Browsing by Author "Luo, Wei"
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Item A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2(Springer Nature, 2023) Yin, Qian; Luo, Wei; Mallajosyula, Vamsee; Bo, Yang; Guo, Jing; Xie, Jinghang; Sun, Meng; Verma, Rohit; Li, Chunfeng; Constantz, Christian M.; Wagar, Lisa E.; Li, Jing; Sola, Elsa; Gupta, Neha; Wang, Chunlin; Kask, Oliver; Chen, Xin; Yuan, Xue; Wu, Nicholas C.; Rao, Jianghong; Chien, Yueh-hsiu; Cheng, Jianjun; Pulendran, Bali; Davis, Mark M.; Microbiology and Immunology, School of MedicineThe ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.Item Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice(Springer Nature, 2022-05-23) Grigoryan, Lilit; Lee, Audrey; Walls, Alexandra C.; Lai, Lilin; Franco, Benjamin; Arunachalam, Prabhu S.; Feng, Yupeng; Luo, Wei; Vanderheiden, Abigail; Floyd, Katharine; Wrenn, Samuel; Pettie, Deleah; Miranda, Marcos C.; Kepl, Elizabeth; Ravichandran, Rashmi; Sydeman, Claire; Brunette, Natalie; Murphy, Michael; Fiala, Brooke; Carter, Lauren; Coffman, Robert L.; Novack, David; Kleanthous, Harry; O'Hagan, Derek T.; van der Most, Robbert; McLellan, Jason S.; Suthar, Mehul; Veesler, David; King, Neil P.; Pulendran, Bali; Microbiology and Immunology, School of MedicineAdjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice-alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)-for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.Item Cell-surface Milieu Remodeling in Human Dendritic Cell Activation(The American Association of Immunologists, 2024) Udeshi, Namrata D.; Xu, Charles; Jiang, Zuzhi; Gao, Shihong Max; Yin, Qian; Luo, Wei; Carr, Steven A.; Davis, Mark M.; Li, Jiefu; Microbiology and Immunology, School of MedicineDendritic cells (DCs) are specialized sentinel and APCs coordinating innate and adaptive immunity. Through proteins on their cell surface, DCs sense changes in the environment, internalize pathogens, present processed Ags, and communicate with other immune cells. By combining chemical labeling and quantitative mass spectrometry, we systematically profiled and compared the cell-surface proteomes of human primary conventional DCs (cDCs) in their resting and activated states. TLR activation by a lipopeptide globally reshaped the cell-surface proteome of cDCs, with >100 proteins upregulated or downregulated. By simultaneously elevating positive regulators and reducing inhibitory signals across multiple protein families, the remodeling creates a cell-surface milieu promoting immune responses. Still, cDCs maintain the stimulatory-to-inhibitory balance by leveraging a distinct set of inhibitory molecules. This analysis thus uncovers the molecular complexity and plasticity of the cDC cell surface and provides a roadmap for understanding cDC activation and signaling.Item Characterizing the Formation and Functionality of Immune Memory Cells in Response to Plasmodium Infection(2025-05) Fusco, Elizabeth Michelle; Schmidt, Nathan W.; Absalon, Sabrina; Bauer, Margaret; Longtin, Krista; Luo, Wei; Richer, MartinMalaria is an infectious disease caused by Plasmodium parasites. Over 40% of the world lives in malaria endemic regions, and children under the age of 5 in Sub-Saharan Africa face the highest burden of this disease. The clinical symptoms of malaria are caused by the cyclical infection and rupture of red blood cells by Plasmodium, and these parasites are cleared from the blood by the immune system. Plasmodium infection does not induce sterilizing immunity; however, individuals can generate clinical immunity to malaria after repeated exposures, but the factors that regulate this process are poorly understood. An emerging modulator of the immune response is the gut microbiome. We previously identified that the composition of the gut microbiome correlates with the outcome of Plasmodium infections in African children and impacts ability of the immune system to fight a Plasmodium infection in mice. We next investigated how the gut microbiome impacts the immune memory response in mice. We determined that the gut microbiome influences the formation of memory B cells and memory T cells during primary Plasmodium yoelii infection. Furthermore, the gut microbiome governs the ability of these immune memory cells to mount a secondary germinal center (GC) response to a Plasmodium berghei ANKA challenge. Curiously, the gut microbiome did not affect the accumulation of plasma cells (PCs) in the bone marrow following P. yoelii infection, and we observed that antigen-specific PC accumulation was poor. It is hypothesized that PCs are important for protection against reinfection with Plasmodium due to their ability to secrete high-affinity antibodies. We next characterized how P. yoelii infection impacted the generation and maintenance of PCs. We discovered that P. yoelii infection impairs the ability of the GC to produce long-lived PCs (LLPCs). Additionally, P. yoelii alters the composition of the bone marrow, negatively impacting the ability of PCs to engraft in the bone marrow as LLPCs. These defects in the generation and maintenance of P. yoelii-induced LLPCs likely impairs the ability of the immune system to protect against future Plasmodium infections.Item Combined Inhibition of SREBP and m-TORC1 Signaling Synergistically Inhibits the Proliferation of B Cell Lymphoma(2024-06) Zhu, Zhenhan; Luo, Wei; Capitano, Meagan L; Yuan, XueSterol regulatory element-binding protein (SREBP) signaling plays a crucial role in maintaining sterol homeostasis during B cell activation and the proliferation of germinal center B cells. It is unclear whether this pathway can be targeted to effectively treat B cell lymphoma. We discovered that inhibiting SREBP signaling or its downstream target HMG-CoA reductase (HMGCR) using Fatostatin or Simvastatin effectively restrains the proliferation of B cell lymphoma cells. However, B cell lymphoma cells activate the mTORC1-pS6 pathway in response to statin treatment, suggesting a possible mechanism to counteract statin-induced cell cycle arrest. Combining low dose statin treatment with the mTORC1 inhibitor rapamycin demonstrates a synergistic effect in inhibiting B cell lymphoma proliferation, cell cycle progression and lipid raft generation. These findings emphasize the potential of a combined therapy approach targeting both SREBP and mTORC1 as a novel treatment strategy for B cell lymphoma.Item Designing spatial and temporal control of vaccine responses(Springer Nature, 2022) Roth, Gillie A.; Picece, Vittoria C. T. M.; Ou, Ben S.; Luo, Wei; Pulendran, Bali; Appel, Eric A.; Microbiology and Immunology, School of MedicineVaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Material platforms, such as nanoparticles, hydrogels and microneedles, can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Materials-based vaccination strategies can augment the immune response by improving innate immune cell activation, creating local inflammatory niches, targeting lymph node delivery and controlling the time frame of vaccine delivery, with the goal of inducing enhanced memory immunity to protect against future infections. In this Review, we highlight the biological mechanisms underlying strong humoral and cell-mediated immune responses and explore materials design strategies to manipulate and control these mechanisms.Item Evaluation of a modified ultrasound-assisted technique for mid-thoracic epidural placement: a prospective observational study(Springer Nature, 2024-01-19) Huang, Chanyan; Chen, Ying; Kou, Mengjia; Wang, Xuan; Luo, Wei; Zhang, Yuanjia; Guo, Yuting; Huang, Xiongqing; Meng, Lingzhong; Xiao, Ying; Anesthesia, School of MedicineBackground: Although mid-thoracic epidural analgesia benefits patients undergoing major surgery, technical difficulties often discourage its use. Improvements in technology are warranted to improve the success rate on first pass and patient comfort. The previously reported ultrasound-assisted technique using a generic needle insertion site failed to demonstrate superiority over conventional landmark techniques. A stratified needle insertion site based on sonoanatomic features may improve the technique. Methods: Patients who presented for elective abdominal or thoracic surgery requesting thoracic epidural analgesia for postoperative pain control were included in this observational study. A modified ultrasound-assisted technique using a stratified needle insertion site based on ultrasound images was adopted. The number of needle passes, needle skin punctures, procedure time, overall success rate, and incidence of procedure complications were recorded. Results: One hundred and twenty-eight subjects were included. The first-pass success and overall success rates were 75% (96/128) and 98% (126/128), respectively. In 95% (122/128) of patients, only one needle skin puncture was needed to access the epidural space. The median [IQR] time needed from needle insertion to access the epidural space was 59 [47-122] seconds. No complications were observed during the procedure. Conclusions: This modified ultrasound-assisted mid-thoracic epidural technique has the potential to improve success rates and reduce the needling time. The data shown in our study may be a feasible basis for a prospective study comparing our ultrasound-assisted epidural placements to conventional landmark-based techniques.Item IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells(American Association for the Advancement of Science, 2023) Luo, Wei; Conter, Laura; Elsner, Rebecca A.; Smita, Shuchi; Weisel, Florian; Callahan, Derrick; Wu, Shuxian; Chikina, Maria; Shlomchik, Mark; Microbiology and Immunology, School of MedicineBoth B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (TFH)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation-engaging unique molecular mechanisms-as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4hi/CD138+ cells, indicative of plasma cell differentiation, along with CCR6+/CD38+ memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific TFH- and Ag-derived signals to GCBC differentiation.Item Ipsilateral immunization after a prior SARS-CoV-2 mRNA vaccination elicits superior B cell responses compared to contralateral immunization(Elsevier, 2024) Jiang, Wenxia; Maldeney, Alexander R.; Yuan, Xue; Richer, Martin J.; Renshaw, Scott E.; Luo, Wei; Microbiology and Immunology, School of MedicinemRNA vaccines have proven to be pivotal in the fight against COVID-19. A recommended booster, given 3 to 4 weeks post the initial vaccination, can substantially amplify protective antibody levels. Here, we show that, compared to contralateral boost, ipsilateral boost of the SARS-CoV-2 mRNA vaccine induces more germinal center B cells (GCBCs) specific to the receptor binding domain (RBD) and generates more bone marrow plasma cells. Ipsilateral boost can more rapidly generate high-affinity RBD-specific antibodies with improved cross-reactivity to the Omicron variant. Mechanistically, the ipsilateral boost promotes the positive selection and plasma cell differentiation of pre-existing GCBCs from the prior vaccination, associated with the expansion of T follicular helper cells. Furthermore, we show that ipsilateral immunization with an unrelated antigen after a prior mRNA vaccination enhances the germinal center and antibody responses to the new antigen compared to contralateral immunization. These findings propose feasible approaches to optimize vaccine effectiveness.Item Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine(Springer Nature, 2022) Li, Chunfeng; Lee, Audrey; Grigoryan, Lilit; Arunachalam, Prabhu S.; Scott, Madeleine K.D.; Trisal, Meera; Wimmers, Florian; Sanyal, Mrinmoy; Weidenbacher, Payton A.; Feng, Yupeng; Adamska, Julia Z.; Valore, Erika; Wang, Yanli; Verma, Rohit; Reis, Noah; Dunham, Diane; O’Hara, Ruth; Park, Helen; Luo, Wei; Gitlin, Alexander D.; Kim, Peter; Khatri, Purvesh; Nadeau, Kari C.; Pulendran, Bali; Microbiology and Immunology, School of MedicineDespite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.