Plasmalogen loss in sepsis and SARS-CoV-2 infection

Pike DP, McGuffee RM, Geerling E, Albert CJ, Hoft DF, Shashaty MGS, Meyer NJ, Pinto AK, and Ford DA. (2022) Plasmalogen loss in sepsis and SARS-CoV-2 infection. Frontiers in Cell and Developmental Biology

Sepsis is a significant threat to global health and occurs when an infection triggers an uncontrolled immune response and leads to systemic microcirculatory and immune dysfunction. Since this response is not properly regulated, this causes damage to cells by reactive oxygen species (ROS) and other inflammatory mediators, coagulation cascade, vasodilation, tissue hypoxia, and mitochondrial dysfunction. Together this all can lead to lethal organ injury and metabolic dysfunction. A timely example of a cause of sepsis is COVID-19 infection where a cause of mortality is sepsis-associated acute respiratory distress syndrome (ARDS). Lipids are thought to be mediators in sepsis and some lipids can be used as sepsis biomarkers. Plasmalogens, a class of lipid that contains a vinyl-ether bond at the sn-1 position, have been shown to be reduced during inflammation and because of this, Pike et al wanted to determine if plasmalogens had a role in sepsis and COVID-19 infection.

Firstly, Pike et al wanted to determine the plasmalogen profile of people with sepsis. Plasma samples from 31 controls and 63 septic people after 7 days in the ICU were collected. Since plasmalogen levels decrease with age and the sepsis group had a higher mean age than the control group, an age-restricted control group was also used as a comparison composed of 7 subjects with a closer mean age to the septic group. Choline plasmalogens were found to be unchanged or increased in the patients with sepsis when compared to the main control group and the age-restricted controls. When looking at ethanolamine plasmalogens, all were found to be decreased in the septic patients compared to both control groups.

To continue studying plasmalogens in sepsis, 8–12-week-old male Sprague-Dawley rats were used as a model of sepsis through intraperitoneal cecal slurry (CS) administration (15 mL/kg) using cecal contents from donor rats or 15% glycerol as the vehicle control in sterile saline. To stimulate sepsis, ceftriaxone, a cephalosporin antibiotic, was administered eight hours later, then at 20 hours post-CS administration, the animals were euthanized. Plasmalogen loss was observed in the plasma of CS treated rats compared to the vehicle group, but choline plasmalogens were the most abundant in both the septic rats and the control group compared to ethanolamine plasmalogen levels. The kidney and liver are primary sites of organ failure, and in these tissues ethanolamine plasmalogens are more abundant than choline plasmalogens. Many ethanolamine plasmalogen species were decreased in both tissues in the CS-administered rats, while all choline plasmalogens were increased in the liver compared to the controls.

It has been shown that plasmalogens are reduced in humans with severe COVID-19 and because SARS-CoV-2 infection can lead to sepsis-associated ARDS, the authors were also interested in studying how plasmalogen levels are affected by airway infection of SARS-CoV-2 in mice. To accomplish this, female K18 mice were intranasally infected with 1 × 10^4 focus forming units (FFU) of the beta variant B.1.351 of SARS-CoV-2 or with a mock infection for a control group. Three days following the infection, a strong viral load was detected in the lungs, and increases were seen in interleukin-1β, interleukin-6, and tumor necrosis factor-α. These increases indicate a cytokine storm response to the SARS-CoV-2 infection, and this was not seen in the animals that received the mock infection. Similar to the rat tissues, ethanolamine plasmalogens were more abundant than choline plasmalogens, and there were significant decreases in choline and ethanolamine plasmalogens in the lungs while only a small decrease was detected in choline plasmalogens in the plasma of these mice.

Pike et al were interested in further studying the effect of sepsis and SAR-CoV-2 infection on plasmalogen levels in plasma and tissues. Their results were the first to show the differences seen in different plasmalogen species in septic humans and they demonstrated that both sepsis and COVID-19 causes ethanolamine plasmalogen reductions in rodent models. Plasmalogens are protective against oxidative stress and have roles in infection and inflammation therefore further work on the protective role of plasmalogens in fighting infection and combating the effects of oxidative stress would be interesting. As well, the authors suggest that plasmalogens may be able to be used as biomarkers of sepsis and COVID-19 progression or recovery.