; 72(11):8586-96. PMC: 110269. DOI: 10.1128/JVI.72.11.8586-8596.1998. View

Meylan E, Tschopp J, Karin M . Intracellular pattern recognition receptors in the host response. Nature. 2006; 442(7098):39-44. DOI: 10.1038/nature04946. View

10.

Lemaitre B, Hoffmann J . The host defense of Drosophila melanogaster. Annu Rev Immunol. 2007; 25:697-743. DOI: 10.1146/annurev.immunol.25.022106.141615. View

11.

Mishra S, Schneider D . Interactions between the cellular and humoral immune responses in Drosophila. Curr Biol. 2000; 10(13):781-4. DOI: 10.1016/s0960-9822(00)00569-8. View

12.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T . The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-6. DOI: 10.1038/nature03029. View

13.

Gupta A, Das T, Banerjee A . Casein kinase II is the P protein phosphorylating cellular kinase associated with the ribonucleoprotein complex of purified vesicular stomatitis virus. J Gen Virol. 1995; 76 ( Pt 2):365-72. DOI: 10.1099/0022-1317-76-2-365. View

14.

Chen G, Lee J, Tang H, Debnath J, Thomas S, Settleman J . Genetic interactions between Drosophila melanogaster Atg1 and paxillin reveal a role for paxillin in autophagosome formation. Autophagy. 2007; 4(1):37-45. DOI: 10.4161/auto.5141. View

15.

Andrade R, Wessendarp M, Gubbels M, Striepen B, Subauste C . CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest. 2006; 116(9):2366-77. PMC: 1555650. DOI: 10.1172/JCI28796. View

16.

Rolls M, Webster P, Balba N, Rose J . Novel infectious particles generated by expression of the vesicular stomatitis virus glycoprotein from a self-replicating RNA. Cell. 1994; 79(3):497-506. DOI: 10.1016/0092-8674(94)90258-5. View

17.

Singh S, Davis A, Taylor G, Deretic V . Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science. 2006; 313(5792):1438-41. DOI: 10.1126/science.1129577. View

18.

Cherry S, Doukas T, Armknecht S, Whelan S, Wang H, Sarnow P . Genome-wide RNAi screen reveals a specific sensitivity of IRES-containing RNA viruses to host translation inhibition. Genes Dev. 2005; 19(4):445-52. PMC: 548945. DOI: 10.1101/gad.1267905. View

19.

Arico S, Petiot A, Bauvy C, Dubbelhuis P, Meijer A, Codogno P . The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2001; 276(38):35243-6. DOI: 10.1074/jbc.C100319200. View

20.

Britton J, Lockwood W, Li L, Cohen S, Edgar B . Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell. 2002; 2(2):239-49. DOI: 10.1016/s1534-5807(02)00117-x. View