Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

Barnes, Henry W.; Demirdjian, Sally; Haddock, Naomi L.; Kaber, Gernot; Martinez, Hunter A.; Nagy, Nadine; Karmouty‐Quintana, Harry; Bollyky, Paul L.

doi:10.1016/j.matbio.2023.02.001

Cited by 11 publications

(4 citation statements)

References 221 publications

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“…Previous studies have indicated the potential long-term effects of COVID-19 on the immune system and the body's ability to produce HA (Barnes et al, 2023;Willyard, 2023). Our study showed that serum HA levels were significantly lower in the reinfection group than in the matched first infection group (Supplementary Table S1 and Figure 1).…”

Section: Discussionsupporting

confidence: 49%

“…As an important component of the extracellular matrix, HA plays a facilitating role in organ fibrosis (Neuman et al, 2016). A recent review summarized the role of HA in the pathogenesis of acute and post-acute COVID-19 infection, and speculated that HA may be involved in the development of long COVID and COVID-related fibrosis (Barnes et al, 2023). However, this speculation has not yet been confirmed by clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…Chinese researchers have identified five identical sequences shared by SARS-CoV-2 and humans that promote the accumulation of HA by upregulating HA synthase gene expression, resulting in the formation of ground-glass lesions (Li et al, 2022;Yang et al, 2022). In addition, Barnes et al (2023) speculated that HA may play a potential role in long COVID and COVID-associated fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and prognostic implications of hyaluronic acid in patients with COVID-19 reinfection and first infection

Li,

Han,

2024

Front. Microbiol.

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ObjectivePrevious research has shown that human identical sequences of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) promote coronavirus disease 2019 (COVID-19) progression by upregulating hyaluronic acid (HA). However, the association of HA with mortality and long COVID in SARS-CoV-2 reinfection and first infection is unclear.MethodsPatients with COVID-19 at Beijing Ditan Hospital from September 2023 to November 2023 were consecutively enrolled. SARS-CoV-2 reinfections were matched 1:2 with first infections using a nearest neighbor propensity score matching algorithm. We compared the hospital outcomes between patients with COVID-19 reinfection and first infection. The association between HA levels and mortality and long COVID in the matched cohort was analyzed.ResultsThe reinfection rate among COVID-19 hospitalized patients was 25.4% (62 cases). After propensity score matching, we found that reinfection was associated with a better clinical course and prognosis, including lower levels of C-reactive protein and erythrocyte sedimentation rate, fewer cases of bilateral lung infiltration and respiratory failure, and shorter viral clearance time and duration of symptoms (p < 0.05). HA levels were significantly higher in patients with primary infection [128.0 (90.5, 185.0) vs. 94.5 (62.0, 167.3), p = 0.008], those with prolonged viral clearance time [90.5 (61.5, 130.8) vs. 130.0 (95.0, 188.0), p < 0.001], and deceased patients [105.5 (76.8, 164.5) vs. 188.0 (118.0, 208.0), p = 0.002]. Further analysis showed that HA was an independent predictor of death (AUC: 0.789), and the risk of death increased by 4.435 times (OR = 5.435, 95% CI = 1.205–24.510, p = 0.028) in patients with high HA levels. We found that patients with HA levels above 116 ng/mL had an increased risk of death. However, the incidence of long COVID was similar in the different HA level groups (p > 0.05).ConclusionSerum HA may serve as a novel biomarker for predicting COVID-19 mortality in patients with SARS-CoV-2 reinfection and first infection. However, HA levels may not be associated with long COVID.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and prognostic implications of hyaluronic acid in patients with COVID-19 reinfection and first infection

Li,

Han,

2024

Front. Microbiol.

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“…We also did not explore all possible mechanisms of virus-susceptibility modulation by IL-13 suggested by our transcriptomic analysis. Recent studies reported that IL-13 modulates hyaluronan polysaccharide and keratan sulfate abundance and influences the outcome of SARS-CoV-2 infection in vitro and in vivo (4, 41, 57).…”

Section: Discussionmentioning

confidence: 99%

IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo

Ghimire,

Xue,

et al. 2024

Preprint

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Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signaling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents. We investigated the role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo. IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2- expressing ciliated cells rather than by neutralization in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened disease severity in mice; the effects were mediated by eicosanoid signaling and were abolished in mice deficient in the phospholipase A2 enzyme PLA2G2D. We conclude that IL-13-induced inflammation differentially affects multiple steps of COVID-19 pathogenesis. IL-13-induced inflammation may be protective against initial SARS-CoV-2 airway epithelial infection; however, it enhances disease progression in vivo. Blockade of IL-13 and/or eicosanoid signaling may be protective against progression to severe respiratory virus-induced lung disease.RESEARCH IN CONTEXTEvidence before this studyPrior to this study, various pieces of evidence indicated the significant role of cytokines in the pathogenesis and progression of COVID-19. Severe COVID-19 cases were marked by cytokine storm syndrome, leading to immune activation and hyperinflammation. Treatments aimed at modulating cytokine signaling, such as IL-6 receptor antagonists, had shown moderate effects in managing severe COVID-19 cases. Studies also revealed an excessive production of type 2 cytokines, particularly IL-13 and IL-4, in the plasma and lungs of COVID-19 patients, which was associated with adverse outcomes. Treatment with anti-IL-13 monoclonal antibodies improved survival following SARS-CoV-2 infection, suggesting that IL-13 plays a role in disease severity. Type 2 cytokines were observed to potentially suppress type 1 responses, essential for viral clearance, and imbalances between these cytokine types were linked to negative COVID-19 outcomes. These findings highlighted the complex interactions between cytokines and the immune response during viral infections, underscoring the importance of understanding IL-13’s role in COVID-19 and related lung diseases for developing effective therapeutic interventions.Added value of this studyIn this study, we explored the impact of IL-13-induced inflammation on various stages of the SARS-CoV-2 infection cycle using both murine (in vivo) and primary human airway epithelial (in vitro) culture models. Our findings indicated that IL-13 provided protection to airway epithelial cells against SARS-CoV-2 infection in vitro, partly by reducing the number of ACE2- expressing ciliated cells. Conversely, IL-13 exacerbated the severity of SARS2-N501YMA30-induced disease in mice, primarily through Pla2g2d-mediated eicosanoid biosynthesis.Implications of the available evidenceCurrent evidence indicates that PLA2G2D plays a crucial role in the IL-13-driven exacerbation of COVID-19 in mice, suggesting that targeting the IL-13-PLA2G2D axis could help protect against SARS-CoV-2 infection. These insights are important for clinical research, especially for studies focusing on drugs that modify IL-13 signaling or modulate eicosanoids in the treatment of asthma and respiratory virus-induced lung diseases.

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Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential

Liu,

Hou,

Fang

et al. 2024

Molecular Oncology

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Hyaluronic acid (HA) is a major component of the extracellular matrix, providing essential mechanical scaffolding for cells and, at the same time, mediating essential biochemical signals required for tissue homeostasis. Many solid tumors are characterized by dysregulated HA metabolism, resulting in increased HA levels in cancer tissue. HA interacts with several cell surface receptors, such as CD44 and RHAMM, thus co‐regulating important signaling pathways in cancer development and progression. In this review, we describe the enzymes controlling HA metabolism and its intracellular effectors emphasizing their impact in cancer chemotherapy resistance. We will also explore the current and future prospects of HA‐based therapy, highlighting the opportunities and challenges in the field.

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Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

Cited by 11 publications

References 221 publications

Clinical and prognostic implications of hyaluronic acid in patients with COVID-19 reinfection and first infection

Clinical and prognostic implications of hyaluronic acid in patients with COVID-19 reinfection and first infection

IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo

Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential

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