Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases.

Bats are special in their ability to live long and host many emerging viruses. Our previous studies showed that bats have altered inflammasomes, which are central players in aging and infection. However, the role of inflammasome signaling in combating inflammatory diseases remains poorly understood. Here, we report bat ASC2 as a potent negative regulator of inflammasomes. Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes. Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles. Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection. Importantly, it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation. Four key residues were identified for the gain of function of bat ASC2. Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.

Efficacy and safety profile of two-dose SARS-CoV-2 vaccines in cancer patients: An observational study in China.

BACKGROUND: The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced a global pandemic of coronavirus disease 2019 (COVID-19), resulting in modifications to public health policies on a universal scale. SARS-CoV-2 vaccine has evolved as the most effective and secure way for protecting healthy individuals against COVID-19. Patients with cancer were excluded from clinical trials due to their increased COVID-19 risk and current immunosuppressing therapy. Safety and effectiveness evidence is insufficient for SARS-CoV-2 vaccination in cancer patients. AIM: To assess the efficacy and safety of two-dose SARS-CoV-2 vaccines in cancer patients. METHODS: A multicenter observational study was performed at ten Chinese hospitals between January 1, 2021 and December 31, 2021. Each participant in the research received two doses of vaccination. A total of 215 healthy people were screened and 132 eligible patients with cancer were recruited. In order to verify the safety of the second dose of the vaccine, a side-effect report was compiled. Two weeks following the second vaccination dose, subjects underwent an analogous questionnaire survey. Utilizing a magnetic particle-based chemiluminescence immunoassay, serum levels of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies were measured to determine the effectiveness of vaccination. IgG levels ≥ 10 AU/mL were considered seropositive. RESULTS: All the 347 eligible patients completed the follow-up, and anti-SARS-CoV-2 IgG antibodies were detected. Local pain at the injection location was the most common side effect mentioned by all responders, with an increased incidence in cancer patients than the healthy people after the second dose vaccine (17.2% vs 9.1%; P = 0.035). There was no significant difference in headache, urticaria, or other adverse reactions between patients with cancer and healthy people. In the group of cancer patients, the seropositivity incidence was 83.3%, while it was 96.3% in the group of healthy people. In the group of cancer patients, the seropositivity incidence and antibody levels were significantly lower (P < 0.001). This analysis showed a poorer response rate in patients on active immunosuppressive treatment and elderly cancer patients. CONCLUSION: Two-dose Chinese vaccines are effective and safe in cancer patients. However, further research is required on the efficacy in elderly cancer patients and those on active immunosuppressive treatment.

Novel coronavirus mutations: Vaccine development and challenges.

The ongoing global pandemic of novel coronavirus pneumonia (COVID-19) caused by the SARS-CoV-2 has a significant impact on global health and economy system. In this context, there have been some landmark advances in vaccine development. Over 100 new coronavirus vaccine candidates have been approved for clinical trials, with ten WHO-approved vaccines including four inactivated virus vaccines, two mRNA vaccines, three recombinant viral vectored vaccines and one protein subunit vaccine on the "Emergency Use Listing". Although the SARS-CoV-2 has an internal proofreading mechanism, there have been a number of mutations emerged in the pandemic affecting its transmissibility, pathogenicity and immunogenicity. Of these, mutations in the spike (S) protein and the resultant mutant variants have posed new challenges for vaccine development and application. In this review article, we present an overview of vaccine development, the prevalence of new coronavirus variants and their impact on protective efficacy of existing vaccines and possible immunization strategies coping with the viral mutation and diversity.

Clinical and Virological Features of the First Occurrence of COVID-19 Delta Variant in Anhui Province, China (preprint)

Objectives Since the outbreak of coronavirus disease 2019 (COVID-19), it has caused serious casualties worldwide. In recent months, the virus has mutated into an increasingly infectious form (Delta variant) and spread rapidly.Methods In the current study, we analyzed the clinical, epidemiological and viral genetic characteristics of the first four imported Delta cases in Anhui Province, China.Results The four imported Delta cases developed chest inflammation, tissue damage and recovered after admission, the serum high-sensitivity C-reactive protein (hs-CRP) and CRP levels showed a first increasing and then decreasing trend. The changes of hs-CRP /CRP and serum neutralizing antibodies (Nab) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) levels were associated with the regression of chest lesions. The combination of genetic sequencing and epidemiological analysis suggested that the SARS-CoV-2 delta variant infection of these four patients may originate from Russia.Conclusions Our study found the certain correlations of serum hs-CRP/CRP and Nab levels with the occurrence, development and outcome of COVID-19 delta variant, suggesting that monitoring hs-CRP/CRP and Nab levels of COVID-19 delta variant patients at hospital admission may be useful for understanding the severity of patients’ current conditions.

Changes in Serum Neutralizing Antibodies Levels During Convalescence of COVID-19 Patients.

Detection of serum-specific SARS-CoV-2 antibody has become a complementary means for the identification of coronavirus disease 2019 (COVID-19). As we already know, the neutralizing antibody titers in patients with COVID-19 decrease during the course of time after convalescence, whereas the duration of antibody responses in the convalescent patients has not been defined clearly. In the current study, we collected 148 serum samples from 37 confirmed COVID-19 cases with different disease severities. The neutralizing antibodies (Nabs), IgM and IgG against COVID-19 were determined by CLIA Microparticle and microneutralization assay, respectively. The time duration of serum titers of SARS-CoV-2 antibodies were recorded. Our results indicate that IgG (94.44%) and Nabs (89.19%) can be detected at low levels within 190-266 days of disease onset. The findings can advance knowledge regarding the antibody detection results for COVID-19 patients and provide a method for evaluating the immune response after vaccination.

Exploring the Role of Innate Lymphocytes in the Immune System of Bats and Virus-Host Interactions.

Bats are reservoirs of a large number of viruses of global public health significance, including the ancestral virus for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the causative agent of coronavirus disease 2019 (COVID-19). Although bats are natural carriers of multiple pathogenic viruses, they rarely display signs of disease. Recent insights suggest that bats have a more balanced host defense and tolerance system to viral infections that may be linked to the evolutionary adaptation to powered flight. Therefore, a deeper understanding of bat immune system may provide intervention strategies to prevent zoonotic disease transmission and to identify new therapeutic targets. Similar to other eutherian mammals, bats have both innate and adaptive immune systems that have evolved to detect and respond to invading pathogens. Bridging these two systems are innate lymphocytes, which are highly abundant within circulation and barrier tissues. These cells share the characteristics of both innate and adaptive immune cells and are poised to mount rapid effector responses. They are ideally suited as the first line of defense against early stages of viral infections. Here, we will focus on the current knowledge of innate lymphocytes in bats, their function, and their potential role in host-pathogen interactions. Moreover, given that studies into bat immune systems are often hindered by a lack of bat-specific research tools, we will discuss strategies that may aid future research in bat immunity, including the potential use of organoid models to delineate the interplay between innate lymphocytes, bat viruses, and host tolerance.

Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors.

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.).

Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles.

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.

A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction.

A robust serological test to detect neutralizing antibodies to SARS-CoV-2 is urgently needed to determine not only the infection rate, herd immunity and predicted humoral protection, but also vaccine efficacy during clinical trials and after large-scale vaccination. The current gold standard is the conventional virus neutralization test requiring live pathogen and a biosafety level 3 laboratory. Here, we report a SARS-CoV-2 surrogate virus neutralization test that detects total immunodominant neutralizing antibodies targeting the viral spike (S) protein receptor-binding domain in an isotype- and species-independent manner. Our simple and rapid test is based on antibody-mediated blockage of the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor protein and the receptor-binding domain. The test, which has been validated with two cohorts of patients with COVID-19 in two different countries, achieves 99.93% specificity and 95-100% sensitivity, and differentiates antibody responses to several human coronaviruses. The surrogate virus neutralization test does not require biosafety level 3 containment, making it broadly accessible to the wider community for both research and clinical applications.

MR1-Restricted T Cells with MAIT-like Characteristics Are Functionally Conserved in the Pteropid Bat Pteropus alecto.

Bats are reservoirs for a large number of viruses which have potential to cause major human disease outbreaks, including the current coronavirus disease 2019 (COVID-19) pandemic. Major efforts are underway to understand bat immune response to viruses, whereas much less is known about their immune responses to bacteria. In this study, MR1-restricted T (MR1T) cells were detected through the use of MR1 tetramers in circulation and tissues of Pteropus alecto (Pa) bats. Pa MR1T cells exhibited weak responses to MR1-presented microbial metabolites at resting state. However, following priming with MR1-presented agonist they proliferated, upregulated critical transcription factors and cytolytic proteins, and gained transient expression of Th1/17-related cytokines and antibacterial cytotoxicity. Collectively, these findings show that the Pa bat immune system encompasses an abundant and functionally conserved population of MR1T cells with mucosal-associated invariant T-like characteristics, suggesting that MR1 and MR1T cells also play a significant role in bat immune defense.