Thoughts on the alveolar phase of COVID-19

Abstract

COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.

Keywords: ACE2; SARS-CoV-2; type II cells.

Fig. 1.

Infection of human type II cells with SARS-CoV. Human type II cells were cultured at an air-liquid interface so as to maintain their state of differentiation and infected with SARS-CoV-1 (26). The viral particles (white arrows) are seen in vesicles near normal-appearing lamellar bodies and mitochondria. There was no observed cytopathic effect under the conditions of these cultures.

Fig. 2.

Bystander amplification and multiple cell-cell interactions in the cytokine response. The cytokine response is very complex. Virus-infected epithelial cells release a variety of cytokines during infection, and nearby bystander cells amplify the response, especially in response to interferon beta and lambda. Soon thereafter the recruited inflammatory cells, immune cells, and other organs such as the liver produce additional mediators and cytokines and further amplify the response.

Fig. 3.

Proposed infection sequence of alveolar epithelial cells to SARS-CoV-2. A: panel shows the virus infecting both type I and type II cells. The relative infectivity will be related to the density of ACE2 expression, which is likely higher on type II cells than type I cells. B: panel describes the early stage of alveolar flooding and hyaline membrane formation followed by inflammation and diffuse alveolar damage (ARDS). The flooding occurs because of damage to the alveolar epithelium and endothelium and high surface tension due to the impaired production and adsorption of pulmonary surfactant. C: panel shows the normal repair process where type II cells proliferate and then differentiate into transitional type II cells and finally into type I cells. Normal transitional type II cells can be identified by coexpression of markers of type II cells and type I cells as well as keratin 8. D: panel depicts the aberrant repair that occurs after severe influenza infection in which distal airway epithelial cells migrate and form a cuboidal epithelium. Some of these cells express keratin 5 and others keratin 8 and markers of club cells.