Lashua, L. P. | Search bioRxiv

bioRxiv2020

Age-dependent glycomic response to the 2009 pandemic H1N1 influenza virus and its association with disease severity

Influenza A viruses cause a spectrum of responses, from mild cold-like symptoms to severe respiratory illness and death. Viral strains and intrinsic host factors, such as age, can influence the severity of the disease. Glycosylation plays a critical role in influenza pathogenesis, however the molecular drivers of influenza outcomes remain unknown. In this work, we characterized the glycomic response to the H1N1 2009 pandemic influenza A virus in age-dependent severity. Using a ferret model and a lectin microarray technology we have developed, we compared responses in newly weaned and aged animals, a model for young children and the elderly, respectively. Glycomic analysis revealed changes in glycosylation over the course of the infection, that were associated with severity in an age-dependent manner. These responses may help explain the differential susceptibility to influenza A virus infection of young children and the elderly. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/165613v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1c5aebdorg.highwire.dtl.DTLVardef@15316e6org.highwire.dtl.DTLVardef@45ff3org.highwire.dtl.DTLVardef@1376533_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2020

Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity

Influenza virus infections cause a wide variety of outcomes, from mild disease to 3-5 million cases of severe illness and ~290,000-645,000 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. SIGNIFICANCEInfluenza 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 turns on expression of 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.

microbiology↗