key: cord-0831466-2sbu6jcj
authors: Meng, Xiang; Lou, Qiu-yue; Yang, Wen-ying; Chen, Ran; Xu, Wen-hua; Yang, Yang; Zhang, Lei; Xu, Tao; Xiang, Hui-fen
title: Gordian Knot: Gastrointestinal lesions caused by three highly pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2
date: 2020-10-22
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173659
sha: a1d1cc2ad9cf377e87ffbe3c78e695597892fd30
doc_id: 831466
cord_uid: 2sbu6jcj

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of 2019 novel coronavirus disease (COVID-19), is currently spreading around the world. The WHO declared on January 31 that the outbreak of SARS-CoV-2 was a public health emergency. SARS-Cov-2 is a member of highly pathogenic coronavirus group that also consists of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Although respiratory tract lesions were regarded as main manifestation of SARS-Cov-2 infection, gastrointestinal lesions were also reported. Similarly, patients with SARS-CoV and MERS-CoV were also observed. Common gastrointestinal symptoms of patients mainly included diarrhea, vomiting and abdominal pain. Gastrointestinal lesions could be used as basis for early diagnosis of patients, and at the same time, controlling gastrointestinal lesions better facilitated to cut off the route of fecal-oral transmission. Hence, this review summarizes the characteristics and mechanism of gastrointestinal lesions caused by three highly pathogenic human coronavirus infections including SARS-CoV, MERS-CoV, as well as SARS-CoV-2. Furthermore, it is expected to gain experience from gastrointestinal lesions caused by SARS-CoV and MERS-CoV infections in order to be able to better relieve SARS-CoV-2 epidemic. Targetin gut microbiota to regulate the process of SARS-CoV-2 infection should be a concern. Especially, the application of nanotechnology may provide help for further controlling COVID-19.

spike glycoproteins were a key structure for SARS-CoV to mediate infection of their target cells. A further research in mouse models revealed that spike glycoproteins could recognize the cell surface receptor, angiotensin-converting enzyme 2 (ACE2) (Kuba et al., 2005) . It was worth noting that in addition to lungs, high expression of ACE2 was detected in gastrointestinal tract, suggesting gastrointestinal tract was a potential target for SARS-CoV (Hamming et al., 2004) . After recognizing ACE2, SARS-CoV interacted with transmembrane protease serine type 2 (TMPRSS2) to activate spike glycoproteins (Shulla et al., 2011) . TMPRSS2, a member of type II transmembrane serine protease family, mediated the entry of SARS-CoV into targeted cells via facilitating virus-cell membrane fusion (Iwata-Yoshikawa et al., 2019) . It can be concluded that spike/ACE2/TMPRSS2 was a key part of virus invading cells and spreading. In addition, spike glycoproteins can also bind dendritic cell specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). DC-SIGN was a C-type (calcium dependent) lectin highly expressed on dendritic cells (DCs), which can enhance virus invasion and promote virus dissemination (Yang et al., 2004; Gramberg et al., 2005) . DC-SIGN was highly expressed in gastrointestinal tract (Geijtenbeek et al., 2000; Koning et al., 2015) . Therefore, SARS-CoV can bind DCs, thereby promoting transfer of virus to susceptible cells. These further proved that SARS-CoV can directly attack gastrointestinal tissue and trigger gastrointestinal tract lesions.

Invading pathogens can activate cellular and humoral responses. Immune responses could lead to production of cytokines and chemokines, which in turn trigger J o u r n a l P r e -p r o o f inflammatory responses that attack pro-inflammatory cells (Perlman and Dandekar, 2005) . The expression levels of cytokines and chemokines were abnormally expressed in serum of SARS-CoV-infected patients. Several studies have found that inflammatory cytokines (Interleukin (IL)-1, IL-6 and IL-12), chemokines (monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10)) were significantly elevated (Wong et al., 2004; Zhang et al., 2004) . The abnormal expression of these cytokines may explain inflammation and lesions of gastrointestinal tissues in SARS-CoV-infected patients. Furthermore, ACE2 was considered as a regulator of intestinal amino acid homeostasis and expression of antimicrobial peptides. It played a key role in intestinal inflammation (Hashimoto et al., 2012) . Hence, in addition to directly invading targeted cells, SARS-CoV can also cause abnormalities in body's immune system, further aggravating gastrointestinal tract lesions.

MERS-CoV is a zoonotic pathogen that was first isolated in Saudi Arabia, 2012 (Zaki et al., 2012) . As of Jan 2020, MERS-CoV eventually caused 2,519 confirmed cases, including 866 deaths, with case fatality ratio of 34.3% (WHO, 2020a). The source of MERS-CoV received widespread attention. The natural reservoir of MERS-CoV was proved to be also bats (Lau et al., 2018 ). Yet, intermediate host was unclear.

MERS-CoV strains isolated from humans were found to be highly consistent with those isolated from camels, suggesting MERS-CoV was most likely transmitted by J o u r n a l P r e -p r o o f camels to humans (Omrani et al., 2015) . MERS-CoV-infected individuals had respiratory tract infection, including dry cough and sore throat (Memish et al., 2013a; 2013b) . Gastrointestinal symptoms were also described as common symptoms in patients with MERS-CoV. One study showed that 35% of diagnosed patients had gastrointestinal symptoms (Assiri et al., 2013a) . In a descriptive study, similar results were obtained. Of the 47 patients with MERS-CoV, 17% of patients had abdominal pain, 21% of patients had vomiting, and 26% of patients had diarrhea (Assiri et al., 2013b) . At the same time, MERS-CoV can also be detected in stool samples of patients (Zhou et al., 2017) , indicating it possessed a fecal-oral transmission ability. 

A previously unknown coronavirus, termed SARS-CoV-2, was firstly identified in December 2019 (Zhu et al., 2020; Wang et al., 2020a) . It was known that J o u r n a l P r e -p r o o f SARS-CoV-2 was believed to be etiologic agent of atypical pneumonia that caused globally nearly 18.4 million confirmed cases, including over 697,000 deaths, reported to WHO as of 5 August 2020 (WHO, 2020b). At the beginning of the outbreak, the source of SARS-CoV-2 received great attention. At whole-genome level, Zhou et al. (2020) found SARS-CoV-2 was 96% identical to a bat coronavirus, suggesting that natural reservoir was bats. Lam et al. (2020) induced production of specific neutralizing antibodies, but also resisted attack of SARS-CoV-2. However, it will take some time for vaccine to be used clinically.

Through next-generation sequencing, it was found that SARS-CoV-2 was more similar to SARS-CoV (about 79%) than MERS-CoV (about 50%). The overlapping genome sequences between SARS-CoV and SARS-CoV-2 can encode and express spike glycoproteins that could bind to ACE2 to enter target cells (Lu et al., 2020) .

Meanwhile, ACE2 was also identified as a functional receptor for SARS-CoV-2 to invade gastrointestinal cells (Zhou et al., 2020; Wu et al., 2020a) . After virus entered cell, TMPRSS2 cleaved hemagglutinin and then activated internalization of virus (Stopsack et al., 2020) . TMPRSS4 also played a similar role. Hence, TMPRSS2 and TMPRSS4 were considered as crucial protease in SARS-CoV-2 intrusion and replication (Hoffmann et al., 2020; Matsuyama et al., 2020; Zang et al., 2020) .

Besides high expression of ACE2 receptors in gastrointestinal tissues (Garg et al., 2020), viral nucleocapsid protein was also detected in cytoplasm of gastric, duodenal and rectal epithelium (Xiao et al., 2020; Zhao et al., 2020; Lamers et al., 2020) . Increasingly, studies have shown that gut and lungs were somehow connected. In respiratory diseases, intestinal dysfunction was observed. Also, alterations in gut microbes affected lung function. For example, chronic obstructive pulmonary disease J o u r n a l P r e -p r o o f increased small intestinal permeability in patients (Sprooten et al., 2018) . Moreover, when influenza struck, endogenous bifidobacterium from the gut could enhance host resistance to influenza . This bi-directional communication network between the gut and the lung is called the "gut-lung axis". Apparently, gut-lung axis existed in SARS-CoV-2 infection. After SARS-CoV-2 invaded the lung, host immune system was activated and inflammatory cytokines were released.

Pulmonary permeability was increased with the release of inflammatory cytokines, which further led to viral invasion of the gut through the gut-lung axis, and vice versa (Ahlawat et al., 2020) . In these processes, the intestinal flora acted as a "bridge". Thus, regulating intestinal flora can improve intestinal lesions and even lung damage. 

At present, SARS-CoV-2 has posed a huge threat to the world. From brain to toes, Compared with healthy controls, COVID-19 patients' opportunistic pathogens increased, and beneficial commensals decreased. At genus level, decreased levels of Clostridium and Bacteroides were observed in some COVID-19 patients. It was further found that Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus could downregulate expression level of ACE2, and was inversely correlated with SARS-CoV-2 load in fecal samples (Zuo et al., 2020; Yang et al., 2020) . Consequently, it can be conjectured that gastrointestinal symptoms and imbalance of immune homeostasis triggered by SARS-CoV-2 can be partly mediated by gut microbiota. It could be a potential treatment strategy to relieve gastrointestinal symptoms via targeted regulation of intestinal species in COVID-19 patients.

Taking into account possible interactions between gut microbiota and SARS-CoV-2, dietary strategies to restore beneficial commensals have been gradually concerned, especially joint application of nanotechnology (Kalantar-Zadeh et al., 2020) . In view of the similarity between size of SARS-CoV-2 and nanoparticles, nanotechnology can be used to design intelligent drugs that target problematic bacterial strains in gastrointestinal tract. Correspondingly, gut barriers against SARS-CoV could be enhanced and gastrointestinal symptoms could be relieved (Sportelli et al., 2020) .

Notably, nano-vaccines, with their unique advantages, have become a new option for treating SARS-CoV-2 ( Figure 5 ). Using nanotechnology to surface functionalization of nanoparticles, nano-vaccines can achieve strong immunogenicity (Nikaeen et al., 2020; Nasrollahzadeh et al., 2020) . Nanomaterials are versatile and can be used in all aspects of viruses. Nanomaterials for disinfection have also been explored. Metal nanoparticles, especially silver nanoparticles, can serve as an effective broad-spectrum antiviral agent (Rai et al., 2016) . However, their antiviral activity is still to be explored in COVID-19. The rapid spread of viruses requires improved detection efficiency. The high surface and volume ratios of nanomaterials improves J o u r n a l P r e -p r o o f the sensor's response, thereby increasing sensitivity. For example, specific probes functionalized with gold are able to form disulfide bonds with complementary RNA of the target virus. This can be used for rapid symptomatic and asymptomatic screening for COVID-19 (Li et al., 2020b) . In addition to diagnostic screenings, nanomaterials can be used to design drugs. Virus-like particles (VLPs), a bionic nanoparticle that are commonly used for vaccine preparation, show considerable potential for application in COVID-19 (Pushko and Tretyakova, 2020) . The VLP vaccine induces comprehensive humoral and cellular immunity. On the one hand, the 

The gastrointestinal lesions caused by three highly pathogenic coronaviruses The whole-body organs of the human body may become the target of SARS-CoV-2 attack. Additionally, SARS-CoV-2 enters the target cell with the help of the ACE2 and TMPRSS2, and completes its own replication, eventually destroying the cell. J o u r n a l P r e -p r o o f 

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