Browsing by Subject "Plasma cells"

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    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, Martin
    Malaria 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.
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    Primary Human B Cells at Different Differentiation and Maturation Stages Exhibit Distinct Susceptibilities to Vaccinia Virus Binding and Infection
    (American Society for Microbiology, 2019-09-12) Shepherd, Nicole; Lan, Jie; Rane, Sushmita; Yu, Qigui; Microbiology and Immunology, School of Medicine
    Vaccinia virus (VACV), the prototypical member of the poxvirus family, was used as a live-virus vaccine to eradicate smallpox worldwide and has recently received considerable attention because of its potential as a prominent vector for the development of vaccines against infectious diseases and as an oncolytic virus for cancer therapy. Studies have demonstrated that VACV exhibits an extremely strong bias for binding to and infection of primary human antigen-presenting cells (APCs), including monocytes, macrophages, and dendritic cells. However, very few studies have assessed the interactions of VACV with primary human B cells, a main type of professional APCs. In this study, we evaluated the susceptibility of primary human peripheral B cells at various differentiation and maturation stages to VACV binding, infection, and replication. We found that plasmablasts were resistant to VACV binding, while other B subsets, including transitional, mature naive, memory, and plasma cells, were highly susceptible to VACV binding. VACV binding preference was likely associated with differential expression of chemokine receptors, particularly CXCR5. Infection studies showed that plasmablast, plasma, transitional, and mature naive B cells were resistant to VACV infection, while memory B cells were preferentially infected. VACV infection in ex vivo B cells was abortive, which occurred at the stage of late viral gene expression. In contrast, activated B cells were permissive to productive VACV infection. Thus, primary human B cells at different differentiation stages exhibit distinct susceptibilities to VACV binding and infection, and the infections are abortive and productive in ex vivo and activated B cells, respectively. IMPORTANCE Our results provide critical information to the field of poxvirus binding and infection tropism. We demonstrate that VACV preferentially infects memory B cells that play an important role in a rapid and vigorous antibody-mediated immune response upon reinfection by a pathogen. Additionally, this work highlights the potential of B cells as natural cellular models to identify VACV receptors or dissect the molecular mechanisms underlying key steps of the VACV life cycle, such as binding, penetration, entry, and replication in primary human cells. The understanding of VACV biology in human primary cells is essential for the development of a safe and effective live-virus vector for oncolytic virus therapy and vaccines against smallpox, other pathogens, and cancer.