STD-NMR as a novel method to study influenza virus-receptor interactions

ABSTRACT Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2−/− Ifnl3−/− mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1−/− mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore genocopy Ifnlr1−/− mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens. IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1. Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.

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Multiple Stages of Virus-Receptor Interactions as Shown by Simian Virus 40

Toward Anti-Adhesion Therapy for Microbial Diseases - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4613-0415-9_18 ◽

1996 ◽

pp. 159-167 ◽

Cited By ~ 6

Author(s):

Leonard C. Norkin ◽

Howard A. Anderson

Keyword(s):

Simian Virus 40 ◽

Simian Virus ◽

Virus Receptor ◽

Receptor Interactions ◽

Multiple Stages

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IILLS: predicting virus-receptor interactions based on similarity and semi-supervised learning

BMC Bioinformatics ◽

10.1186/s12859-019-3278-3 ◽

2019 ◽

Vol 20 (S23) ◽

Cited By ~ 3

Author(s):

Cheng Yan ◽

Guihua Duan ◽

Fang-Xiang Wu ◽

Jianxin Wang

Keyword(s):

Infectious Diseases ◽

Cross Validation ◽

Sequence Similarity ◽

Least Square ◽

Computational Method ◽

Receptor Interaction ◽

Virus Receptor ◽

Receptor Interactions ◽

Leave One Out ◽

Fold Cross Validation

Abstract Background Viral infectious diseases are the serious threat for human health. The receptor-binding is the first step for the viral infection of hosts. To more effectively treat human viral infectious diseases, the hidden virus-receptor interactions must be discovered. However, current computational methods for predicting virus-receptor interactions are limited. Result In this study, we propose a new computational method (IILLS) to predict virus-receptor interactions based on Initial Interaction scores method via the neighbors and the Laplacian regularized Least Square algorithm. IILLS integrates the known virus-receptor interactions and amino acid sequences of receptors. The similarity of viruses is calculated by the Gaussian Interaction Profile (GIP) kernel. On the other hand, we also compute the receptor GIP similarity and the receptor sequence similarity. Then the sequence similarity is used as the final similarity of receptors according to the prediction results. The 10-fold cross validation (10CV) and leave one out cross validation (LOOCV) are used to assess the prediction performance of our method. We also compare our method with other three competing methods (BRWH, LapRLS, CMF). Conlusion The experiment results show that IILLS achieves the AUC values of 0.8675 and 0.9061 with the 10-fold cross validation and leave-one-out cross validation (LOOCV), respectively, which illustrates that IILLS is superior to the competing methods. In addition, the case studies also further indicate that the IILLS method is effective for the virus-receptor interaction prediction.

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Virus—Receptor Interactions

ACS Symposium Series - Conformationally Directed Drug Design ◽

10.1021/bk-1984-0251.ch001 ◽

1984 ◽

pp. 1-7

Author(s):

BERNARD N. FIELDS ◽

MARK I. GREENE

Keyword(s):

Virus Receptor ◽

Receptor Interactions

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Prediction of Virus–Receptor Interactions Based on Improving Similarities

Journal of Computational Biology ◽

10.1089/cmb.2020.0544 ◽

2021 ◽

Author(s):

Lingzhi Zhu ◽

Cheng Yan ◽

Guihua Duan

Keyword(s):

Virus Receptor ◽

Receptor Interactions

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Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants

Journal of Virology ◽

10.1128/jvi.00534-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 21

Author(s):

Kayla M. Peck ◽

Trevor Scobey ◽

Jesica Swanstrom ◽

Kara L. Jensen ◽

Christina L. Burch ◽

...

Keyword(s):

Middle East ◽

Guinea Pig ◽

Host Range ◽

Dipeptidyl Peptidase ◽

Glycosylation Site ◽

Middle East Respiratory Syndrome ◽

Virus Receptor ◽

Dipeptidyl Peptidase 4 ◽

Receptor Interactions ◽

Species Specific

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of virus-receptor interactions associated with disease emergence and host susceptibility. IMPORTANCE MERS-CoV is a recently emerged zoonotic virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the virus spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.

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