Jahar Battacharya: Effects of SARS-CoV-2 on Alveolar Epithelial Cells and Macrophages (covid-19 symposium)
Summary by: Arooba Ahmed (CC '23)
Dr. Battacharya wants to understand COVID pathology. The underlying cause of death of COVID patients is in a subgroup of people who develop Acute Respiratory Distress Syndrome (ARDS). This is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs, where air spaces of lungs fill up with liquid. The COVID-19 disease is vicious because it is rapid, there is 30-50% mortality, and currently there is no cure.
Pulmonary alveoli constitute 95% of epithelial surface area of lungs and it is where gas exchange occurs. In the case of coronavirus, the inhaled virus makes its way to the alveoli where the disease happens. Although receptors exist in the airway, ARDS is not a disease of the airway but of the alveoli. This is important to remember when designing mouse models to study coronavirus, because current available mouse models address attacks in the airway but not ARDS.
The Alvelorial Epithelial is critical because it is a barrier which prevents entry of fluid from the blood vessel. When a person is infected, the barriers break down and there is fluid flow into alveoli, causing pulmonary edema hypoxia (fluid accumulation in the lungs which blocks gas exchange) and death.
Type 2 cells are special cells in alveoli which secrete surfactant. The secretion is a critical process that lines a mixture of phospholipids throughout the Alveolar Epithelium. This reduces air-liquid surface tension and maintains stability of alveolus. This secretion is aggregated with infection, which makes the lungs prone to pulmonary edema.
Macrophages have the ability to regulate inflammation through resolution. This occurs when the alveolus adheres to the epithelium and communicates information from itself, to the macrophage, and then to the type 2 cell. The macrophage-type 2 cell communication is done through calcium signals. These are generated between macrophage, but also go into type 2 cells. Generating calcium spikes under stress conditions can lead to information transmission that allows for resolution.
Infection of the alveoli generates an early inflammatory response where neutrophils enter the alveolar spaces from blood. Monocytes enter as well and convert to macrophages to generate lipid proteins and other factors. These factors act on a variety of cells to actively dampen inflammation. This process begins as the inflammatory process initiates.
Two types of cells of the alveoli are targets for the virus, and express a protein called Angiotensin Converting Enzyme type 2. Angiotensin-converting enzyme, or ACE, is a central component of the renin–angiotensin system, which controls blood pressure by regulating the volume of fluids in the body. ACE2 generates peptides called angiotensins 1-7 (a vasodilator) which eventually leads to inflammation resolution.
The CoV-2 spike protein targets this protein on the domain that interacts with the ACE2 receptor. If ACE2 is degraded, which some data in the literature implies, the entire process is abrogated and resolution will not happen.
Dr. Battacharya’s group saw how macrophages sent calcium signals to the Type 2 cell to activate surfactant secretion followed by the Type 2 cell sending signals back to the macrophage to initiate inflammation resolution. They are interested in knowing how these interactions start, and what happens in the context of coronavirus infection. They wish to study cell to cell communication in mice which have a mutation in surfactant protein A (which only exists in type 2 cells), which generates a stress phenotype and a high inflammatory response.