SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release.

BACKGROUND: Diarrhea is present in up to 30-50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte-enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage associated molecular patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. METHODS: Primary mouse enteric neurons (EN) were exposed to a conditioned medium from ACE2-expressing Caco-2 colonic epithelial cells infected with SARS-CoV-2 or treated with tunicamycin (ER stress inducer). Vasoactive intestinal peptides (VIP) expression and secretion by EN were assessed by RT-PCR and ELISA, respectively. Membrane expression of NHE3 was determined by surface biotinylation. RESULTS: SARS-CoV-2 infection led to increased expression of BiP/GRP78, a marker and key regulator for ER stress in Caco-2 cells. Infected cells secreted the DAMP protein, heat shock protein 70 (HSP70), into the culture media, as revealed by proteomic and Western analyses. The expression of VIP mRNA in EN was up-regulated after treatment with a conditioned medium of SARS-CoV-2-infected Caco-2 cells. CD91, a receptor for HSP70, is abundantly expressed in the cultured mouse EN. Tunicamycin, an inducer of ER stress, also induced the release of HSP70 and Xbp1s, mimicking SARS-CoV-2 infection. Co-treatment of Caco-2 with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in membrane expression of Na+/H+ exchanger (NHE3), an important transporter that mediates intestinal Na+/fluid absorption. CONCLUSIONS: Our findings demonstrate that SARS-CoV-2 enterocyte infection leads to ER stress and the release of DAMPs that up-regulates the expression and release of VIP by EN. VIP in turn inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in enterocytes. These data highlight the role of epithelial-enteric neuronal crosstalk in COVID-19-related diarrhea.

Gastrointestinal injury in COVID-19.

The literature review summarizes the main aspects of the impact of SARS-CoV-2 on the gastrointestinal tract, which must be taken into account during a difficult epidemiological situation, and shows the main clinical and functional changes that affect the condition of patients and the activities of the healthcare system. The clinical manifestations caused by the action of SARS-CoV-2 on the organs of the gastrointestinal tract are described in detail. Clinical and laboratory methods established the fact of the development of a multi-inflammatory syndrome, which determines the systemic profile of the lesion and determines the nature and severity of the course of the disease, its complications and outcome. The histological picture of the lesion of the digestive system by the virus is described. The necessity of further studies of the mechanisms of interaction of the virus with the cells of the intestine and the immune system in order to develop methods for early diagnosis, effective treatment and prevention of complications of a new coronavirus infection is substantiated. The E-library, MedLine, National Center for Biotechnology Information databases were used to search for literature sources. (English) [ FROM AUTHOR] В обзоре литературы обобщены основные аспекты влияния SARS-CoV-2 на желудочно-кишечный тракт и связанные с этим особенности организации медицинской помощи, которые необходимо учитывать во время сложной эпидемиологической ситуации. Приведены основные клинико-функциональные изменения в состоянии пациентов. Клинико-лабораторными методами установлен факт развития мультивоспалительного синдрома, обусловливающего системный профиль поражения, определяющего характер и тяжесть течения болезни, ее осложнения и исход. Описана гистологическая картина поражения вирусом органов пищеварения. Обоснована необходимость дальнейших исследований механизмов взаимодействия вируса с клетками кишечника и иммунной системы для разработки методов ранней диагностики, эффективного лечения и профилактики осложнений новой коронавирусной инфекции. Для поиска источников литературы использованы базы данных e-Library, MedLine, National Center for Biotechnology Information. (Russian) [ FROM AUTHOR] Copyright of Profilakticheskaya Meditsina is the property of Media Sphere Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Coronaviruses in swine

This work aims to review about coronaviruses in swine, emblazoning there's differences. Transmissible gastroenteritis and epidemic diarrhea are imported diseases, as they generate a high mortality rate in lactating piglets and economic losses. These viruses reach enterocytes, causing villous atrophy;affected animals present watery diarrhea, vomiting, hypoxia and dehydration. Two other viruses have recently emerged, the swine deltacoronavirus and the swine acute diarrhea syndrome virus, which have pathogenicity and clinical signs similar to those described in previous diseases. In the other hand, the porcine respiratory coronavirus and the hemagglutinating encephalomyelitis virus have distinct clinical signs. The first causes mild or subclinical respiratory manifestations and the second neurological signs, vomiting and emaciation, mostly affecting piglets younger than 4 weeks. As there is no specific treatment for these diseases, and vaccines do not provide full protection, a good biosecurity program is the main way to control and prevent them.

Molecular Insights into SARS-CoV2-Induced Alterations of the Gut/Brain Axis.

For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.

Targeting the intestinal TMPRSS2 protease to prevent SARS-CoV-2 entry into enterocytes-prospects and challenges.

The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.

Role of Porcine Aminopeptidase N and Sialic Acids in Porcine Coronavirus Infections in Primary Porcine Enterocytes.

Porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) have been reported to use aminopeptidase N (APN) as a cellular receptor. Recently, the role of APN as a receptor for PEDV has been questioned. In our study, the role of APN in PEDV and TGEV infections was studied in primary porcine enterocytes. After seven days of cultivation, 89% of enterocytes presented microvilli and showed a two- to five-fold higher susceptibility to PEDV and TGEV. A significant increase of PEDV and TGEV infection was correlated with a higher expression of APN, which was indicative that APN plays an important role in porcine coronavirus infections. However, PEDV and TGEV infected both APN positive and negative enterocytes. PEDV and TGEV Miller showed a higher infectivity in APN positive cells than in APN negative cells. In contrast, TGEV Purdue replicated better in APN negative cells. These results show that an additional receptor exists, different from APN for porcine coronaviruses. Subsequently, treatment of enterocytes with neuraminidase (NA) had no effect on infection efficiency of TGEV, implying that terminal cellular sialic acids (SAs) are no receptor determinants for TGEV. Treatment of TGEV with NA significantly enhanced the infection which shows that TGEV is masked by SAs.