Name: Dr Peng Gao

Title: Antivirulence Agent as an Adjuvant of Antibiotics in Treating Staphylococcal Infections

Abstract: Antibiotics are widely applied to treat infectious diseases. Empirically treatment with incorrect antibiotics, or even correct antibiotics always falls into subinhibitory concentrations, due to dosing, distribution, or secretion. In this study, we have systematically evaluated in vitro virulence induction effect of antibiotics and in vivo exacerbated infection. The major highlight of this work is to prove the β-lactam and tetracyclines antibiotics exacerbated disease is due to their induction effect on staphylococcal virulence. The combination of antivirulence agents and antibiotics can be a novel approach to controlling antibiotic-induced S. aureus pathogenicity. This phenomenon is common and suggests that if β-lactam antibiotics remain the first line of defense during empirical therapy, we either need to increase patient reliability or the treatment approach may improve in the future when paired with anti-virulence drugs. Our findings from this study demonstrated the benefits of antivirulence-antibiotic combinatorial treatment against S. aureus infections and provide a new perspective on the development of antibiotic adjuvants.

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Name: Dr Cun Li

Title: Human Nasal Organoids Model SARS-CoV-2 Upper Respiratory Infection and Recapitulate the Differential Infectivity of Emerging Variants

Abstract: The human upper respiratory tract, specifically the nasopharyngeal epithelium, is the entry portal and primary infection site of respiratory viruses. Productive infection of SARS-CoV-2 in the nasal epithelium constitutes the cellular basis of viral pathogenesis and transmissibility. Yet a robust and well-characterized in vitro model of the nasal epithelium remained elusive. Here we report an organoid culture system of the nasal epithelium. We derived nasal organoids from easily accessible nasal epithelial cells with a perfect establishment rate. The derived nasal organoids were consecutively passaged for over 6 months. We then established differentiation protocols to generate 3-dimensional differentiated nasal organoids and organoid monolayers of 2-dimensional format that faithfully simulate the nasal epithelium. Notably, the differentiated nasal organoid monolayers accurately recapitulated higher infectivity and replicative fitness of the Omicron variant than the prior variants. SARS-CoV-2, especially the more transmissible Delta and Omicron variants, destroyed ciliated cells and disassembled tight junctions, thereby facilitating virus spread and transmission. In conclusion, we establish a robust organoid culture system of the human nasal epithelium for modeling upper respiratory infections and provide a physiologically-relevant model for assessing the infectivity of SARS-CoV-2 emerging variants.

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Name: Dr Li Liu

Title: Δ42PD-1 suppresses BCR-mediated B cell activation in HIV-1 infection

Abstract: HIV-1 antibody responses are drained into exhausted B cells, yet the suppressor of B cell activation after B cell receptor (BCR) stimulation remains incompletely understood. Here, we report that Δ42PD-1, an isoformic PD-1, is predominantly up-regulated on activated memory, anergic naïve and tissue like memory B cells compared with PD-1 and FcRL4 in chronic HIV-1 patients (CHPs). BCR-stimulation up-regulates Δ42PD-1, resulting in B cell exhaustion, cell cycle arrest and death. Mechanistically, Δ42PD-1 recruits Src homology region 2 domain containing phosphatase 1 (SHP1) via its intracellular immunoreceptor tyrosine-based switch motif (ITSM). SHP1 then binds and inhibits AKT1 activation and thereby suppresses the AKT1/FOXO1 pathway. Δ42PD-1-specific antibody, however, reduces the SHP1 recruitment, increasing the AKT1/FOXO1 activation and proliferation of B cells derived from CHPs. Our findings demonstrate that Δ42PD-1 is a previously unrecognized suppressor of BCR-mediated B cell activation, which may serve as a potential immunotherapeutic target for restoring B cell functionality.

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Name: Dr Zhiwu Tan

Title: Isoformic PD-1-mediated Immunosuppression Underlies Resistance to PD-1 Blockade in Hepatocellular Carcinoma Patients

Abstract: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we investigated 3 cohorts of 74 HCC patients, including 41 untreated, 28 treated with Nivolumab and 5 treated with Pembrolizumab. We found distinct T cell subsets, which did not express PD-1 but expressed the isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes. Δ42PD-1+ T cells were tumor-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time. Tumor-infiltrated Δ42PD-1+ T cells likely sustained HCC through TLR4-signaling for tumorigenesis. Anti-Δ42PD-1 antibody, but not Nivolumab, inhibited tumor growth in three HCC humanized mouse models. Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.

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Name: Dr Bingpeng Yan and Dr Kong Hung Sze

Title: Phosphatidic acid phosphatase 1 (PAP-1) impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway.

Abstract: Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients’ plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects’ plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. PAP-1 is encoded by a group of genes named LPINs and has three lipin proteins (lipin 1, 2 and 3), with each of them having PAP-1 activity. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load in multiple cell lines. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.

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Name: Dr Pui Wang

Title: An intranasal influenza virus-vectored vaccine protects against SARS-CoV-2 variants in mice and Syrian hamsters

Abstract: Vaccination is the most effective means of alleviating COVID-19 disease burden. However, emerging variants have led to continuing immune evasion since early 2021. Moreover, current mRNA vaccines do not elicit sufficient local mucosal immunity in the respiratory tract, which is important for preventing or reducing the transmission of SARS-CoV-2. There have been suggestions that the next generation of vaccines for SARS-CoV-2 should aim to offer higher protection by blocking infections altogether.

This study reports an influenza virus-vectored SARS-CoV-2 intranasal vaccine based on a live attenuated influenza virus with the NS1 gene deleted that expresses the receptor binding domain (RBD) of SARS-CoV-2 spike protein, designated as DelNS1-RBD4N-DAF.

Immune responses and protection against virus challenge after two doses of the BNT162b2 mRNA vaccine (intramuscular injection) or various DelNS1-RBD4N-DAF vaccines (intranasal) were analysed in mouse and hamster models. Our vaccines induced high levels of neutralizing antibodies against various variants, including Omicron BA.2 and stimulated robust T cell responses in mice. Intranasal inoculation with our vaccines elicited effective protection against challenge with SARS-CoV-2 variants in the upper and lower respiratory tracts of both animals.

In conclusion, our vaccine induced strong immune responses with cross protection against different SARS-CoV-2 variants. Our vaccine platform can be used to make bivalent vaccines against both influenza and COVID-19 in response to dual circulation of seasonal influenza and SARS-CoV-2 in the future.

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Name: Dr Anna Jinxia Zhang

Title: COVID-19 mRNA vaccine restore impaired innate antiviral responses protects against SARS-CoV-2 Omicron infection in diet-induced obesity mice

Abstract: The pathogenicity of SARS-CoV-2 and host immune responses to infection and vaccination in individuals with obesity remain incompletely understood. We studied SARS-CoV-2 Alpha- and Omicron BA.1-induced disease and immune responses after infection or COVID-19 mRNA vaccination in diet-induced obese mice. Unlike in lean mice, Omicron BA.1 and Alpha replicated to comparable levels in the lungs of DIO mice and resulted in similar degree of tissue damages. Importantly, both T cell and B cell mediated adaptive immune responses to SARS-CoV-2 infection or COVID-19 mRNA vaccination are impaired in DIO mice, leading to higher propensity of re-infection and lower vaccine efficacy. However, in the absent of neutralizing antibody, vaccinated DIO mice are protected from lung damage upon Omicron challenge, accompanied with significant more IFN-α and IFN-β production in the lung tissue. Lung RNAseq and ex vivo culture of alveolar macrophages indicated COVID-19 mRNA vaccination in DIO mice boosted antiviral interferon response compared to nonvaccinated controls, with significant enhancement of IFN-α production from alveolar macrophages in responses to Poly(I:C) or recombinant SARS-CoV-2 spike protein stimulation. Our findings suggested that COVID-19 mRNA vaccination enhances host innate antiviral responses in obesity which is still beneficial to certain degree when adaptive immunity is suboptimal.

Name: Dr Hanjun Zhao

Title: A triple-functional peptide broadly inhibits SARS-CoV-2 variants in hamsters

Abstract: The emergence of highly transmissible SARS-CoV-2 variants has led to the waves of resurgence of COVID-19 cases. Effective antivirals against variants are required. Here we demonstrate that a human-derived peptide 4H30 has broad antiviral activity against the ancestral virus and four Variants of Concern (VOCs) in vitro. Mechanistically, 4H30 can inhibit three distinct steps of the SARS-CoV-2 life cycle. Specifically, 4H30 blocks viral entry by clustering SARS-CoV-2 virions; prevents membrane fusion by inhibiting endosomal acidification; and inhibits release of virions by cross-linking SARS-CoV-2 with cellular glycosaminoglycans. In vivo studies show that 4H30 significantly reduces the lung viral titers in hamsters, with a more potent reduction for Omicron variant than Delta variant. This is likely because the entry of Omicron variant mainly relies on the endocytic pathway which is targeted by 4H30. Moreover, 4H30 reduces syncytia formation in infected hamster lungs. These findings provide a proof of concept that a single antiviral can inhibit viral entry, fusion and release.