Prospective Observational Study on the Association Between Serum Mannose-Binding Lectin Levels and Severe Outcome in Critically Ill Patients with Pandemic Influenza Type A (H1N1) Infection

Proc. Natl. Acad. Sci. U.S.A.

et al. 2020

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.

Section: Significancementioning

confidence: 52%

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

Heindel

Koppolu

Proc. Natl. Acad. Sci. U.S.A.

et al. 2020

“…5a ) (11, 29–31). Taken together, our work provides a new mechanism that could explain the observation that both UPR activation and MBL2 levels directly associate with severity of outcome from influenza infection (13, 18, 19).…”

Section: Resultsmentioning

confidence: 67%

“…Upon binding, MBL2 activates the complement cascade and corresponding inflammatory response (44). A recent study on critically ill patients infected with H1N1pdm09 virus showed a strong correlation between levels of MBL2 in the blood and patient death (19). In addition, schizophrenics and multiple sclerosis patients, both have high levels of MBL2 and unusually high death rates from influenza and pneumonia (45–48).…”

Section: Resultsmentioning

confidence: 99%

“…Lewis structures (14, 15), high mannose (16), yeast mannans (17), fucose (15)), recognizes influenza virus infected cells in a high mannose dependent manner. MBL2 is also associated with the severity of influenza in mouse models (18) and more recently in clinical analysis (19). Together, our data argue that the high mannose motif is an influenza infection-associated molecular pattern on host cells that guides immune responses leading to the concomitant damage associated with influenza disease severity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Heindel

Koppolu

et al. 2020

Preprint

“…The complement inducing lectin MBL2, which binds this induced glycan epitope has been strongly associated with influenza severity. 20,21 We hypothesize that the induced high mannose may play a causative role in the damage observed from MBL2 levels in influenza.…”

Section: Introductionmentioning

confidence: 98%

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

Chen

Kasper

et al. 2020

Preprint

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.