COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

Kimberly A. Queisser; Rebecca A. Mellema; Elizabeth A. Middleton; Irina Portier; Bhanu Kanth Manne; Frederik Denorme; Ellen J. Beswick; Matthew T. Rondina; Robert A. Campbell; Aaron C. Petrey

doi:10.1172/jci.insight.147472

COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

Kimberly A. Queisser, Rebecca A. Mellema, Elizabeth A. Middleton, Irina Portier, Bhanu Kanth Manne, Frederik Denorme, Ellen J. Beswick, Matthew T. Rondina, Robert A. Campbell, Aaron C. Petrey

Internal Medicine

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

Original language	English
Article number	e147472
Journal	JCI insight
Volume	6
Issue number	17
DOIs	https://doi.org/10.1172/jci.insight.147472
State	Published - Sep 8 2021

Bibliographical note

Funding Information:
The authors acknowledge the figure preparation expertise of Diana Lim and assistance with participant recruitment from Antoinette Blair, Macy Barrios, Amber Plante, Jordan Greer, Amy DeNardo, Amanda Bailey, and Lindsey Waddoups. This work was supported by the following NIH grants: National Heart, Lung, and Blood Institute grant R00HL135265 (ACP); National Institute on Aging grant K01AG059892 (RAC); National Institute on Aging grants R01AG048022 and R56AG059877; and National Heart, Lung, and Blood Institute grant R01HL130541 and R01HL142804 (MTR); and National Institute of Neurological Disorders and Stroke grant U24NS107228 (FD). This work was supported by startup funds from the University of Utah (ACP). This work was supported in part by Merit Review Award Number I01 CX001696 from the United States Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service. This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah, USA.

Publisher Copyright:
© 2021, Queisser et al.

ASJC Scopus subject areas

Medicine (all)

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10.1172/jci.insight.147472

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title = "COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction",

abstract = "Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.",

author = "Queisser, {Kimberly A.} and Mellema, {Rebecca A.} and Middleton, {Elizabeth A.} and Irina Portier and Manne, {Bhanu Kanth} and Frederik Denorme and Beswick, {Ellen J.} and Rondina, {Matthew T.} and Campbell, {Robert A.} and Petrey, {Aaron C.}",

note = "Funding Information: The authors acknowledge the figure preparation expertise of Diana Lim and assistance with participant recruitment from Antoinette Blair, Macy Barrios, Amber Plante, Jordan Greer, Amy DeNardo, Amanda Bailey, and Lindsey Waddoups. This work was supported by the following NIH grants: National Heart, Lung, and Blood Institute grant R00HL135265 (ACP); National Institute on Aging grant K01AG059892 (RAC); National Institute on Aging grants R01AG048022 and R56AG059877; and National Heart, Lung, and Blood Institute grant R01HL130541 and R01HL142804 (MTR); and National Institute of Neurological Disorders and Stroke grant U24NS107228 (FD). This work was supported by startup funds from the University of Utah (ACP). This work was supported in part by Merit Review Award Number I01 CX001696 from the United States Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service. This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah, USA. Publisher Copyright: {\textcopyright} 2021, Queisser et al.",

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doi = "10.1172/jci.insight.147472",

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AU - Mellema, Rebecca A.

AU - Middleton, Elizabeth A.

AU - Portier, Irina

AU - Manne, Bhanu Kanth

AU - Denorme, Frederik

AU - Beswick, Ellen J.

AU - Rondina, Matthew T.

AU - Campbell, Robert A.

AU - Petrey, Aaron C.

N1 - Funding Information: The authors acknowledge the figure preparation expertise of Diana Lim and assistance with participant recruitment from Antoinette Blair, Macy Barrios, Amber Plante, Jordan Greer, Amy DeNardo, Amanda Bailey, and Lindsey Waddoups. This work was supported by the following NIH grants: National Heart, Lung, and Blood Institute grant R00HL135265 (ACP); National Institute on Aging grant K01AG059892 (RAC); National Institute on Aging grants R01AG048022 and R56AG059877; and National Heart, Lung, and Blood Institute grant R01HL130541 and R01HL142804 (MTR); and National Institute of Neurological Disorders and Stroke grant U24NS107228 (FD). This work was supported by startup funds from the University of Utah (ACP). This work was supported in part by Merit Review Award Number I01 CX001696 from the United States Department of Veterans Affairs Clinical Sciences R&D (CSRD) Service. This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah, USA. Publisher Copyright: © 2021, Queisser et al.

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N2 - Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

AB - Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

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COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

Abstract

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