Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality

Snider, Justin; You, Jeehyun Karen; Wang, Xia; Snider, Ashley J.; Hallmark, Brian; Zec, Manja; Seeds, Michael C.; Sergeant, Susan; Johnstone, Laurel; Wang, Qiuming; Sprissler, Ryan; Carr, Tara F.; Lutrick, Karen; Parthasarathy, Sairam; Bime, Christian; Zhang, Hao Helen; Luberto, Chiara; Kew, Richard R.; Hannun, Yusuf A.; Guerra, Stefano; McCall, Charles E.; Yao, Guang; Poeta, Maurizio Del; Chilton, Floyd H.

doi:10.1172/jci149236

Cited by 83 publications

(96 citation statements)

References 48 publications

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“…SP-A, via its ability to inhibit surfactant phospholipid hydrolysis and thus maintain, to a certain extent a well-functioning surfactant, plays a protective role in lung injury. This is of great relevance to the current Covid-19 pandemic, as sPLA2-IIA was shown to associate with markers more likely to lead to mortality after SARS-CoV-2 infection (63).…”

Section: Surfactant-related Activitiesmentioning

confidence: 90%

Surfactant Protein-A Function: Knowledge Gained From SP-A Knockout Mice

2022

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Pulmonary surfactant proteins have many roles in surfactant- related functions and innate immunity. One of these proteins is the surfactant protein A (SP-A) that plays a role in both surfactant-related processes and host defense and is the focus in this review. SP-A interacts with the sentinel host defense cell in the alveolus, the alveolar macrophage (AM), to modulate its function and expression profile under various conditions, as well as other alveolar epithelial cells such as the Type II cell. Via these interactions, SP-A has an impact on the alveolar microenvironment. SP-A is also important for surfactant structure and function. Much of what is understood of the function of SP-A and its various roles in lung health has been learned from SP-A knockout (KO) mouse experiments, as reviewed here. A vast majority of this work has been done with infection models that are bacterial, viral, and fungal in nature. Other models have also been used, including those of bleomycin-induced lung injury and ozone-induced oxidative stress either alone or in combination with an infectious agent, bone marrow transplantation, and other. In addition, models investigating the effects of SP-A on surfactant components or surfactant structure have contributed important information. SP-A also appears to play a role in pathways involved in sex differences in response to infection and/or oxidative stress, as well as at baseline conditions. To date, this is the first review to provide a comprehensive report of the functions of SP-A as learned through KO mice.

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Section: Surfactant-related Activitiesmentioning

confidence: 90%

Surfactant Protein-A Function: Knowledge Gained From SP-A Knockout Mice

2022

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“…Recent data has highlighted a new link between hGIIA and SARS-CoV-2 infection during the COVID-19 pandemic [ 97 ]. Out of 80 clinical indices measured, including age and body mass index, hGIIA and blood urea nitrogen (BUN) were the strongest predictors of severe disease, with a decision tree based on these two indicators being able to stratify patients with mild severe or fatal infection on a validation cohort of COVID-positive patients.…”

Section: Hgiia Functionmentioning

confidence: 99%

“…Out of 80 clinical indices measured, including age and body mass index, hGIIA and blood urea nitrogen (BUN) were the strongest predictors of severe disease, with a decision tree based on these two indicators being able to stratify patients with mild severe or fatal infection on a validation cohort of COVID-positive patients. Sars-CoV-2 infection also alters the lipidome, resulting in higher concentrations of lyso-PE and lyso-PS, with no changes in lyso-PC, which is a hallmark of hGIIA activity [ 97 ]. Other research suggests COVID-19 may also increase levels of PS on the surface of the cell membrane, exposing cells to catalytic activity of hGIIA [ 97 , 98 ].…”

Section: Hgiia Functionmentioning

confidence: 99%

“…Sars-CoV-2 infection also alters the lipidome, resulting in higher concentrations of lyso-PE and lyso-PS, with no changes in lyso-PC, which is a hallmark of hGIIA activity [ 97 ]. Other research suggests COVID-19 may also increase levels of PS on the surface of the cell membrane, exposing cells to catalytic activity of hGIIA [ 97 , 98 ]. The authors suggest that hGIIA may mediate severe COVID-19 disease and as its expression is closely linked to disease outcome, that hGIIA is an attractive therapeutic target.…”

Section: Hgiia Functionmentioning

confidence: 99%

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Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

et al. 2021

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Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

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“…Under infectious and inflammatory conditions, sPLA 2 -IIA expression is highly induced in numerous cell types, including endothelial, hepatic, renal, smooth muscle, macrophages, mast cells, platelets, astrocytes, and glial cells (34,45,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The serum concentration of sPLA 2 -IIA can increase up to 1000fold during sepsis, to reach concentrations of ~5 μg/mL (~350 nM) (64), and recent studies revealed that it is also induced in COVID-19 patients (65). Investigation of the gene promoter revealed that sPLA 2 -IIA is induced by proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (66-69), while activation of TLR and nucleotide-binding oligomerization domain-like receptors (NLR) by pathogen-associated molecular patterns (PAMPs) also trigger sPLA 2 -IIA expression through the NF-κB pathway (70)(71)(72)(73)(74).…”

Section: Introductionmentioning

confidence: 99%