Patients with SARS-CoV-2-Induced Viral Sepsis Simultaneously Show Immune Activation, Impaired Immune Function and a Procoagulatory Disease State.

BACKGROUND: It is widely accepted that SARS-CoV-2 causes a dysregulation of immune and coagulation processes. In severely affected patients, viral sepsis may result in life endangering multiple organ dysfunction. Furthermore, most therapies for COVID-19 patients target either the immune system or coagulation processes. As the exact mechanism causing SARS-CoV-2-induced morbidity and mortality was unknown, we started an in-depth analysis of immunologic and coagulation processes. METHODS: 127 COVID-19 patients were treated at the University Hospital Essen, Germany, between May 2020 and February 2022. Patients were divided according to their maximum COVID-19 WHO ordinal severity score (WHO 0-10) into hospitalized patients with a non-severe course of disease (WHO 4-5, n = 52) and those with a severe course of disease (WHO 6-10, n = 75). Non-infected individuals served as healthy controls (WHO 0, n = 42). Blood was analyzed with respect to cell numbers, clotting factors, as well as pro- and anti-inflammatory mediators in plasma. As functional parameters, phagocytosis and inflammatory responses to LPS and antigen-specific stimulation were determined in monocytes, granulocytes, and T cells using flow cytometry. FINDINGS: In the present study, immune and coagulation systems were analyzed simultaneously. Interestingly, many severe COVID-19 patients showed an upregulation of pro-inflammatory mediators and at the same time clear signs of immunosuppression. Furthermore, severe COVID-19 patients not only exhibited a disturbed immune system, but in addition showed a pronounced pro-coagulation phenotype with impaired fibrinolysis. Therefore, our study adds another puzzle piece to the already complex picture of COVID-19 pathology implying that therapies in COVID-19 must be individualized. CONCLUSION: Despite years of research, COVID-19 has not been understood completely and still no therapies exist, fitting all requirements and phases of COVID-19 disease. This observation is highly reminiscent to sepsis. Research in sepsis has been going on for decades, while the disease is still not completely understood and therapies fitting all patients are lacking as well. In both septic and COVID-19 patients, immune activation can be accompanied by immune paralysis, complicating therapeutic intervention. Accordingly, therapies that lower immune activation may cause detrimental effects in patients, who are immune paralyzed by viral infections or sepsis. We therefore suggest individualizing therapies and to broaden the spectrum of immunological parameters analyzed before therapy. Only if the immune status of a patient is understood, can a therapeutic intervention be successful.

Effectiveness of Sotrovimab in the Omicron Storm Time: A Case Series.

Neutralizing monoclonal antibodies (mAbs) for pre- and post-exposure prophylaxis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are largely used to prevent the progression of the disease by blocking viral attachment, host cell entry, and infectivity. Sotrovimab, like other available mAbs, has been developed against the receptor binding Domain of the Spike (S) glycoprotein of the virus. Nevertheless, the latest Omicron variant has shown marked mutations within the S gene, thus opening the question of the efficacy of these neutralizing molecules towards this novel variant. In the present observational study, we describe the effects of Sotrovimab in the treatment of 15 fully vaccinated patients, infected by SARS-CoV-2 Omicron sub-variants, who were selected on the basis of factors widely considered to affect a worse prognosis: immune suppression (n = 12) and/or chronic kidney disease (n = 5) with evidence of interstitial pneumonia in nine patients. The effectiveness of Sotrovimab in the treatment of severe cases of COVID-19 was demonstrated by the regression of symptoms (mean 5.7 days), no need of hospitalisation, improvement of general health conditions and viral clearance within 30 days in all patients. In conclusion, although loss or reduction of mAbs neutralizing activity against the Omicron variant have been described, Sotrovimab has clinically proven to be a safe and useful treatment for patients with high risk of progression to severe COVID-19 infected by Omicron sub-variants.

Targeting viral proteins for restraining SARS-CoV-2: focusing lens on viral proteins beyond spike for discovering new drug targets.

INTRODUCTION: Emergence of highly infectious SARS-CoV-2 variants are reducing protection provided by current vaccines, requiring constant updates in antiviral approaches. The virus encodes four structural and sixteen nonstructural proteins which play important roles in viral genome replication and transcription, virion assembly, release , entry into cells, and compromising host cellular defenses. As alien proteins to host cells, many viral proteins represent potential targets for combating the SARS-CoV-2. AREAS COVERED: Based on literature from PubMed and Web of Science databases, the authors summarize the typical characteristics of SARS-CoV-2 from the whole viral particle to the individual viral proteins and their corresponding functions in virus life cycle. The authors also discuss the potential and emerging targeted interventions to curb virus replication and spread in detail to provide unique insights into SARS-CoV-2 infection and countermeasures against it. EXPERT OPINION: Our comprehensive analysis highlights the rationale to focus on non-spike viral proteins that are less mutated but have important functions. Examples of this include: structural proteins (e.g. nucleocapsid protein, envelope protein) and extensively-concerned nonstructural proteins (e.g. NSP3, NSP5, NSP12) along with the ones with relatively less attention (e.g. NSP1, NSP10, NSP14 and NSP16), for developing novel drugs to overcome resistance of SARS-CoV-2 variants to preexisting vaccines and antibody-based treatments.

Synthetic Mucin Gels with Self-Healing Properties Augment Lubricity and Inhibit HIV-1 and HSV-2 Transmission.

Mucus is a self-healing gel that lubricates the moist epithelium and provides protection against viruses by binding to viruses smaller than the gel's mesh size and removing them from the mucosal surface by active mucus turnover. As the primary nonaqueous components of mucus (≈0.2%-5%, wt/v), mucins are critical to this function because the dense arrangement of mucin glycans allows multivalence of binding. Following nature's example, bovine submaxillary mucins (BSMs) are assembled into "mucus-like" gels (5%, wt/v) by dynamic covalent crosslinking reactions. The gels exhibit transient liquefaction under high shear strain and immediate self-healing behavior. This study shows that these material properties are essential to provide lubricity. The gels efficiently reduce human immunodeficiency virus type 1 (HIV-1) and genital herpes virus type 2 (HSV-2) infectivity for various types of cells. In contrast, simple mucin solutions, which lack the structural makeup, inhibit HIV-1 significantly less and do not inhibit HSV-2. Mechanistically, the prophylaxis of HIV-1 infection by BSM gels is found to be that the gels trap HIV-1 by binding to the envelope glycoprotein gp120 and suppress cytokine production during viral exposure. Therefore, the authors believe the gels are promising for further development as personal lubricants that can limit viral transmission.

COVID-19 infection in liver transplant recipients: Clinical features and outcomes from a Canadian multicentre cohort

BACKGROUND: Prior studies have assessed risk factors and clinical outcomes in liver transplant (LT) recipients infected with COVID-19 globally;however, there is a paucity of Canadian data. Our multicentre study aims to examine the characteristics and clinical outcomes of LT patients with COVID-19 infection in Canada. METHODS: Adult LT recipients with reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19, from Canadian tertiary care centres between March 2020 and June 2021 were included. RESULTS: A total of 49 patients with a history of LT and COVID-19 infection were identified. Twenty nine patients (59%) were male, median time from LT was 66 months (IQR 1, 128), and median age was 59 years (IQR 52, 65). At COVID-19 diagnosis, the median alanine transaminase (ALT) was 37 U/L (IQR 21, 41), aspartate aminotransferase (AST) U/L was 34 (IQR 20, 37), alkaline phosphatase (ALP) U/L was 156 (IQR 88, 156), total bilirubin was 11 umol/L (IQR 7, 14), and international normalized ratio (INR) was 1.1 (IQR 1.0, 1.1). The majority of patients (86%) were on tacrolimus (monotherapy or combined with mycophenolate mofetil);median tacrolimus level at COVID-19 diagnosis was 5.3 ug/L (IQR 4.0, 8.1). Immunosuppression was modified in eight (16%) patients post-infection. Eighteen patients (37%) required hospitalization, and three (6%) required intensive care unit (ICU) admission and mechanical ventilation. Four patients (8%) died from complications related to COVID-19 infection. On univariate analysis, neither age, sex, comorbidities nor duration post-transplant were associated with risk of hospitalization or ICU admission. CONCLUSIONS: LT recipients with COVID-19 have high rates of hospitalization but fortunately have low rates of ICU admission and mortality in this national registry.

Comprehensive Analysis of Disease Pathology in Immunocompetent and Immunocompromised Hosts following Pulmonary SARS-CoV-2 Infection.

The Coronavirus disease 2019 (COVID-19) pandemic disproportionately affects immunocompetent and immunocompromised individuals, with the latter group being more vulnerable to severe disease and death. However, the differential pathogenesis of SARS-CoV-2 in the context of a specific immunological niche remains unknown. Similarly, systematic analysis of disease pathology in various extrapulmonary organs in immunocompetent and immunocompromised hosts during SARS-CoV-2 infection is not fully understood. We used a hamster model of SARS-CoV-2 infection, which recapitulates the pathophysiology of patients with mild-to-moderate COVID-19, to determine the dynamics of SARS-CoV-2 replication and histopathology at organ-level niches and map how COVID-19 symptoms vary in different immune contexts. Hamsters were intranasally infected with low (LD) or high (HD) inoculums of SARS-CoV-2, and the kinetics of disease pathology and viral load in multiple organs, antibody response, inflammatory cytokine expression, and genome-wide lung transcriptome by RNAseq analysis were determined and compared against corresponding responses from chemically induced immunocompromised hamsters. We observed transient body weight loss proportional to the SARS-CoV-2 infectious dose in immunocompetent hamsters. The kinetics of viral replication and peak viral loads were similar between LD and HD groups, although the latter developed more severe disease pathology in organs. Both groups generated a robust serum antibody response. In contrast, infected immunocompromised animals showed more prolonged body weight loss and mounted an inadequate SARS-CoV-2-neutralizing antibody response. The live virus was detected in the pulmonary and extrapulmonary organs for extended periods. These hamsters also had persistent inflammation with severe bronchiolar-alveolar hyperplasia/metaplasia. Consistent with the differential disease presentation, distinct changes in inflammation and immune cell response pathways and network gene expression were seen in the lungs of SARS-CoV-2-infected immunocompetent and immunocompromised animals.

EXPERIMENTAL COMBINED MYCOTOXICOSIS IN PIGS AS AFFECTED BY INFECTION LOAD

Animal and human mycotoxicoses occur due to the ingestion of metabolites of toxicogenic microfungi. The effect increases in case of the co-ingestion of several mycotoxins, their mix with another ecotoxicants and biological agents. However, published research data only partially cover the nature of mixed mycotoxicoses in infectious diseases. This work shows for the first time the effect on pigs of the infection load of Clostridium perfringes and the combined effect of T-2 toxin, zearalenone, and deoxynivalenol in low doses. Our goal was to study the chronic form of combined mycotoxicosis in weaned pigs with a persistent infection in herd on the animal productivity, blood morpho-biochemical and immunological parameters, pathological changes in organs and tissues. Combined experimental mycotoxicosis with infectious load was modeled under the conditions of the vivarium complex (the Federal Center for Toxicological, Radiation and Biological Safety, 2018) on the weaning Large White piglets (Sus scrofa domesticus) divided into three groups 3 pigs each. Group I received no mycotoxins, group II received dietary T-2 toxin (70 µg/kg feed), group III received mixed dietary mycotoxins (DON 1000 µg/kg, ZEN 50 µg/kg and T-2 70 µg/kg). All animals were orally administered a suspension of Clostridium perfringes No. 392 type C (1½106 CFU/ml, 2 ml). On day 15, the animals were vaccinated intramuscularly in the posterior thigh with 1 ml of the associated vaccine against rota-, coronavirus and colorectal diarrhea of newborn piglets (FCTRB-VNIVI). Group I (control) was considered clinically healthy. Signs of intoxication, blood biochemical parameters (total protein, total bilirubin, glucose, malondialdehyde, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase activity), blood morphology (counts of erythrocytes, leukocytes, the hemoglobin level) and immunological parameters (T- and B-lymphocytes, titer of antibodies to vaccine antigens) on day 10, 20 and 30. The antibody titers to the Escherichia coli vaccine strain were determined by the agglutination reaction, to the coronavirus vaccine antigen by the ELISA test using a Multiscan FC photometer (Thermo Scientific, USA), and to the rotavirus antigen by an indirect hemagglutination test. At the end of the experiment, pieces of organs were fixed in 10 % neutral formalin, followed by generally accepted pathomorphological processing for histological studies. Histopreparations were stained with hematoxylin and eosin. Feed contamination with mycotoxins combined with clostridiosis had an adverse effect on the clinical and immune status, blood morpho-biochemical parameters, and pathoanatomical patterns. The changes were more apparent in co-contamination with ecotoxicants. Average daily bodyweight gain in piglets of group II was lower by 20.5 % compared to the control (p ≥ 0.05), of group III by 39.2 % (p ≤ 0.05). In group III, by the end of the experiment, there was a decrease in the erythrocyte counts by 40 % (p ≤ 0.001), in the level of hemoglobin by 20 % (p ≤ 0.01), glucose by 57 % (p ≤ 0.001), and total protein by 13 % (p ≤ 0.05). The concentration of bilirubin increased 5.1-fold (p ≤ 0.001), the activity of alanine aminotransferase and aspartate aminotransferase 2.2- and 1.8-fold (p ≤ 0.001), respectively, the concentration of malondialdehyde 2.8-fold (p ≤ 0.001), the activity of alkaline phosphatase decrease by 41.5 % (p ≤ 0.001). Co-mycotoxicosis combined with an infectious load led to immunological changes. Titers of specific antibodies to rotavirus were 8 times lower, to coronavirus 6.4 times lower (p ≤ 0.05), to Escherichia 5 times lower (p ≤ 0.05) compared to the control. Marked pathological changes in the internal organs also occurred. Therefore, the co-mycotoxicosis due to T-2 toxin-, deoxynivalenol- and zearalenone-contaminated feed combined with the persistence of Clostridium perfringens, the causative agent of intestinal infection lead to suppression of immunological parameters (a decrease in the titer of specific protective ntibodies, the number of T- and B-lymphocytes), activation of lipid peroxidation, and pathological changes in tissues and organs of the piglets. © 2022 Russian Academy of Agricultural Sciences. All rights reserved.

Proposal for a New Protocol for the Management of Immune Thrombocytopenia (ITP).

For many decades immune thrombocytopenia (ITP) was managed using therapies which had not undergone randomised clinical trials and included corticosteroids, immune suppression or splenectomy. These older therapies are associated with an increase in morbidity and mortality. These empirical therapies have variable efficacy and well-described side effects for many patients with minimal benefit to the patient. Over the past 10 years there has been a shift away from immune suppression and non-evidence-based therapies towards using treatments with reduced or no immune suppression with an increasing reliance on the recently developed and approved thrombopoietin receptor agonists. The recent COVID-19 pandemic has made it more urgent that we develop non-immune suppressive strategies for ITP. In this commentary we describe our proposal for a contemporary approach to the management of ITP in adults that is based on our hospital practices and published guidelines.

Long-Term Expansion of Porcine Intestinal Organoids Serves as an in vitro Model for Swine Enteric Coronavirus Infection.

A reliable and reproducible model in vitro for swine enteric coronaviruses infection would be intestinal models that support virus replication and can be long-term cultured and manipulated experimentally. Here, we designed a robust long-term culture system for porcine intestinal organoids from the intestinal crypt or single LGR5+ stem cell by combining previously defined insights into the growth requirements of the intestinal epithelium of humans. We showed that long-term cultured swine intestinal organoids were expanded in vitro for more than 6 months and maintained the potential to differentiate into different types of cells. These organoids were successfully infected with porcine enteric coronavirus, including porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV), and were capable of supporting virus replication and progeny release. RNA-seq analysis showed robust induction of transcripts associated with antiviral signaling in response to enteric coronavirus infection, including hundreds of interferon-stimulated genes and cytokines. Moreover, gene set enrichment analysis indicated that PEDV infection could suppress the immune response in organoids. This 3D intestinal organoid model offers a long-term, renewable resource for investigating porcine intestinal infections with various pathogens.

COVID-19 in Patients with Inflammatory Bowel Disease: The Israeli Experience.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated inflammatory bowel diseases (IBD) affecting millions of people worldwide. IBD therapies, designed for continuous immune suppression, often render patients more susceptible to infections. The effect of the immune suppression on the risk of coronavirus disease-19 (COVID-19) is not fully determined yet. OBJECTIVE: To describe COVID-19 characteristics and outcomes and to evaluate the association between IBD phenotypes, infection outcomes and immunomodulatory therapies. METHODS: In this multi-center study, we prospectively followed IBD patients with proven COVID-19. De-identified data from medical charts were collected including age, gender, IBD type, IBD clinical activity, IBD treatments, comorbidities, symptoms and outcomes of COVID-19. A multivariable regression model was used to examine the effect of immunosuppressant drugs on the risk of infection by COVID-19 and the outcomes. RESULTS: Of 144 IBD patients, 104 (72%) were CD and 40 (28%) were UC. Mean age was 32.2 ± 12.6 years. No mortalities were reported. In total, 94 patients (65.3%) received biologic therapy. Of them, 51 (54%) at escalated doses, 10 (11%) in combination with immunomodulators and 9 (10%) with concomitant corticosteroids. Disease location, behavior and activity did not correlate with the severity of COVID-19. Biologics as monotherapy or with immunomodulators or corticosteroids were not associated with more severe infection. On the contrary, patients receiving biologics had significantly milder infection course (p = 0.001) and were less likely to be hospitalized (p = 0.001). Treatment was postponed in 34.7% of patients until recovery from COVID-19, without consequent exacerbation. CONCLUSION: We did not witness aggravated COVID-19 outcomes in patients with IBD. Patients treated with biologics had a favorable outcome.

Decoupling SARS-CoV-2 ORF6 localization and interferon antagonism.

Like many pathogenic viruses, SARS-CoV-2 must overcome interferon (IFN)-mediated host defenses for infection establishment. To achieve this, SARS-CoV-2 deploys overlapping mechanisms to antagonize IFN production and signaling. The strongest IFN antagonist is the accessory protein ORF6, which localizes to multiple membranous compartments, including the nuclear envelope, where it directly binds nuclear pore component Nup98-Rae1 to inhibit nuclear translocation of activated STAT1 and IRF3 transcription factors. However, this direct cause-and-effect relationship between ORF6 localization and IFN antagonism has yet to be explored experimentally. Here, we use extensive mutagenesis studies to define the structural determinants required for steady-state localization and demonstrate that mis-localized ORF6 variants still potently inhibit nuclear trafficking and IFN signaling. Additionally, expression of a peptide that mimics the ORF6-Nup98 interaction domain robustly blocked nuclear trafficking. Furthermore, pharmacologic and mutational approaches combined to suggest that ORF6 is likely a peripheral membrane protein, as opposed to being a transmembrane protein as previously speculated. Thus, ORF6 localization and IFN antagonism are independent activities, which raises the possibility that ORF6 may have additional functions within membrane networks to enhance virus replication. This article has an associated First Person interview with the first author of the paper.

Perspective of HLA-G Induced Immunosuppression in SARS-CoV-2 Infection.

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened public health worldwide. Host antiviral immune responses are essential for viral clearance and disease control, however, remarkably decreased immune cell numbers and exhaustion of host cellular immune responses are commonly observed in patients with COVID-19. This is of concern as it is closely associated with disease severity and poor outcomes. Human leukocyte antigen-G (HLA-G) is a ligand for multiple immune inhibitory receptors, whose expression can be upregulated by viral infections. HLA-G/receptor signalling, such as engagement with immunoglobulin-like transcript 2 (ILT-2) or ILT-4, not only inhibit T and natural killer (NK) cell immune responses, dendritic cell (DC) maturation, and B cell antibody production. It also induces regulatory cells such as myeloid-derived suppressive cells (MDSCs), or M2 type macrophages. Moreover, HLA-G interaction with CD8 and killer inhibitory receptor (KIR) 2DL4 can provoke T cell apoptosis and NK cell senescence. In this context, HLA-G can induce profound immune suppression, which favours the escape of SARS-CoV-2 from immune attack. Although detailed knowledge on the clinical relevance of HLA-G in SARS-CoV-2 infection is limited, we herein review the immunopathological aspects of HLA-G/receptor signalling in SARS-CoV-2 infection, which could provide a better understanding of COVID-19 disease progression and identify potential immunointerventions to counteract SARS-CoV-2 infection.

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis.

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.

Modulation of immunosuppressant drug treatment to improve SARS-CoV-2 vaccine efficacy in mice.

The COVID-19 pandemic dramatically demonstrated the need for improved vaccination strategies and therapeutic responses to combat infectious diseases. However, the efficacy of vaccines has not yet been demonstrated in combination with commonly used immunosuppressive drug regimens. We sought to determine how common pharmaceutical drugs used in autoimmune disorders can alter immune responses to the SARS-CoV-2 spike protein vaccination. We treated mice with five immunosuppressant drugs (cyclophosphamide, leflunomide, methotrexate, methylprednisolone, and mycophenolate mofetil), each with various mechanisms of action prior to and following immunization with SARS-CoV-2 spike protein. We assessed the functionality of antibody responses to spike protein and compared immune cell populations in mice that received no treatment with those that received continuous or temporarily suspended immune suppressive therapy. All tested immunosuppressants significantly reduced the antibody titers in serum and functional antibody response against SARS-CoV-2 spike protein in immunized mice. Temporarily halting selected immunosuppressants (methylprednisolone and methotrexate, but not cyclophosphamide) improved antibody responses significantly. Through proof-of-principle experiments utilizing a mouse model, we demonstrated that immune suppression in autoimmune disorders through pharmaceutical treatments may impair vaccine response to SARS-CoV-2, and temporary suspension of immunosuppressant treatment may be necessary to mount an effective antibody vaccine response. This work provides feasibility for future clinical assessment of the impact of immunosuppressants on vaccine efficacy in humans.

Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests.

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

Recovery From COVID-19 Pneumonia in a Heart Transplant Recipient: A Case Report.

Solid-organ transplant patients have a high risk of severe infection related to acute respiratory syndrome coronavirus-2 (SARS-Cov-2). This case represents a 54-year-old woman known as a diabetic, hypothyroidism, and a recent heart transplant recipient who presented with a 1-week history of cough and fatigue. She was hypoxic on presentation to the hospital and progressively declined and required invasive mechanical ventilation. She had respiratory distress and hypoxia and chest x-ray showed progressive bilateral chest infiltrates. She had leukopenia of 3.5 cells *109/L and lymphopenia of 0.2 cells *109/L. The inflammatory markers were increased: C-reactive protein, 25 mg/L; ferritin, 1106 ng/mL; lactate dehydrogenase, 632 U/L; and interleukin-6, 87 pg/mL. She was treated for severe coronavirus disease 2019 (COVID-19) pneumonia. Her treatment involved supportive care with mechanical ventilation, convalescent plasma transfusion, antiviral therapy with favipiravir, intravenous dexamethasone, and reduction of immune suppression medication. This case had a successful recovery through multidisciplinary team management. Solid-organ transplant recipients are a high-risk population who need an individualized care plan for the optimization of immunosuppressive medication and treatment of the COVID-19 infection.

Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition.

Coronaviruses have brought severe challenges to public health all over the world in the past 20years. SARS-CoV-2, the causative agent of the COVID-19 pandemic that has led to millions of deaths, belongs to the genus beta-coronavirus. Alpha- and beta-coronaviruses encode a unique protein, nonstructural protein 1 (Nsp1) that both suppresses host immune responses and reduces global gene expression levels in the host cells. As a key pathogenicity factor of coronaviruses, Nsp1 redirects the host translation machinery to increase synthesis of viral proteins. Through multiple mechanisms, coronaviruses impede host protein expression through Nsp1, while escaping inhibition to allow the translation of viral RNA. In this review, we discuss current data about suppression of the immune responses and inhibition of protein synthesis induced by coronavirus Nsp1, as well as the prospect of live-attenuated vaccine development with virulence-attenuated viruses with mutations in Nsp1.

Adequate immune response after SARS-CoV-2 infection and single dose vaccination despite rapid heart transplantation.

Adequate immune response to vaccination remains a challenge in patients after solid organ transplantation. We report a case of a 61-year-old male patient who received a left ventricular assist device as a bridge to transplant therapy. Three months before transplantation, he suffered mild SARS-CoV-2 infection and was successfully discharged thereafter. Eight days before his successful heart transplantation, he received mRNA BNT 162b2 vaccination. Immediately after transplantation, we detected sufficient rise of nucleocapsid and spike antibodies despite immune suppression therapy. We suspect potential booster effects of the previous SARS-CoV-2 infection giving rise to adequate immune response following single vaccination.