Physical-Chemical Regulation of Membrane Receptors Dynamics in Viral Invasion and Immune Defense.

Mechanical cues dynamically regulate membrane receptors functions to trigger various physiological and pathological processes from viral invasion to immune defense. These cues mainly include various types of dynamic mechanical forces and the spatial confinement of plasma membrane. However, the molecular mechanisms of how they couple with biochemical cues in regulating membrane receptors functions still remain mysterious. Here, we review recent advances in methodologies of single-molecule biomechanical techniques and in novel biomechanical regulatory mechanisms of critical ligand recognition of viral and immune receptors including SARS-CoV-2 spike protein, T cell receptor (TCR) and other co-stimulatory immune receptors. Furthermore, we provide our perspectives of the general principle of how force-dependent kinetics determine the dynamic functions of membrane receptors and of biomechanical-mechanism-driven SARS-CoV-2 neutralizing antibody design and TCR engineering for T-cell-based therapies.

Mechanosensing view of SARS-CoV-2 infection by a DNA nano-assembly.

The mechanical force between a virus and its host cell plays a critical role in viral infection. However, characterization of the virus-cell mechanical force at the whole-virus level remains a challenge. Herein, we develop a platform in which the virus is anchored with multivalence-controlled aptamers to achieve transfer of the virus-cell mechanical force to a DNA tension gauge tether (Virus-TGT). When the TGT is ruptured, the complex of binding module-virus-cell is detached from the substrate, accompanied by decreased host cell-substrate adhesion, thus revealing the mechanical force between whole-virus and cell. Using Virus-TGT, direct evidence about the biomechanical force between SARS-CoV-2 and the host cell is obtained. The relative mechanical force gap (<10 pN) at the cellular level between the wild-type virus to cell and a variant virus to cell is measured, suggesting a possible positive correlation between virus-cell mechanical force and infectivity. Overall, this strategy provides a new perspective to probe the SARS-CoV-2 mechanical force.

Toward an optimized strategy of using various airway mucus clearance techniques to treat critically ill COVID-19 patients

Coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is still threatening the human life and society throughout the world. For those critically ill patients, mechanical ventilation (MV) is essential to provide life support during treatment. However, both the virus infection and MV disrupt the balance between secretion and elimination of airway mucus and lead to mucus accumulation in the lung. Postmortem examination verified that the lungs in patients died of COVID-19 are indeed filled with sticky mucus, suggesting a great need to improve airway mucus clearance in critically ill COVID-19 patients. Therefore, it may be helpful to comprehensively review the current understanding regarding the changes of biochemical and rheological features of airway mucus associated with the disease, as well as the physiological principles and algorithm to decide airway clearance techniques suitable for the critically ill COVID-19 patients. Based on these considerations, optimized strategies may be developed to eliminate the airway mucus accumulated in the airways of critically ill COVID-19 patients.