Neuronal, gastrointestinal, hepatic system and COVID-19
COVID-19 leads to lung injury, ARDS, and respiratory failure. The respiration is mainly regulated by the respiratory center, which is located in the medulla oblongata and pons, in the brain stem (Ikeda et al., 2017). Reports show that Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV infect the brain stem leading to neurological complications (Algahtani, Subahi & Shirah, 2016; Arabi et al., 2015; Hwang, 2006; McCray et al., 2007; Tsai et al., 2004). Growing evidence shows that patients infected with SARS-CoV-2 present neurological symptoms like headache, nausea, vomiting, cerebrovascular disease, skeletal muscle injury and impaired consciousness (Li, Bai & Hashikawa, 2020; Mao et al., 2020). The consciousness is regulated by the reticular activating system via activation of the cerebral cortex and here arises a question that could SARS-CoV-2 alter the reticular activating system and as well, brain stem function. Aforementioned, SARS-COV-2 induces lung injury, alters RAAS system in the pneumocytes which leads to the production of cytokines and cytokine storm has been observed in patients underlying with pre-existing diseases such as diabetes, myocardial injury. Yarlagadda et al. reported that cytokines can cross the blood-brain barrier and cause significant brain damage (Yarlagadda, Alfson & Clayton, 2009). Further, circulating cytokines alters the hypothalamus function which regulates body temperature and causes high fever; a common symptom in COVID-19 patients (Netea, Kullberg & Van der Meer, 2000). Xia et al. reported that neuronal ACE 2 plays an important role in the compensatory regulation of neurogenic hypertension in mice due to dysregulated RAAS (Feng et al., 2010). Hence, if SARS-CoV-2 crosses the blood-brain barrier then it might interact with neuronal ACE 2 which can affect the brain functions and capable enough to induce fatal neurological changes. Further fever, pneumonia is a common symptom among COVID-19 disease but patients are also reporting with gastrointestinal issues like abdominal pain, anorexia, vomiting and diarrhea (Pan et al., 2020; Song et al., 2020; Wong & Lui, 2020; Zhang et al., 2020a). Wang et al. reported that respiratory influenza virus infection induces injury in intestine cells, altered the intestinal microbiota composition, enhances the production of the pro-inflammatory cytokine, altered immune cells functions and induces Th17 cell-dependent inflammation (Wang, Li, Wei, Lian, Sun & Tian, 2014). Hamming et al. reported that ACE 2 is most profusely present in the epithelial cells of the intestine, duodenum, jejunum and ileum which is a pivotal entry point of SARS-CoV-2 and may infect the intestinal cells, alter the functioning of immune cells, imbalance the microbiota composition, impaired the intestinal function and causes diarrhea (Hamming, Timens, Bulthuis, Lely, Navis & van Goor, 2004b). Further, several reports are advocating that detection of SARS-CoV-2 in the stools samples of COVID-19 patients which may strengthen the fact that invasion of the virus to the intestine and incidence of diarrhea. Hence, there would be chances of virus transmission through the fecal-oral route (Wang et al., 2020a; Wu et al., 2020; Zhang et al., 2020b).
Non-alcoholic steatohepatitis (NASH), which is characterized by liver cell injury with high levels of pro-inflammatory cytokines that makes COVID-19 patients more prone to additive cytokine burden leading to severe liver damage that amplify the risk for liver fibrosis and carcinogenesis (Syn, Choi & Diehl, 2009). Further, patients with non-alcoholic fatty liver diseases (NAFLD) and NASH have impaired intestinal permeability with a disrupted tight junction in the intestine, altered gut microbiota, increased production of endotoxins (Lau, Carvalho & Freitas, 2015; Takaki, Kawai & Yamamoto, 2013). Lau et al. reported that liver received about 70% of blood supply from the intestine and this enhance the endotoxin translocation from gut to the liver, which in turn to activates toll-like receptors which further promotes inflammation and fibrosis in the liver (Lau, Carvalho & Freitas, 2015). Further, there is evidence of SARS-CoV-2 infection in the intestine and is presence in faecal samples. Therefore, due to impaired permeability of intestinal tight junction virus may invade the hepatic tissue and may further aggravate the cytokine release in NASH patients. Moreover, reports show that ACE 2 is expressed in the epithelial cells of the bile duct and hepatic tissue with lower abundance but the chronic liver injury upregulates the hepatic ACE 2 expression which is a key entry point for SARS-CoV-2 (Huang et al., 2009; Paizis et al., 2005). Hence, NAFLD and NASH patients with the high level of cytokines are more prone to the cytokine storm and this may induce irreversible damage of hepatic tissue and at later stage liver transplantation can only be viable option. Further, careful monitoring is needed among patients on the drugs that have a potential to upregulates the ACE 2.