Pathogenesis Of SARS Research Articles

Pathological changes in the osteoarticular system during COVID-19 drug therapy (review of literature)

The recommended drugs for the treatment of COVID-19 are, on the one hand, experimental in nature, but at the same time, they have many side effects that cause long-term complications in organs and systems, including osteoarticular. Based on the analysis of modern domestic and foreign literature, to determine the effect of not only the new coronavirus infection COVID-19, but also the drugs used to treat it, on the human osteoarticular system. In the course of the study, a scientific search was made for publications in the electronic databases PubMed, MedLine and e-Library for the period from January 2000 to October 2021 for the main keywords. Due to successive “waves” of the COVID-19 pandemic, the number of patients receiving non-specific therapy, including corticosteroids, will increase in the coming years. Preliminary data on COVID-19 and similar trends during the Sars-COV-1 epidemic of 2003 show that the pathogenesis of Sars- Cov-2 and its treatment with high doses of corticosteroids may increase the risk of osteonercosis in patients, which will inevitably lead to an increase in orthopedic diseases in patients not only the middle age group, but also young patients in the near future. Currently, studies are required aimed at risk stratification, studying the pathogenesis of damage to the musculoskeletal system after COVID-19 and the effectiveness of preventive and therapeutic measures in such patients.

COVID-19-ASSOCIATED MENINGOENCEPHALITIS TREATED WITH STEROIDS AND REMDESIVIR

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: The novel coronavirus, named SARS-CoV-2, is known to have emerged in Wuhan, China in late 2019. A wide variety of organs have been found to be involved with SARS-CoV-2 infection. Recent reports indicate that the CNS is not spared. Headache, dysguesia and hyposmia, some more serious neurologic manifestations including encephalopathy Guillain Barre syndrome and stroke are now being reported as the number of patients with COVID-19 across the globe. We report a case of meningoencephalitis associated with SARS-CoV-2 who presented with altered mental status. CASE PRESENTATION: 43-year-old male with a PMH significant for insulin-dependent diabetes presented with altered mental status. In Emergency department was noted to have rhythmic jerking movements and his gaze was deviated to the right, concerning for seizure activity. Upon admission it was confirmed to have COVID-19 via detection of SARS-CoV-2 viral nucleic acid in a nasopharyngeal swab specimen using the Simplexa SARS-CoV-2 assay. Neurological examination revealed confusion with orientation only to self, inability to follow commands, and no apparent focal neurological deficits. Otherwise, general examination was unremarkable and vital signs were within normal. CT head was negative for any acute pathology. His cerebrospinal fluid (CSF) was clear and color less with an elevated CSF cell count and lymphocytic predominance suspicious for viral encephalitis.The CSF glucose (70 mg/dL) was increased and CSF protein levels (19 mg/dL) were decreased. A CSF PCR panel including Cryptococcus neoformans, HSV, varicella zoster virus, Streptococcus pneumoniae, Neisseria meningitidis and enterovirus was negative. The SARS-CoV-2 CSF PCR was negative. Labs were significant for elevated ferritin, LDH, C reactive protein and Di dimer. EEG shows diffuse slowing in the theta range indicative of encephalopathy and lacked any epileptogenic activity. Patient started on steroids, Remedesivir with concern of COVID 19 meningoencephalitis. Within the next 3 days, his mentation progressively improved;he was able to communicate, and was following commands. DISCUSSION: The neuroinvasive nature of human coronavirus has been previously reported during the 2002–2003 SARS-CoV pandemic when viral nucleic acids were found in the human brain upon autopsies. It was postulated by scientists in China that SARS-CoV-2, a novel coronavirus from the SARS-CoV family, could also infect the brain when they observed neurologic signs among patients with COVID-19 related respiratory illness. CONCLUSIONS: Although rare, meningoencephalitis should be considered as a possible manifestation of COVID-19 disease. A suspicion for SARS-CoV-2 meningitis or encephalitis should be high among patients presenting with neurological symptoms during this era of pandemic. SARS-CoV-2 testing should be included as part of the workup in addition to other infectious causes. REFERENCE #1: Gu J., Gong E., Zhang B. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202(3):415–424. doi: 10.1084/jem.20050828 REFERENCE #2: Moriguchi T., Harii N., Goto J. A first case of meningitis/encephalitis associated with SARS-coronavirus-2. Int J Infect Dis. 2020;94:55–58. doi: 10.1016/j.ijid.2020.03.062 DISCLOSURES: No relevant relationships by Ajay Adial, source=Web Response No relevant relationships by Muhammad Azaz Cheema, source=Web Response No relevant relationships by Asma Iftikhar, source=Web Response No relevant relationships by Hamza Quadri, source=Web Response

Expression and Possible Significance of ACE2 in the Human Liver, Esophagus, Stomach, and Colon.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the key receptor of SARS coronavirus that plays a key role in the pathogenesis of SARS. It is known that ACE2 mRNA can be expressed in most organs. However, the protein expression of ACE2 is not clear yet. To explore the role of ACE2 as a precipitating factor in digestive organ damage in COVID-19, this study investigated the expression of ACE2 protein in the human liver, esophagus, stomach, and colon. The result showed that ACE2 can be expressed in the liver, esophagus, stomach, and colon, which suggests SARS-CoV-2 may enter the digestive system through ACE2 and cause liver damage and gastrointestinal damage. It is hoped that the result of the study will provide a new strategy for the prevention and treatment of digestive organ damage under COVID-19.

Challenges in the Production of Convalescent Hyperimmune Plasma in the Age of COVID-19.

In December 2019, the first patients were diagnosed with coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[1] In only a few months, COVID-19 has spread globally, affecting over 3 million individuals with over 250,000 deaths (data updated on May 2).[2] This has prompted the World Health Organization (WHO) to declare the COVID-19 outbreak a pandemic.[3] Unfortunately, no uniformly standardized therapy has been endorsed for COVID-19 and a number drugs are currently being investigated in several nonrandomized or randomized trials for patients with life-threatening COVID-19.[3] [4] These agents includes steroids, chloroquine, antiviral medications (i.e., remdesivir, loparinir/ritonavir), and anti-inflammatory agents (i.e., tocilizumab, sarilumab, baricitinib), the latter being utilized following the discovery of the involvement of SARS-CoV-2-induced inflammatory response in the pathogenesis of SARS.[5] [6]

SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy.

The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.

Investigation of Antibody-Dependent Enhancement (ADE) of SARS coronavirus infection and its role in pathogenesis of SARS

Antibody-dependent enhancement (ADE) is a mechanism by which viruses, such as dengue, HIV and Ebola, gain entry into some target cells through the use of host antiviral humoral immune responses [1]. Here, we studied the ability of severe acute respiratory syndrome coronavirus (SARS-CoV) [2] to use ADE mechanisms to enhance its infectivity towards cells of the hematopoietic lineage. We found that heat-inactivated immune serum from rodents vaccinated with recombinant native full-length Spike protein trimers [3] triggered infection of human immune cells (monocytic and B cell lines) by SARS-CoV Spike pseudotyped particle (SARS-CoVpp). The occurrence of antibody-mediated infection of human Raji B cells was further investigated by using live SARS-CoV. Similarly to results obtained with the SARS-CoVpp, only anti-SARS-CoV Spike serum, but not mock immune-serum, induced a massive increase of SARS-CoV viral genes (ORF1b and Nucleocapsid) and viral proteins (Membrane and Nucleocapsid) in Raji B cells. As revealed by immunostaining, only a relatively low, however significant percentage of the Raji cells get infected by antibody-mediated infection and did not allow direct assessment of productive replication by conventional cytopathic assays and TCID50 titration. Taken together, our data suggested that SARS-CoV is able to enter human immune cells via an antibody-mediated pathway and immunological consequences of such infection are under investigation (productive replication, cytokines secretion profile and cell death etc). Our data raise reasonable concerns regarding the use of SARS-CoV vaccine in humans and pave the way to further studies focusing on the role of immune-mediated infection phenomenon during SARS pathogenesis.

Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+T Cells Are Important in Control of SARS-CoV Infection

We characterized the cellular immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 12- to 14-month-old BALB/c mice, a model that mimics features of the human disease. Following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. Enhanced production of cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) correlated with migration of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of cytokines (TNF-alpha, IL-6, gamma interferon [IFN-gamma], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. Depletion of CD8(+) T cells at the time of infection did not affect viral replication or clearance. However, depletion of CD4(+) T cells resulted in an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs, which was associated with reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of lymphocytes. Innate defense mechanisms are able to control SARS-CoV infection in the absence of CD4(+) and CD8(+) T cells and antibodies. Our findings provide new insights into the pathogenesis of SARS, demonstrating the important role of CD4(+) but not CD8(+) T cells in primary SARS-CoV infection in this model.

Transcriptional profiling of Vero E6 cells over-expressing SARS-CoV S2 subunit: Insights on viral regulation of apoptosis and proliferation

We have previously demonstrated that over-expression of spike protein (S) of severe acute respiratory syndrome coronavirus (SARS-CoV) or its C-terminal subunit (S2) is sufficient to induce apoptosis in vitro. To further investigate the possible roles of S2 in SARS-CoV-induced apoptosis and pathogenesis of SARS, we characterized the host expression profiles induced upon S2 over-expression in Vero E6 cells by oligonucleotide microarray analysis. Possible activation of mitochondrial apoptotic pathway in S2 expressing cells was suggested, as evidenced by the up-regulation of cytochrome c and down-regulation of the Bcl-2 family anti-apoptotic members. Inhibition of Bcl-2-related anti-apoptotic pathway was further supported by the diminution of S2-induced apoptosis in Vero E6 cells over-expressing Bcl-xL. In addition, modulation of CCN E2 and CDKN 1A implied the possible control of cell cycle arrest at G1/S phase. This study is expected to extend our understanding on the pathogenesis of SARS at a molecular level.

The Immune Response in Patients with SARS: differential gene expression profiling.

AbstractSevere acute respiratory syndrome (SARS) emerged in 2003, as a new epidemic form of life-threatening infection. As of 26th September 2003, there were 8422 cases of SARS from 29 countries with 908 deaths (WHO). However, the pathogenesis of SARS is poorly understood. To understand the host response to this pathogen, we profiled the gene expression patterns of peripheral blood mononuclear cells (PBMC) from SARS patients compared to healthy controls using one of the latest techniques, high density oligonucleotide expression probe array (HG-Focus array, Gene Chip, Affymetrix, Santa Clara, CA). High-density oligonucleotide microarray is a promising approach for high throughput analysis. It has been extensivelyused in many areas of biomedical research for different purposes. Thus we could compare the expression levels of thousands of genes which are differentially expressed in SARS patients over healthy controls. Among the most prominent findings, we observed 2 to 200-fold increased expression of transcripts of various genes. This enabled us to classify and cluster genes by functional families as well as to understand known genes in signalingpathways.

Analysis of proteins that interact with nucleocapsid protein of SARS-CoV using 15-mer phage-displayed library.

Analysis of proteins that interact with N protein of SARS-CoV using 15-mer phage-displayed library will help to explore the virus pathogenesis and to develop new drugs and vaccines against SARS. In this study, we cloned, expressed and purified N protein of SARS-CoV. This 46-kD N protein was verified by SDS-PAGE and Western-blot. Then, the peptides binding-specific to N protein were identified using 15-mer phage-displayed library. Surprisingly, all of the 89 clones from monoclonal ELISA were positive (S/N>2.1) and the result was further confirmed experimentally once again. Six N protein-binding peptides, designated separately as SNA1, SNA2, SNA4, SNA5, SNA9 and SNG11, were selected for sequencing. Sequence analysis suggested that SNA5 shared approximatively 100% sequence identity to SNA4, SNA2, SNA9 and SNA1. In addition, the binding specificity of the 15-mer peptides with the SARS-CoV N protein was further demonstrated by blocking ELISA using the synthetical 15-mer peptide according to the deduced amino acid sequence of SNA5. Also, the deduced amino sequence of SNA5 was compared with proteins in translated database using the tblastx program, and the results showed that the proteins with the highest homology were Ubiquinol-cytochrome c reductase iron-sulfur subunits (UCRI or UQCR), otherwise known as the Rieske iron-sulfur proteins (RISP). Notablely, in the [2Fe-2S] redox centre of UCRI, there were 6 residues [GGW(Y)F(Y)CP] compatible to the residues (position 2→7, GGWFCP7) of the NH2-terminal of the 15-mer peptide, which indicated higher binding specificity between the N protein of SARS-CoV and the redox centre of UCRI to some extent. Here, the possible molecular mechanisms of SARS-CoV N protein in the pathogenesis of SARS are discussed.

Authors' Response to Hogan

In response to our Perspective on nonhuman primate models for SARS [1], which accompanied the article by Lawler et al. [2], Robert Hogan questions the usefulness of nonhuman primates as good models for SARS [3]. As demonstrated by several groups, SARS coronavirus (SARS-CoV) replicates to high titers in the respiratory tract of a surprisingly broad range of animal species, albeit showing remarkable differences in cell tropism. We have argued that efficient infection of type 1 and 2 pneumocytes as seen in macaques and humans—most likely due to the similarities in the spike protein binding domains of the host SARS-CoV receptor ACE2—is a prerequisite for the SARS-CoV infection–induced pathology observed in humans. So far there is no strong evidence that a similar tropism is observed in other animal species. However, the tropism of SARS-CoV for pneumocytes may not suffice to induce severe clinical signs in primates. In case of a resolving infection in macaques, pathological changes are evident four to six days after infection and may have become inapparent by days 12–14. In addition, in young adult humans, SARS-CoV infection generally causes relatively mild disease. Viral sequence differences in the SARS-CoV isolate HKU 39849 obtained from and distributed to several groups by Peiris et al. [4], as compared to other strains used, may determine the outcome of SARS-CoV infection in macaques. Furthermore, recent experiments from our group indicate that clinical signs after infection with this virus are more likely to occur in aged macaques (unpublished data). Clinical signs observed in our earlier experiments were largely characterised by lethargy, whereas respiratory distress was observed in one animal [5,6]. The apparent differences observed in clinical outcome of the infection in macaques, which is similar to the outcome in humans, may limit the utility of SARS-CoV–infected macaques as a model for severe SARS. However, none of the other models available produces clinical disease related to respiratory distress, except for ferrets that are inoculated with the HKU 39849 virus intratracheally [7]. Therefore, we feel that the macaque model may indeed provide important clues to the pathogenesis of SARS. As also argued by Subbarao and Roberts [8], there is no single preferred model for SARS and combining the data obtained in different animal models may help to solve the question of why SARS is so devastating in some humans. This also holds true for the development of effective vaccines and other intervention strategies against possible future SARS-CoV outbreaks which may be caused by genetically quite distinct viruses.

Activation of NF-κB by the Full-length Nucleocapsid Protein of the SARS Coronavirus

The severe acute respiratory syndrome coronavirus (SARS‐CoV) is the major causative agent for the worldwide outbreak of SARS in 2003. The mechanism by which SARS‐CoV causes atypical pneumonia remains unclear. The nuclear factor kappa B (NF‐κB) is a key transcription factor that activates numerous genes involved in cellular immune response and inflammation. Many studies have shown that NF‐κB plays an important role in the pathogenesis of lung diseases. In this study, we investigated the possible regulatory interaction between the SARS‐CoV nucleocapsid (N) protein and NF‐κB by luciferase activity assay. Our results showed that the SARS‐CoV N protein can significantly activate NF‐κB only in Vero E6 cells, which are susceptible to SARS‐CoV infection, but not in Vero or HeLa cells. This suggests that NF‐κB activation is cell‐specific. Furthermore, NF‐κB activation in Vero E6 cells expressing the N protein is dose‐dependent. Further experiments showed that there is more than one function domain in the N protein responsible for NF‐κB activation. Our data indicated the possible role of the N protein in the pathogenesis of SARS.Edited by Bing SUN

Structure-Based Preliminary Analysis of Immunity and Virulence of SARS Coronavirus

The research on SARS-associated coronavirus (SARS-CoV) has not stopped since its discovery, but the pathogenesis of SARS is still unclear. To explore the possible molecular mechanisms of the invasion and virulence of SARS-CoV, we investigated the structural basis of the viral proteins using computational biology. Forty-five motifs relating to superantigens, toxins and other bioactive molecules were detected in the proteins of SARS-CoV. The results showed that the distribution of the motifs varied in different proteins. Enzyme-like motifs were located in the R protein, while ICAM- 1-like and toxin-like molecules were located in the spike, envelop, nucleocapsid, PUP1, PUP 2 and PUP 4 proteins. Comparison of SARS-CoV with other viruses (OC43, PEDV, HRSV, HHerpV and HAdenoV) showed that each group of motifs was different for each type of virus. Data suggest that the proteins of SARS-CoV with toxic motifs might play crucial roles in targeting host cells and interfering with the immune system. This study provides new information for drug and vaccine design, as well as therapeutic strategies against SARS.

EPIDEMIOLOGY AND OTHERS

SARS ABSTRACTS: Proceedings of the International Symposium on the Pathogenesis of SARS: July 12–13, 2003, Beijing, China Sponsored by Peking University (Part 2. Continued from the last issue of AIMM)

Immunology

Proceedings of the International Symposium on the Pathogenesis of SARS: July 12–13, 2003, Beijing, China Sponsored by Peking University

Pathology

Proceedings of the International Symposium on the Pathogenesis of SARS: July 12–13, 2003, Beijing, China Sponsored by Peking University