Disparate Entry of Adenoviruses Dictates Differential Innate Immune Responses on the Ocular Surface

Pennington, Matthew R.; Saha, Amrita; Painter, David F; Gavazzi, Christina; Ismail, Ashrafali Mohamed; Zhou, Xiaohong; Chodosh, James; Rajaiya, Jaya

doi:10.3390/microorganisms7090351

Cited by 15 publications

(10 citation statements)

References 208 publications

(279 reference statements)

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“…The data presented here suggest that replication-competent oncolytic adenoviruses may be particularly sensitive to the adverse effects of the Hsp90 inhibitors. The HAdV infections tend to be mild, but they can be serious in young and immunocompromised individuals, and specific drugs to treat such infections are lacking [ 73 , 74 , 75 ]. Our results indicate that Hsp90 inhibitors could be used to suppress the adenoviral infection.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus

Dalidowska

Gazi

Sulejczak

et al. 2021

IJMS

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Adenovirus infections tend to be mild, but they may pose a serious threat for young and immunocompromised individuals. The treatment is complicated because there are no approved safe and specific drugs for adenovirus infections. Here, we present evidence that 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 chaperone, decreases the rate of human adenovirus 5 (HAdV-5) replication in cell cultures by 95%. 17-AAG inhibited the transcription of early and late genes of HAdV-5, replication of viral DNA, and expression of viral proteins. 6 h after infection, Hsp90 inhibition results in a 6.3-fold reduction of the newly synthesized E1A protein level without a decrease in the E1A mRNA level. However, the Hsp90 inhibition does not increase the decay rate of the E1A protein that was constitutively expressed in the cell before exposure to the inhibitor. The co-immunoprecipitation proved that E1A protein interacted with Hsp90. Altogether, the presented results show, for the first time. that Hsp90 chaperones newly synthesized, but not mature, E1A protein. Because E1A serves as a transcriptional co-activator of adenovirus early genes, the anti-adenoviral activity of the Hsp90 inhibitor might be explained by the decreased E1A level.

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Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus

Dalidowska

Gazi

Sulejczak

et al. 2021

IJMS

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“…Variation in subcellular trafficking routes has been shown to influence innate immune responses to other viruses. Different trafficking mechanisms during HAdV entry of several cell types have been shown to affect the stimulation of certain PRRs, influencing distinct immune responses that are dependent on particular virus- and cell-type combinations [ 123 ]. For example, different HAdV serotypes naturally vary in their receptor usage as well as downstream early vs. late endosomal trafficking pathways.…”

Section: Discussionmentioning

confidence: 99%

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Uhlorn

Jackson

et al. 2020

PLoS Pathog

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Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.

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“…There are many classes of PRRs, with toll-like receptors being one of the most studied [ 50 , 51 ]. Many serotypes of adenovirus interact with PRRs, and the biology of these interactions has been studied with particular intensity at the ocular surface, where they are critically important to adenoviral keratoconjunctivitis [ 52 ]. Interestingly, innate responses to Ad5 may be quite broad and evoke proinflammatory responses from “nonimmune” cell types, including epithelial cells [ 53 - 55 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant adenovirus causes prolonged mobilization of macrophages in the anterior chamber of mice

Meyer

Pellack

Hedberg-Buenz

et al. 2021

Preprint

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Purpose: Ocular tissues of mice have been studied in many ways using replication deficient species C type 5 adenoviruses (Ad5) as tools for manipulating gene expression. While refinements to injection protocols and tropism have led to several advances in targeting cells of interest, there remains a relative lack of information concerning how Ad5 may influence other ocular cell types capable of confounding experimental interpretation. Here, a slit-lamp is used to thoroughly photodocument the sequalae of intraocular Ad5 injections over time in mice, with attention to potentially confounding indices of inflammation. Methods: A cohort of C57BL/6J mice were randomly split into 3 groups (Virus, receiving unilateral intraocular injection with 5x107 pfu of a cargo-less Ad5 construct; Saline, receiving unilateral balanced salt solution injection; and Naïve, receiving no injections). A total of 52 eyes from 26 mice were photodocumented via slit-lamp at 4 timepoints (baseline, 1, 3, and 10 weeks following initiation of the experiment) by an observer masked to treatments and other parameters of the experimental design. Following the last in vivo exam, tissues were collected. Based on the slit-lamp data, tissues were studied via immunostaining with the macrophage marker F4/80. Results: The masked investigator was able to use the sequential images from each mouse to assign each mouse into its correct treatment group with near perfect fidelity. Virus injected eyes were characterized by corneal damage indicative of intraocular injection and a prolonged mobilization of clump cells on the surface of the iris. Saline injected eyes had only transient corneal opacities indicative of intraocular injections, and Naïve eyes remained normal. Immunostaining with F4/80 was consistent with ascribing the clump cells visualized via slit-lamp imaging as a type of macrophage.

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Disparate Entry of Adenoviruses Dictates Differential Innate Immune Responses on the Ocular Surface

Cited by 15 publications

References 208 publications

Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus

Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus

Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

Recombinant adenovirus causes prolonged mobilization of macrophages in the anterior chamber of mice

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