Defensin-driven viral evolution

Diaz, Karina; Hu, Ciara T; Sul, Youngmee; Bromme, Beth A.; Myers, Nicolle D.; Skorohodova, Ksenia V.; Gounder, Anshu P.; Smith, Jason G.

doi:10.1371/journal.ppat.1009018

Cited by 12 publications

(27 citation statements)

References 45 publications

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“…Wild-type Ad5 was obtained from ATCC and recombinant adenovirus vectors rAd VII-GFP and rAd GFP were a gift from D. Curiel [ 72 ]. Ad5 VII-HA was generated using bacterial recombineering with an E3-deleted Ad5 bacterial artificial chromosome (BAC) vector [ 73 , 74 ]. Briefly, an HA tag was added to the protein VII gene through PCR amplification, and then protein VII was introduced into the Ad5 genome through recombineering.…”

Section: Methodsmentioning

confidence: 99%

Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses

Arnold,

Kaai,

Leung

et al. 2023

PLoS Pathog

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Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes inside the virion and disrupt host chromatin. Protein VII binds the abundant nuclear protein high mobility group box 1 (HMGB1) and sequesters HMGB1 in chromatin. HMGB1 is an abundant host nuclear protein that can also be released from infected cells as an alarmin to amplify inflammatory responses. By sequestering HMGB1, protein VII prevents its release, thus inhibiting downstream inflammatory signaling. However, the consequences of this chromatin sequestration on host transcription are unknown. Here, we employ bacterial two-hybrid interaction assays and human cell culture to interrogate the mechanism of the protein VII-HMGB1 interaction. HMGB1 contains two DNA binding domains, the A- and B-boxes, that bend DNA to promote transcription factor binding while the C-terminal tail regulates this interaction. We demonstrate that protein VII interacts directly with the A-box of HMGB1, an interaction that is inhibited by the HMGB1 C-terminal tail. By cellular fractionation, we show that protein VII renders A-box containing constructs insoluble, thereby acting to prevent their release from cells. This sequestration is not dependent on HMGB1’s ability to bind DNA but does require post-translational modifications on protein VII. Importantly, we demonstrate that protein VII inhibits expression of interferon β, in an HMGB1-dependent manner, but does not affect transcription of downstream interferon-stimulated genes. Together, our results demonstrate that protein VII specifically harnesses HMGB1 through its A-box domain to depress the innate immune response and promote infection.

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Section: Methodsmentioning

confidence: 99%

Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses

Arnold,

Kaai,

Leung

et al. 2023

PLoS Pathog

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“…we created an α-defensin-resistant HAdV-B-based vector expressing eGFP following the principles of Diaz et al [8]. We substituted sequences in three capsid proteins of HAdV-B35 (fiber, hexon, and penton base) with the corresponding amino acids of HAdV-D37 (Fig 6A ), which like HAdV-D64 is an EKC-causing virus that is naturally resistant to HD5 and HNP1 [10].…”

Section: Defensin-dependent Binding Expands the Cellular Tropism Of H...mentioning

confidence: 99%

“…Although the antimicrobial activities of defensins have been investigated most extensively, particular types of human adenovirus (HAdV), adeno-associated virus (AAV), mouse adenovirus (MAdV), rotavirus, and human immunodeficiency virus have been shown to be either resistant to α-defensin neutralization or even able to commandeer α-defensins to enhance their infection [6][7][8][9][10][11][12][13]. Similarly, infection by the bacterial pathogen Shigella is increased by α-defensins, and some commensal bacterial species are resistant to α-defensin killing [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Alpha-defensin binding expands human adenovirus tropism

Zhao,

Porter,

Burke

et al. 2024

Preprint

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Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture andin vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropismin vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.Author SummaryIn this study, we demonstrate a novel mechanism for binding of human adenoviruses (HAdVs) to cells that is dependent upon interactions with α-defensin host defense peptides but is independent of known viral receptors and co-receptors. To block normal receptor-mediated HAdV infection, we made genetic changes to both host cells and HAdVs. Under these conditions, α-defensins restored cell binding; however, infection still required the function of HAdV integrin co-receptors. This was true for multiple types of HAdVs that use different primary receptors and for cells that are either naturally devoid of HAdV receptors or were engineered to be receptor deficient. These observations suggest that in the presence of concentrations of α-defensins that would be found naturally in the lung or intestine, there are two parallel pathways for HAdV binding to cells that converge on integrins for productive infection. Moreover, these binding pathways function independently, and both operate in mixed culture. Thus, we have found that viruses can co-opt host defense molecules to expand their tropism.

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“…In HAdV-F41 and HAdV-D26, HVR1 is shorter than in HAdV-C5 and could be fully traced in cryo-EM maps [ 29 , 30 ]. The acidic HVR-1 in HAdV-C5 seems to be involved in electrostatic interactions with neutralizing defensins, and its absence in species D and F may play a role in determining the enteric or ocular tropism of these viruses, although this aspect is not well understood yet [ 30 , 49 ]. In lizard adenovirus type 2 (LAdV-2), an Atadenovirus, the loops are shorter and could be modeled without gaps.…”

Section: Structure Of the Capsid Proteinsmentioning

confidence: 99%

“…Nevertheless, it has been recently shown that HAdV-F41 binds laminin-binding integrins [ 53 ]. Since the RGD loop is also involved in neutralization by the enteric defensin HD5, it has been proposed that lack of both this sequence motif and the acidic HVR1 in hexon may play a role in facilitating infection of intestinal cells by HAdV-F40 and HAdV-F41 [ 30 , 49 ]. Another surface-exposed variable loop presents sequence divergence and different conformations in the human adenoviruses [ 7 , 29 , 30 , 51 ].…”

Section: Structure Of the Capsid Proteinsmentioning

confidence: 99%

Adenovirus Structure: What Is New?

Gallardo

Pérez-Illana

Martín-González

et al. 2021

IJMS

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Adenoviruses are large (~950 Å) and complex non-enveloped, dsDNA icosahedral viruses. They have a pseudo-T = 25 triangulation number with at least 12 different proteins composing the virion. These include the major and minor capsid proteins, core proteins, maturation protease, terminal protein, and packaging machinery. Although adenoviruses have been studied for more than 60 years, deciphering their architecture has presented a challenge for structural biology techniques. An outstanding event was the first near-atomic resolution structure of human adenovirus type 5 (HAdV-C5), solved by cryo-electron microscopy (cryo-EM) in 2010. Discovery of new adenovirus types, together with methodological advances in structural biology techniques, in particular cryo-EM, has lately produced a considerable amount of new, high-resolution data on the organization of adenoviruses belonging to different species. In spite of these advances, the organization of the non-icosahedral core is still a great unknown. Nevertheless, alternative techniques such as atomic force condensation and virion stability. Here we summarize the current knowledge on adenovirus structure, with an emphasis on high-resolution structures obtained since 2010.

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Defensin-driven viral evolution

Cited by 12 publications

References 45 publications

Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses

Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses

Alpha-defensin binding expands human adenovirus tropism

Adenovirus Structure: What Is New?

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