Abstract
The blue blood of the horseshoe crab is a natural, irreplaceable, and precious resource that is highly valued by the biomedical industry. The Limulus amebocyte lysate (LAL) obtained from horseshoe crab blood cells functions as a surprisingly sophisticated sensing system that allows for the extremely sensitive detection of bacterial and fungal cell-wall components. Notably, LAL tests have markedly contributed to the quality control of pharmaceutical drugs and medical devices as successful alternatives to the rabbit pyrogen test. Furthermore, LAL-based endotoxin and (1→3)-β-D-glucan (β-glucan) assay techniques are expected to have optimal use as effective biomarkers, serving as adjuncts in the diagnosis of bacterial sepsis and fungal infections. The innovative β-glucan assay has substantially contributed to the early diagnosis and management of invasive fungal diseases; however, the clinical significance of the endotoxin assay remains unclear and is challenging to elucidate. Many obstacles need to be overcome to enhance the analytical sensitivity and clinical performance of the LAL assay in detecting circulating levels of endotoxin in human blood. Additionally, there are complex interactions between endotoxin molecules and blood components that are attributable to the unique physicochemical properties of lipopolysaccharide (LPS). In this regard, while exploring the potential of new LPS-sensing technologies, a novel platform for the ultrasensitive detection of blood endotoxin will enable a reappraisal of the LAL assay for the highly sensitive and reliable detection of endotoxemia.
Highlights
It has been more than five decades since the discovery of the remarkable benefits of horseshoe crab blood in the rapid detection of bacterial components [1]
Limulus amebocyte lysate (LAL) is an aqueous extract of horseshoe crab (Limulus polyphemus) blood cells, and the LAL test is the most sensitive and reliable method applied for in vitro detection of bacterial endotoxins [2]
The gel-clot LAL test was approved by the Food and Drug Administration (FDA) in the 1970s and has been widely adopted as the official method for detecting bacterial endotoxins [3]
Summary
It has been more than five decades since the discovery of the remarkable benefits of horseshoe crab blood in the rapid detection of bacterial components [1]. Biomedicines 2021, 9, 536 from the fungal cell wall, β-glucan, via the β-glucan-activated factor-G (FG)-mediated coagulation pathway (Figure 1) [5] Based on these findings, we successfully developed the world’s first endotoxin and β-glucan-specific chromogenic LAL reagents (Endospecy and Gluspecy; Seikagaku Corp., Tokyo, Japan) [6,7]. In Japan, chromogenic and turbidimetric techniques with endotoxin-specific LAL assays after appropriate pretreatment have been used extensively since their approval by the Ministry of Health, Labour and Welfare (MHLW, Tokyo, Japan) [8]; there are several unresolved technical issues related to plasma extraction methods, the physical and biological properties of endotoxin circulating in the blood, and the enzymatic degradation of endotoxin molecules, and these limitations have negative impacts on the early intervention for patients at risk for severe sepsis [9]. We introduce the diagnostic performance of the serum β-glucan assay and its contribution to the early diagnosis of patients at risk for invasive fungal diseases and fungal septicemia
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