Mucins produced by type II pneumocyte: culprits in SARS-CoV-2 pathogenesis

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sweeping across the world and has caused the loss of more than 3.3 million lives. Before clearance by virus-speci ﬁ c T and B cell-mediated adaptive immunity, excessive in ﬂ ammation by innate immune cells might cause severe lung and even multiorganic pathologies, thus interfering with antiviral immunity. To curb infection and subsequent organic damage, a deep understanding of the pathogenetic process is highly desirable. Recently, we found that IFN-driven mucin expression in type II alveolar epithelial cells is crucial in initiating hypoxia and early lung pathology 1 , and SARS-CoV-2 is disposed of by M1 and M2 alveolar macrophages (AMs) in distinct manners 2 . In this correspondence, we propose that (1) following the invasion of the alveoli and uptake by local alveolar macrophages, SARS-CoV-2 may stimulate macrophages to produce proin ﬂ ammatory cyto-kines, including type I interferon; (2) type I interferon acts on neighboring alveolar type II pneumocytes and activates the cytoplasmic transcription factor aryl hydrocarbon receptor (AhR); (3) subsequently, AhR is translocated to the nucleus, where it promotes the expression of mucin genes, leading to mucus production; and (4) mucus begins to accumulate in the alveoli and gradually impairs the exchange of O 2 and CO 2 , initially causing hypoxia and then dampening CO 2 exhalation, leading to a critical illness. Here, we dissect these early pathogenic events, which might provide clues to interfering with SARS-CoV-2 infection at an early stage.


2
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is 1 sweeping across the world and has caused the loss of more than 3.3 million lives. Before 2 the clearance by virus-specific T and B cells-mediated adaptive immunity, excessive 3 inflammation by innate immune cells might cause severe lung and even multi-organic 4 pathologies, thus interfering with the antiviral immunity. To curb the infection and the 5 subsequent organic damage, a deep understanding of the pathogenetic process is highly 6 desirable. Recently, we found that IFNs-driven mucin expression in type II alveolar 7 epithelial cells is crucial to initiate hypoxia and early lung pathology, 1 and SARS-CoV-8 2 is disposed of by M1 and M2 alveolar macrophages (AMs) in distinct manners. 2 In 9 this correspondence, we propose that (1) following the invasion of the alveoli and the 10 uptake by local alveolar macrophages, SARS-CoV-2 may stimulate the macrophages 11 to produce proinflammatory cytokines, including type I interferon; (2) type I interferon 12 acts on neighbor alveolar type II pneumocytes and activates the cytoplasmic 13 transcription factor AhR; (3) subsequently, AhR is translocated to the nucleus where it 14 promotes the expression of mucin genes, leading to mucus production; (4) mucus is 15 beginning to accumulate in the alveoli and gradually impairs the exchange of O2 and 16 CO2, initially causing hypoxia and then dampening CO2 exhalation, leading to a critical 17 illness. Here, we dissect these early pathogenic events which might provide clues to 18 interfere with SARS-CoV-2 infection at an early stage. The primary function of the lungs is to inhale oxygen and exhale carbon dioxide.

21
Anatomically, the respiratory trachea branches off into two bronchi. The latter 22 further branch off into bronchioles and respiratory bronchioles, which end in alveoli.

23
Histologically, bronchial and bronchiolar ciliated cells and brush cells have the cilia 24 that discharge particle-trapping mucus mainly produced by goblet cells. In contrast,  3. CO 2 retention is the key event for switching hypoxia to rapid illness 20 In the lungs, O2 is inhaled from air but CO2 is generated from tissue cells where 21 CO2 is produced through the tricarboxylic acid (TCA) cycle. As a waste product,

22
CO2 is released from cells to the interstitial fluid and further diffuses into capillary 23 vessels. Subsequently, the CO2 is brought to the lungs and expelled out by crossing 24 the blood-gas barrier during exhalation. Normally, O2 and CO2 exchange between 25 4 alveoli and pulmonary capillary blood is achieved through a passive diffusion 1 process, which can be influenced by the thickness of the blood-gas barrier and the 2 solubility of gas. Mucus in the alveoli adheres to and increases the barrier thickness, 3 thus hindering gas diffusion. Although O2 and CO2 face the same barrier, the fact is 4 that CO2 has 20-fold higher solubility than O2. 6 Thus, at an early stage, a certain 5 degree of increased mucus probably might only influence O2 but not CO2 diffusion. 6 As long as CO2 can be expelled, the blood pH homeostasis can be maintained and    Once entering the alveoli, SARS-CoV-2 can be quickly taken up by AMs. Thus, the 5 activated PAMP-PRR recognition system results in IFN production, which then acts 6 on local type II pneumocytes, leading to mucus production. Indeed, we found that 7 a large amount of IFNs is produced by AMs following SARS-CoV-2 infection 2 .
8 Intriguingly, the virus can be amplified in AMs dependent on their phenotype 2 . 9 10 Based on the above analyses, we draw an outline of the early events following SARS-

11
CoV-2 infection in Figure 1. We suggest that the production of mucins by type II 12 pneumocytes is a triggering point for silent hypoxia and CO2 expel impairment is the 13 turning point for the patients from silent hypoxia to critical illness.

20
The author declares no competing financial interests. (3) other innate immune cells such as plasmacytoid DCs and γδ T cells may also 6 respond to the viruses and produce IFNs, including IFN-β and IFN-γ; (4) type II 7 pneumocytes are mainly stimulated by locally released IFN-β, thus activating the 8 IDO1-Kyn-AhR signaling pathway; (5) activated AhR transcriptionally promotes the 9 expression of mucin genes; (6) the generated mucus adheres to the surface of alveoli 10 and impairs oxygen entering the blood but not CO2 entering the alveoli, leading to silent 11 hypoxia; (7) mucus is further accumulated in the alveoli and proinflammatory factors 12 8 at the alveolar site stimulate capillary vessels to allow the leakage of blood, thus 1 together leading to the hindrance of CO2 exchange; (8) once CO2 exchange is impeded, 2 the illness rapidly switches to a critical state. Here, 3