1. Glycomic analysis of host response reveals high mannose as a key mediator of influenza severity
- Author
-
Sujeethraj Koppolu, Lauren P. Lashua, Yue Zhang, Joaquin Lopez-Orozco, Chalise E. Carter, Lawrence Meche, Tom C. Hobman, Stephanie J. Bissel, Ted M. Ross, Tsui-wen Chou, Lara K. Mahal, Bin Zhang, Christopher A. Vaiana, Daniel W. Heindel, Elodie Ghedin, Brian Kasper, Bin Zhou, Mohamed Elaish, and Alyson A. Kelvin
- Subjects
0301 basic medicine ,X-Box Binding Protein 1 ,Glycosylation ,lectin array ,Disease ,Biology ,Microbiology ,Mannose-Binding Lectin ,Virus ,Epitope ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,lectin microarray ,Influenza A Virus, H1N1 Subtype ,mannan binding lectin ,Influenza, Human ,Animals ,Humans ,Glycomics ,Lung ,Mannan-binding lectin ,Glycoproteins ,Multidisciplinary ,Innate immune system ,mannose binding lectin ,Ferrets ,Biological Sciences ,030104 developmental biology ,MBL2 ,A549 Cells ,Immunology ,Host-Pathogen Interactions ,Unfolded protein response ,Carbohydrate Metabolism ,Female ,Mannose ,030217 neurology & neurosurgery - Abstract
Significance Influenza virus infection causes a range of outcomes from mild illness to death. The molecular mechanisms leading to these differential host responses are currently unknown. Herein, we identify the induction of high mannose, a glycan epitope, as a key mediator of severe disease outcome. We propose a mechanism in which activation of the unfolded protein response (UPR) upon influenza virus infection induces cell surface high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and leading to subsequent inflammation. This work is the first to systematically study host glycomic changes in response to influenza virus infection, identifying high mannose as a key feature of differential host response., Influenza virus infections cause a wide variety of outcomes, from mild disease to 3 to 5 million cases of severe illness and ∼290,000 to 645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose-dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity.
- Published
- 2020