Goblet Cells in SARS-CoV-2 Pathogenesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a causative agent of coronavirus disease 2019, COVID-19) cellular tropism depends on its receptor-binding specificity. Therefore, the answer for why SARS-CoV-2 is more transmissible than SARS-CoV may find in the expression of the entry receptor angiotensin-converting enzyme II (ACE2) on host cells. SARS-CoV-2 spike protein shows ten times more affinity in binding ACE2 than does SARS-CoV [1]. For successful SARS-CoV-2 entry, spike protein priming is required by a host cell co-factor transmembrane serine protease 2 (TMPRSS2) [2]. Thus, cells with high ACE2 and TMPRSS2 expression are more susceptible to SARS-CoV-2. Previously, RNA-seq based studies suggested that both ACE2 and TMPRSS2 predominately express by the secretory cells in the respiratory system [3-5]. Recent studies suggest that mucus-secreting goblet cells are permissive to SARS-CoV-2 infection [6-8]. Osan et al. [9] have confirmed that the virus preferentially infects goblet cells in the bronchial airway due to harboring higher levels of ACE2 and TMPRSS2 compared to that of ciliated cells. The ability to infect goblet cells may explain the efficient replication and transmission of SARS-CoV-2 as similar to pandemic influenza viruses [10]. Thus, the growing evidence on SARS-CoV-2 infection in goblet cells urges for focusing virus-host tropism studies on goblet cells. Goblet Cell Hyperplasia


SARS-CoV-2 Cell Tropism
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a causative agent of coronavirus disease 2019, COVID-19) cellular tropism depends on its receptor-binding specificity. Therefore, the answer for why SARS-CoV-2 is more transmissible than SARS-CoV may find in the expression of the entry receptor angiotensin-converting enzyme II (ACE2) on host cells. SARS-CoV-2 spike protein shows ten times more affinity in binding ACE2 than does SARS-CoV [1]. For successful SARS-CoV-2 entry, spike protein priming is required by a host cell co-factor transmembrane serine protease 2 (TMPRSS2) [2]. Thus, cells with high ACE2 and TMPRSS2 expression are more susceptible to SARS-CoV-2. Previously, RNA-seq based studies suggested that both ACE2 and TMPRSS2 predominately express by the secretory cells in the respiratory system [3][4][5]. Recent studies suggest that mucus-secreting goblet cells are permissive to SARS-CoV-2 infection [6][7][8]. Osan et al. [9] have confirmed that the virus preferentially infects goblet cells in the bronchial airway due to harboring higher levels of ACE2 and TMPRSS2 compared to that of ciliated cells. The ability to infect goblet cells may explain the efficient replication and transmission of SARS-CoV-2 as similar to pandemic influenza viruses [10]. Thus, the growing evidence on SARS-CoV-2 infection in goblet cells urges for focusing virus-host tropism studies on goblet cells.

Goblet Cell Hyperplasia
Goblet cells are the major mucin-producing cell in the superficial epithelium of the large airway [11]. Mucins are large heavily-glycosylated multi-domain protein, which may play a pivotal role in protecting the respiratory tract by entrapping microbes and facilitating removal of them via coordinated beating of motile cilia [12]. The interaction between respiratory pathogens and mucin is far more complicated and understudied. Therefore, SARS-CoV-2 and mucins interaction is an active area of research. Disparities in mucin expression based on gender and age may responsible for different COVID-19 outcomes, such as the higher susceptibility of elderly individuals to SARS-CoV-2 may in part be explained by reduced mucus production and impaired mucociliary clearance [12][13][14][15]. However, transient mucus hypersecretion is a known phenomenon caused by an increase in goblet cell number in response to the pathogen [16]. Mucus hypersecretion, which is an underlying condition of hypoxia, caused acute respiratory distress syndrome (ARDS) in the SARS-CoV-2 infected patients [17,18]. Therefore, goblet cell hyperplasia, a common clinical manifestation in patients with asthma and chronic obstructive pulmonary disease (COPD), could be responsible for severe disease associated with COVID-19 in the chronic disease patients [16,19,20]. Indeed, COVID severity and COVID-associated mortality rate are higher in COPD patients compared to patients without COPD [21]. A gene expression-based study has recently suggested that ACE2 expression is significantly higher in bronchial epithelial cells in COPD patients compared to the control subject [22]. Osan et al. [9] have recently shown that SARS-CoV-2 replicates better in the in vitro COPD airway epithelium, which is likely due to COPD-associated goblet cell hyperplasia.
Thus, more research needs to determine whether SARS-CoV-2 preferential infection in goblet cells makes patients with chronic lung diseases (such as asthma and COPD) more vulnerable to severe disease outcomes associated with COVID-19.

Multifaceted Goblet Cells
Goblet cells are not solely mucin-producing cells rather an active regulator of innate and adaptive immune systems. Goblet cells can deliver antigens to the specific dendritic cells in the small intestine [23]. Goblet cells contribute to immunity at mucosal surfaces through several activities: barrier maintenance, goblet cell-associated antigen passage, interaction with antigen-presenting cells, and secretion of immunomodulatory factors [24]. However, mucin or goblet cell-based immune regulation is tissue-specific [11].
SARS-CoV-2 produces protean manifestations ranging from head to toe, infects multiple organ systems including lung, heart, brain, kidney, and vasculature [25]. It is prudent to determine whether SARS-CoV-2 infection in goblet cells allows the virus to be systemic through the bronchiole similar to the lung alveoli [26].

Treatment Options
Therapeutic strategies targeting goblet cell differentiation (GCD) may be useful to combat COVID-19 disease exacerbation in chronic disease patients. Corticosteroids are the most commonly prescribed medication for the treatment of asthma, offer a substantial reduction of airway inflammation [27]. A recent study suggested that inhaled corticosteroid attenuates pulmonary expression of SARS-CoV-2 entry receptor ACE2, which may contribute to altered susceptibility to COVID-19 in COPD patients [28]. Corticosteroids such as dexamethasone reduced mortality in COVID-19 hospitalized patients [29,30]. The WHO has provided guidelines for corticosteroid use under the COVID-19 drug treatment [31]. However, corticosteroids should be used with caution in patients with COVID-19, as there is a report of increased risk of death and side effects such as bacterial infection and hypokalemia [32]. The author thinks therapeutic drugs targeting viral replication more likely to be effective to combat COVID-19. Encouraging news is that five COVID-19 vaccines are at different stages of large-scale (Phase 3) clinical trials in the USA [33].