A group of scientists in China has recently developed an antacid nanoantidote that can effectively improve blood acidosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study has been published in the journal VIEW.
Study: Nanoantidote for pH Suppression of Acidosis Promoting COVID-19 Infection. Image credit: ANDREI ASKIRKA/Shutterstock
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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is known to induce respiratory and metabolic acidosis, especially diabetic ketoacidosis. In critically ill patients with COVID-19, acidosis (reduced blood pH) has been found to increase the risk of mortality.
Intravenous administration of sodium bicarbonate is considered the standard treatment for acidosis. However, the treatment has many disadvantages, including sodium overload, hypokalemia, and hypocalcemia. This highlights the need to develop new therapeutic interventions with minimal side effects.
In the current study, the scientists investigated whether acidosis induced by SARS-CoV-2 infection further promotes SARS-CoV-2 infection through a positive feedback loop. In addition, they have developed an antacid nanoantidote and evaluated its efficacy in mitigating acidosis related to COVID-19.
Impact of acidosis on SARS-CoV-2 infection
Acidosis is characterized by increased acid content (increased hydrogen ion concentration) in the blood or other tissues. The condition is associated with a reduction in blood pH from its normal value of 7.35 – 7.45.
The impact of COVID-19-related acidosis on the efficiency of SARS-CoV-2 infection was investigated by culturing human cells expressing angiotensin-converting enzyme 2 (ACE2) under different conditions of pH in the presence of SARS-CoV-2. The pH values of 6.8, 7.4, and 7.8 were considered for the experiments as acidic, normal, and alkaline conditions, respectively.
The findings revealed that the acidosis associated with COVID-19 (pH 6.8) increases the efficiency of SARS-CoV-2 to infect cells compared to normal blood pH (7.4). In contrast, alkaline pH (7.8) reduced the viral efficacy of infected cells.
These observations highlight the existence of a positive feedback loop in which SARS-CoV-2-induced acidosis further facilitates viral spread in human cells.
Development of antacid nanoantidote
The antacid antidote was initially constructed by synthesizing functional block copolymers (polyglutamic acid-PEG), followed by the interactions of copolymers with calcium ions and carboxyl groups to form calcium carbonate nanoparticles (nanoantidote).
Regarding the mode of action, the nanoparticles gradually increased the pH from 6.8 to 7.4 in a dose-dependent manner. In other words, the nanoparticles neutralized the hydrogen ions in the solution to restore the normal pH.
Functional characterization of the nanoantidote
The nanoantidote developed in the study showed high efficacy in preventing acidosis-mediated induction (pH 6.8) in the efficacy of SARS-CoV-2 infection.
The analysis revealed that an acidic pH helps to increase the efficiency of infection by increasing the expression of ACE2 in the cell membrane. In contrast, nanoantidote treatment led to a reduction in ACE2 expression, which is likely the mechanism of nanoantidote-mediated attenuation of viral infection at acidic pH.
ACE2 is known to colocalize with actin, and the actin filament-bundling protein Fascin-1 regulates the expression and cellular localization of ACE2.
Morphological analysis of actin performed in the study revealed that actin polymerization remains stable at both normal and alkaline pH. In contrast, acidic pH induced a fuzzy scattering actin morphology in the cells.
Treatment of cells with nanoantidote revealed that the nanoparticles can restore actin polymerization and stabilization by increasing the acidic pH to the normal level. This could be a possible nanoantidote mechanism to mitigate the efficacy of viral infection.
Further validation of the mode of action of the nanoantidote was done using an inducer of actin stabilization and polymerization. The inducer was found to reduce ACE2 expression at the cell membrane as well as the efficiency of viral infection at acidic pH.
Overall, these observations indicate that acidic pH favors SARS-CoV-2 infection by reducing actin polymerization, which is associated with higher expression of ACE2 at the cell membrane.
Study the importance
The study describes the development and validation of calcium carbonate nanoparticles that can be used as a nanoantidote to neutralize acidic pH and reduce the efficiency of SARS-CoV-2 infection.
The nanoantidote reduces the cell surface expression of ACE2 probably by increasing actin polymerization and stabilization in acidic pH. Based on these findings, the scientists suggest that the nanoantidote could be used as a safer alternative to sodium bicarbonate to treat acidosis in critically ill patients with COVID-19.