The novel SARS-CoV-2 causes the COVID-19, which has rapidly spread worldwide, threatening global health. SARS-CoV-2 is a single-stranded, enveloped RNA virus that belongs to the betacoronavirus 2b lineage [1, 3]. Its diameter is approximately 65–125 nm. Structurally, it has four main proteins, including spike (S) glycoprotein, small envelope (E) glycoprotein, membrane (M) glycoprotein, and nucleocapsid (N) protein. The S glycoprotein is a transmembrane protein that protrudes from the viral surface and facilitates binding and entry of the virus into host cells by interacting with the ACE2 receptor . According to the Human Protein Atlas database (proteinatlas.org), ACE2 is widely expressed in various human organs and tissues, including the oral and nasal mucosa, nasopharynx, lung, small intestine, colon, liver, spleen, kidney, and brain. It has been shown that the ACE2 expression is approximately 100-fold higher in the GIT than in the respiratory system. This makes GIT highly susceptible to SARS-CoV-2 infections. ACE2 is expressed on the luminal surface of the absorptive enterocytes of the small intestine and colon, with lower expression in crypt epithelial cells . A previous study showed that both RNA and protein expression of ACE2 is higher in the small intestine than that in the colon . ACE2 plays an important role in the regulation of dietary amino acid homeostasis, innate immunity, microbial ecology, and susceptibility to colitis .
SARS-CoV-2 has a tropism to the GIT, similar other members of the coronavirus family, although it affects the GIT at a lower frequency than the respiratory system. Up to 30% of patients with pulmonary infection complain of GIT symptoms, mostly in association with respiratory symptoms; however, only 4% of patients complain of GIT symptoms alone . The most common GIT symptoms were nausea and vomiting (41.6%), diarrhea (17.2%), abdominal pain, and anorexia . Several studies have documented the presence of SARS-CoV-2 RNA in stool or anal/rectal swabs in COVID-19 patients and suggested that the virus can replicate and exist in the GIT .
The pathogenesis associated with the GIT infection with SARS-CoV-2 mainly relies on the entry of the virus into the cytoplasm of absorptive enterocytes through its interaction with ACE2. Successful virus entry depends not only on the ACE2 receptor, but also on endogenous serine proteases such as furin and cellular transmembrane protease serine 2 (TMPRSS2), which cleaves the S protein of SARS-CoV-2 into two segments (S1 and S2) [4, 7]. Both furin and TMPRSS2 are widely distributed in the small bowel mucosa. This cleavage is critical for the attachment of the virus to both the ACE2 receptor and the cellular membrane. This attachment is followed by endocytosis of viral genomic material (RNA). Next, the viral mRNA is translated into new structural proteins with subsequent insulation in the endoplasmic reticulum-Golgi intermediate compartment, from which they form small vesicles that eventually undergo exocytosis [4, 7]. This explains the presence of intracytoplasmic vesicles/vacuoles that are noted in the affected enterocytes from our samples, some of which contain periodic acid-Schiff positive material that represent the newly formed structural glycoproteins of SARS-CoV-2. Furthermore, the partial or complete blockage of the ACE2 receptor by a large viral load impairs the host cell nourishment supply and capabilities necessary to ensure a balanced immune response. The transport of amino acids, particularly tryptophan, is also impaired. This results in aberrant mTOR activation and impaired expression of antimicrobial peptides from Paneth cells, which eventually leads to alterations in the gut microbial environment [5, 7]. The infected cells probably undergo subcellular alterations that might lead to certain pathological changes, as seen in our case. One of these alterations represents the loss of brush borders of the enterocytes, which is known to occur in the setting of active enteritis and is the leading cause of diarrhea. This alteration was best evaluated by performing CD10 immunohistochemical staining. CD10 is a membrane-associated neutral peptidase which is normally observed as a linear brush-border staining pattern of the small intestinal mucosa. Variable loss of brush-border immunostaining for CD10 is usually observed in the setting of active enteritis . Another alteration is represented by the reduced expression of E-cadherin. E-cadherins are a major constituent of adherens junctions and play an essential role in intestinal homeostasis by providing mechanical integrity as well as maintaining cell polarization. Additionally, E-cadherins are necessary for the proper maturation and differentiation of secretory cell lineages, including Paneth and goblet cells. Downregulation of E-cadherin function due to decreased expression occurs secondary to the effect of inflammatory cytokines that lead to the activation of signaling pathway mediators, such as GTPases, which in turn destabilize adherens junctions and disrupt cell contacts; thus, facilitating pathogen invasion. Loss of E-cadherin function has been reported in inflammatory conditions of the intestine, such as Crohn’s disease and ulcerative colitis . This explains the obvious detachment and "hobnailing" appearance of the enterocytes as well as the diminished immunostaining for E-cadherin seen in our case. Similarly, possible alterations in the expression of EpCAM, which is a transmembrane glycoprotein, may occur secondary to SARS-CoV-2 infection. EpCAM plays an important role in intercellular adhesion, cell signaling, proliferation, differentiation, and cell polarity. Furthermore, EpCAM is enriched in the basolateral membrane of the intestinal absorptive cells . Diminished or loss of immunostaining for this adhesion molecule was noted in our case. This suggests that significant subcellular alterations are induced by SARS-CoV-2 infection. In addition, Mycobacterium Tuberculosis co-infection certainly played a significant synergistic role in causing the overwhelming SARS-CoV-2 infection in this case.
Review of Literature
Few studies describing the pathological findings of SARS-CoV-2 in the intestine have been reported to date. Liu et al. described an autopsy finding from a COVID-19 patient who developed alternating segmental dilation and stenosis of the small intestine . Xiao et al. performed an endoscopy of the GIT for a confirmed COVID-19 patient. They observed damage to the esophageal mucosa, numerous plasma cells, as well as lymphocytes in the lamina propria of the stomach, duodenum, and rectum. Furthermore, viral nucleocapsid proteins were detected in the cytoplasm of the infected cells . A reported case of acute hemorrhagic colitis showed a slight expansion of the lamina propria due to edema with normal cellularity and intact crypts was found . A study of 67 autopsies performed on patients who died due to COVID-19 infection revealed no gross or microscopic abnormalities of 16 small intestine and 17 colons examined. However, hemophagocytic histiocytes (with engulfment of red blood cells) were noted in the spleen (9 out of 22 cases), bone marrow (4 out of 6 cases), thoracic lymph nodes (9 out of 11 cases), liver Kupffer cells, and epicardial inflammation in one case. According to this observation, the study suggested that SARS-CoV-2 may induce a macrophage activation syndrome-like state, which might occur secondary to the cytokine storm .