miR-200c-3p upregulation and ACE2 downregulation via bacterial LPS and LTA as interesting aspects for COVID-19 treatment and immunity.

Commentary

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak was occurred in December 2019 [1]. Coronavirus disease 2019 (COVID-19) was considered a pandemic by the WHO on 12 March 2020. So far, many attempts have been made to design effective antiviral agents and vaccines against SARS-CoV-2. Current studies discussed ACE2, which plays an essential role in the pathophysiology of COVID-19 as a virus receptor [2]. According to studies finding, respiratory microbiota has been considered a notable factor in viral infections [3]. The human respiratory microbiota carries a wide range of gram-positive and gram-negative bacterial cells as the main composition, with different roles in physiological conditions and respiratory diseases [4].

Recent studies have suggested the role of respiratory microbiota in COVID-19 [5]. This commentary's hypothesis is based on the cellular function of gram-positive and gram-negative respiratory bacteria as a co-factor to prevent the expression of ACE2 and thus inhibit SARS-CoV-2. Lipopolysaccharide (LPS) is the outer membrane component in gram-negative bacteria [6]. Also, lipoteichoic acid (LTA) is the primary cell wall constituent in gram-positive bacteria [6]. Bacterial LPS and LTA can be involved in various cellular signaling mechanisms and pathways, including microRNA expression [7]. MicroRNAs are the small non-coding RNAs that impact viral respiratory infections pathogenesis [8]. Besides, the role of microRNAs as therapeutic agents and vaccine design has been discussed [8].

According to evidence, LPS activates NF-κB via TLR4 and LTA via TLR2 [7]. On the other hand, activation of the NF-κB pathway increases the expression of miR-200c-3p, which is an important factor in ARDS [7]. Increased expression of miR-200c-3p has been observed to decrease ACE2 expression [7]. It should be noted that low expression of ACE2 in the lungs and the upper respiratory tract in some COVID-19 cases may be associated with a reduction in disease severity [9]. Therefore, it is hypothesized that bacterial LPS and LTA can reduce the expression of ACE2 in the lungs of COVID-19 patients through upregulation of miR-200c-3p.

Murine models of SARS-CoV have confirmed that the virus may stimulate TNF-α and IL-6 through the NF-κB pathway[10]. Shaath et al. reported, NF-κB was activated in B.A.L. cells of severe COVID-19 [11]. This issue would clarify the high levels of cytokine responses, leading to inflammation and cytokines storm in COVID-19 patients. The cytokines storm in COVID-19 could result in ARDS and multi-organ dysfunction. This aspect could help in the design of effective vaccine and therapeutic approaches [10, 12]. Respiratory bacterial can also develop NF-κB activation, which induces a pro-inflammatory response in epithelial cells [13, 14]. The human microbiota can be altered after SARS-CoV-2 infection [15]. It is a hypothesis that these microbiota changes can illustrate the cytokines storm progression in COVID-19. Therapy using NF-κB inhibitor drugs leads to decreased inflammation and lung injury in SARS-CoV-infection models [16]. The differential miRNA expression in COVID-19 patients may regulate the inflammatory responses during infection [17]. Also, Some miRNAs can target ACE2 [18]. The “microRNA targeting” as anti-inflammatory agents should be carefully considered. It is well known that microRNAs are strongly involved in cytokines and chemokines expression, leading to cytokines storm in COVID-19 [19].

In conclusion, the composition of bacterial respiratory microbiota can be an indicator of COVID-19 severity. Future clinical trials are needed to investigate the role of probiotics containing LPS and LTA in affect on COVID-19 symptoms by upregulation miR-200c-3p levels and downregulation ACE2 levels in COVID-19 patients. Future studies in the gene therapy field could also directly investigate the role of miR-200c-3p as a biomarker in reducing ACE2 expression and COVID-19 severity to provide immunity against SARS-CoV-2.