Xiaoyan Zhang

Can allogeneic invariant natural killer T (iNKT) cell-based immunotherapy achieve durable remission in an human immunodeficiency virus (HIV)-positi...

Background: Zika virus (ZIKV) has been associated with neonatal microcephaly or atypical Guillain-Barré syndrome in adults since 2016. However, despite considerable progress in understanding the biology and pathogenesis of ZIKV infection, little is known about its entry factors. This study aimed to identify host-cell proteins essential for ZIKV entry enriched by labeled viral envelope particles. The identification of solute carrier family 3 member 2 (SLC3A2) (CD98 heavy chain) through this approach highlights its potential as a novel target for therapeutic intervention against ZIKV. Methods: Gene editing via CRISPR-Cas9 and classical virological experiments were performed to identify SLC3A2 functions in ZIKV entry and infection processes. Immunofluorescence, quantitative real-time PCR (RT-qPCR), and western blotting technologies were further used to detect viral proteins and genomes. Besides, coimmunoprecipitation and protein/antibody blocking assay were also conducted to identify direct interactions between SLC3A2 and the ZIKV envelope protein. Results: Several human membrane proteins were overexpressed in HEK293 T cells, but only SLC3A2 could significantly promote ZIKV entry into host cells by two- to three- fold compared with the control. During authentic ZIKV infection, the genetic ablation of SLC3A2 in SLC3A2-KO1 JEG-3 cells reduced the viral infection rate to 59.00% ± 5.10% of the wild-type level (100.00% ± 4.97%) ( P < 0.001), but its overexpression increased the susceptibility of human placenta- and brain-derived cell lines to the virus. SLC3A2 overexpression increased attached ZIKV levels to 3.4-fold of the control (3.423 ± 0.715 vs . 1.000 ± 0.897, P < 0.001) and internalized ZIKV levels to 1.7-fold of the control (3.782 ± 0.512 vs . 2.293 ± 0.272, P = 0.013) due to direct interaction with the ZIKV envelope protein in U-251MG cells. Our data further showed the close association of SLC3A2 with the ZIKV envelope protein via its extracellular domain during authentic viral infection. Notably, SLC3A2 ectodomain decoys and blocking antibodies markedly reduced ZIKV infection rather than affecting influenza A virus infection. Conclusion: SLC3A2 promotes ZIKV infection in placenta- or brain-derived cells by directly interacting with the ZIKV envelope protein and improving virus entry. SLC3A2 may be implicated in early-phase ZIKV infection as its entry factor, thereby identifying a potential therapeutic target and a basis for formulating antiviral strategies against ZIKV.

Streptococcus pneumoniae (S. pneumoniae) is a leading cause of pneumonia, meningitis, and sepsis worldwide, posing a major threat to young children and older adults. In China, it is a key pathogen responsible for life-threatening invasive pneumococcal disease (IPD)—including pneumonia, bacteremia, and meningitis—and contributes substantially to hospitalizations and deaths each year. The high disease burden, together with rising antibiotic resistance, underscores the urgent need for more effective strategies for prevention and control. Currently, the most established pneumococcal vaccines include polysaccharide vaccines (e.g., PPV23) and polysaccharide conjugate vaccines (e.g., PCV13), both of which provide effective protection against pneumococcal infections. However, challenges remain, such as the T-cell-independent nature of polysaccharide antigens and inadequate coverage against prevalent strains, which hinder to improve their overall effectiveness. In this review, we trace the progression from pneumococcal pathogenesis to vaccine development. We first outline the mechanisms of colonization, invasion, and key virulence factors, and then critically summarize historical and current vaccine strategies. A systematic literature search was conducted in PubMed and Web of Science (2010–present) using relevant keyword and MeSH combinations. A total of 10,273 articles were identified from PubMed; after removal of duplicates and non-full-text records, 260 research articles were included in the final analysis. Based on this body of evidence, we evaluate emerging approaches toward broadly protective, serotype-independent vaccines and discuss how advances in antigen design, delivery systems, and adjuvants may further optimize next-generation pneumococcal vaccines.

The African Swine Fever Virus (ASFV) poses a major threat to global livestock production by infecting both domestic and wild pigs, causing significant economic loss. Despite promising protective results observed with live attenuated viruses, the safety concern blocked its extensive application. In this study, we developed a novel vaccine combining two recombinant vaccinia viruses-rTTV-D-A and rTTV-K-J-that together express eight ASFV genes, including EP402R (CD2v), B646L (p72), B602L (pB602L), D117L (p17), H240R (pH240R), B438L (p49), E183L (p54), CP204L (p30), and a synthetic T antigen composed of conserved T cell epitopes from multiple ASFV proteins, aiming to induce both humoral and T-cell immune responses against different viral antigens. After demonstrating that this vaccine induced antigen-specific humoral and cellular responses in both mice and swine, its protective efficacy in swine was examined using a lethal challenge model. The vaccinated pigs showed a promising protection against the lethal challenge of a virulent genotype II ASFV strain (100 HAD₅₀/pig), with 4 out of 6 surviving, while all control animals succumbed from 9 to 15 days post challenge. Importantly, the protection was further evidenced by the recovery to normal temperature and no ASFV infection-related clinical signs or virus shedding in surviving pigs over a 21-day observation period. Our results support the potential of rTTV-D-A and rTTV-K-J as a novel multi-immunogen vaccinia-vectored ASFV vaccine. Further studies are warranted to explore and improve its use as a standalone vaccine or in combination with other vaccine platforms to achieve broad and effective protection against ASFV.

Purpose: The aim of this study was to determine the expression of Glypican-3(GPC-3) and AXL in hepatocellular carcinomas (HCCs). Methods: A total of 140 patients diagnosed with HCC were included in this study. All patients had undergone radical surgery and had complete clinical information. Formalin-fixed paraffin-embedded tissue blocks of HCC from these patients were collected, and the expression levels of GPC-3 and AXL were detected by immunohistochemical (IHC) staining. Results: Immunohistochemical analysis showed that GPC-3 and AXL were diffusely expressed in HCCs. The positive expression rate of GPC-3 was 77.1% (108/140) and that of AXL was 85.7% (120/140). Additionally, the proportion of cases with positive expression for either GPC-3 or AXL is 93.6%. Conclusions: The findings of this study confirm that both GPC-3 and AXL are highly expressed in HCCs tissues, and the high co-expression rate supports the development of dual-target chimeric antigen receptor T (CAR-T) cell therapy for HCC treatment.

Chimeric antigen receptor-T (CAR-T) cell therapy has revolutionized cancer immunotherapy, enlightening new hope for patients with hematological malignancies and emerging potential in solid tumors and other refractory diseases. This review delves into the fundamentals, challenges, technological innovations, clinical breakthroughs, and future prospects of CAR-T cell therapy. It explores the mechanisms of action, evolution, key challenges such as toxicity and solid tumor resistance, recent technological advancements in CAR engineering, clinical breakthroughs in solid tumors and other refractory diseases, and future directions including next-generation constructs, gene editing, manufacturing scalability, and expansion beyond cancers. By synthesizing the latest research, this review aims to provide a comprehensive understanding of CAR-T cell therapy and its potential to transform cancer treatment and other therapeutic areas.

Influenza A virus (IAV) relies on the host cellular machinery to support its replication. Understanding these host dependencies can inform the development of novel antiviral strategies. In this study, we identified conserved oligomeric Golgi complex subunit 6 (COG6) as a novel host factor critical for IAV replication through a genome-wide clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) knockout screen. Disruption of COG6 significantly impaired viral replication. Mechanistically, COG6 supports IAV replication via two distinct means. First, consistent with the role of the COG complex in Golgi homeostasis, COG6 is required for the proper presentation of surface sialic acids, the primary receptor for IAV entry. Second, COG6 deficiency unexpectedly led to lysosome-dependent degradation of viral proteins. Notably, lysosomal activity was also upregulated in IAV-infected wild-type cells, albeit to a lesser extent than in COG6-deficient cells. Treatment with lysosomal inhibitors rescued viral protein stability in COG6 knockout cells. Protein interaction analysis further demonstrated that COG6-mediated stabilization of viral proteins did not rely on viral protein-COG6 interaction, refuting the hypothesis that COG6 acts as a shield factor to protect viral protein from lysosomal degradation. Moreover, knockout of other COG subunits produced similar antiviral effects, suggesting that an intact COG complex is required for IAV replication. Together, these findings uncover a critical role of the COG complex in regulating IAV replication and highlight a previously unappreciated functional link between the Golgi and lysosomes that could be exploited for treating IAV infections. IMPORTANCE: Despite advances in virology, numerous host determinants facilitating influenza A virus (IAV) pathogenesis remain uncharacterized. Our study establishes conserved oligomeric Golgi complex subunit 6 (COG6) as a critical host factor promoting IAV infection through complementary mechanisms: receptor modulation and viral protein stabilization. This represents the first demonstration that the COG complex regulates viral pathogenesis through proteostasis mechanisms, fundamentally expanding our understanding of host-virus interactions at the organelle interface. These findings not only provide new perspectives on viral exploitation of Golgi trafficking networks but also identify potential therapeutic targets against evolving influenza strains.

Background: Rabies remains a devastating and fatal infectious disease worldwide. To date, vaccination is the most reliable and effective strategy for controlling rabies. However, despite the effectiveness of inactivated vaccines, cumbersome vaccination procedures and the high costs of post-exposure prophylaxis impose a significant economic burden, particularly in developing countries with limited access to vaccines. Therefore, there is an urgent need to develop a novel rabies vaccine that reduces costs while enhancing safety and efficacy. Methods: We developed a novel mRNA rabies vaccine called RABV-G-LT, which incorporates two immunogens: RABV-G, a glycoprotein designed mainly to elicit neutralizing antibody responses, and RABV-LT, a T-cell immunogen derived from the large protein of the rabies virus. Additionally, we evaluated the immunogenicity of RABV-G-LT in both mice and non-human primates. Results: The RABV-LT mRNA vaccination alone induced potent RABV-LT-specific T-cell responses and provided modest protection against rabies virus challenge in mice. Importantly, the dual-immunogen mRNA vaccine RABV-G-LT elicited vigorous and persistent neutralization antibody and T-cell responses, resulting in significantly more efficient clearance of the rabies virus in the brain and spinal cord. This conferred enhanced protection, evidenced by lesser initial weight loss and earlier recovery of body weight compared with the RABV-G mRNA or inactivated vaccine groups. Moreover, RABV-G-LT also mounted persistent strong antigen-specific T-cell and antibody immune responses in nonhuman primates. Conclusions: Our study suggested that combining the T-cell immunogen and virus-neutralizing antibody immunogen was a practical approach to strengthening the defense against the rabies virus.