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Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 23570

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Dr. Jonathan Lovell

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Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
Interests: nanotechnology; vaccines; malaria; cancer

Special Issue Information

Dear Colleagues,

A Special Issue in honor of Moriya Tsuji is being prepared for the journal Biomolecules.

Moriya Tsuji is currently a Professor of Medicine at the Aaron Diamond AIDS Research Center, in Columbia University in New York City. He has spent most of his life in the Big Apple after relocating from Japan. Dr. Tsuji completed medical school at Jikei University then pursued his doctorate with the renowned immunologist Dr. Tomio Tada at the University of Tokyo. Dr. Tsuji has made diverse contributions to immunology and vaccinology. He broke new ground in uncovering the protective role of various T cell subsets, ranging from CD4+ T cells to gamma-delta T cells, against malaria infection. Soon afterwards, Dr. Tsuji expanded his research to the field of vaccine development, particularly, the development of viral vector-based malaria vaccines that can elicit a potent protective CD8+ T-cell response. He demonstrated adenovirus as an excellent vector for inducing CD8+ T cell-mediated immunity. More recently, Dr. Tsuji identified CD1d-binding natural killer T (NKT)-cell stimulatory glycolipids as a superb adjuvant capable of enhancing CD8+ T cell response induced by various vaccines. Most recently, he established a humanized mouse model that mimics human immune system that possess functional human CD4+ and CD8+ T cells, B cells and dendritic cells, and can mount cell-mediated immunity upon immunization with various vaccines.

Those that have met Dr. Tsuji know it is difficult to find a more passionate scientist, who loves nothing more than carrying out challenging experiments working on the bench himself. More than that, Dr. Tsuji has an undeniable lust for life that inspires us all. This special issue will include topics broadly related to Dr. Tsuji’s fields of interest.

Dr. Jonathan Lovell
Guest Editor

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Keywords

HIV
malaria
NK T cell
immunology
vaccinology

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Published Papers (9 papers)

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Research

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13 pages, 1981 KiB

Open AccessArticle

High-Throughput Antibody Profiling Identifies Targets of Protective Immunity against P. falciparum Malaria in Thailand

by Ifra Hassan, Bernard N. Kanoi, Hikaru Nagaoka, Jetsumon Sattabongkot, Rachanee Udomsangpetch, Takafumi Tsuboi and Eizo Takashima

Biomolecules 2023, 13(8), 1267; https://doi.org/10.3390/biom13081267 - 18 Aug 2023

Cited by 1 | Viewed by 1521

Abstract

Malaria poses a significant global health challenge, resulting in approximately 600,000 deaths each year. Individuals living in regions with endemic malaria have the potential to develop partial immunity, thanks in part to the presence of anti-plasmodium antibodies. As efforts are made to optimize and implement strategies to reduce malaria transmission and ultimately eliminate the disease, it is crucial to understand how these interventions impact naturally acquired protective immunity. To shed light on this, our study focused on assessing antibody responses to a carefully curated library of P. falciparum recombinant proteins (n = 691) using samples collected from individuals residing in a low-malaria-transmission region of Thailand. We conducted the antibody assays using the AlphaScreen system, a high-throughput homogeneous proximity-based bead assay that detects protein interactions. We observed that out of the 691 variable surface and merozoite stage proteins included in the library, antibodies to 268 antigens significantly correlated with the absence of symptomatic malaria in an univariate analysis. Notably, the most prominent antigens identified were P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains. These results align with our previous research conducted in Uganda, suggesting that similar antigens like PfEMP1s might play a pivotal role in determining infection outcomes in diverse populations. To further our understanding, it remains critical to conduct functional characterization of these identified proteins, exploring their potential as correlates of protection or as targets for vaccine development. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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24 pages, 9263 KiB

Open AccessArticle

Short Carbon Nanotube-Based Delivery of mRNA for HIV-1 Vaccines

by Yang Xu, Tammy Ferguson, Kazuya Masuda, Mohammad Adnan Siddiqui, Kelsi Poole Smith, Olivia Vest, Brad Brooks, Ziyou Zhou, Judy Obliosca, Xiang-Peng Kong, Xunqing Jiang, Masahiro Yamashita, Tsuji Moriya and Christopher Tison

Biomolecules 2023, 13(7), 1088; https://doi.org/10.3390/biom13071088 - 7 Jul 2023

Cited by 4 | Viewed by 2763

Abstract

Developing a safe and effective preventive for HIV-1 remains the hope for controlling the global AIDS epidemic. Recently, mRNA vaccines have emerged as a promising alternative to conventional vaccine approaches, primarily due to their rapid development and potential for low-cost manufacture. Despite the advantages of mRNA vaccines, challenges remain, especially due to the adverse effects of the delivery vehicle and low delivery efficiency. As a result, Luna Labs is developing a short carbon nanotube-based delivery platform (NanoVac) that can co-deliver mRNA and HIV-1 glycoproteins to the immune system efficiently with negligible toxicity. Surface chemistries of NanoVac were optimized to guide antigen/mRNA loading density and presentation. Multiple formulations were engineered for compatibility with both intramuscular and intranasal administration. NanoVac candidates demonstrated immunogenicity in rabbits and generated human-derived humoral and cellular responses in humanized mice (HIS). Briefly, 33% of the HIV-1–infected HIS mice vaccinated with NanoVac–mRNA was cleared of virus infection by 8–weeks post-infection. Finally, NanoVac stabilized the loaded mRNA against degradation under refrigeration for at least three months, reducing the cold chain burden for vaccine deployment. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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11 pages, 2375 KiB

Open AccessArticle

Molecular Mechanism behind the Safe Immunostimulatory Effect of Withania somnifera

by Kriti Kalpana, Shen Yap, Moriya Tsuji and Akira Kawamura

Biomolecules 2023, 13(5), 828; https://doi.org/10.3390/biom13050828 - 12 May 2023

Cited by 1 | Viewed by 2101

Abstract

Withania somnifera (L.) Dunal (family Solanaceae) is a medicinal plant known for, among many pharmacological properties, an immune boosting effect. Our recent study revealed that its key immunostimulatory factor is lipopolysaccharide of plant-associated bacteria. This is peculiar, because, although LPS can elicit protective immunity, it is an extremely potent pro-inflammatory toxin (endotoxin). However, W. somnifera is not associated with such toxicity. In fact, despite the presence of LPS, it does not trigger massive inflammatory responses in macrophages. To gain insights into the safe immunostimulatory effect of W. somnifera, we conducted a mechanistic study on its major phytochemical constituent, withaferin A, which is known for anti-inflammatory activity. Endotoxin-triggered immunological responses in the presence and absence of withaferin A were characterized by both in vitro macrophage-based assay and in vivo cytokine profiling in mice. Collectively, our results demonstrate that withaferin A selectively attenuates the pro-inflammatory signaling triggered by endotoxin without impairing other immunological pathways. This finding provides a new conceptual framework to understand the safe immune-boosting effect of W. somnifera and possibly other medicinal plants. Furthermore, the finding opens a new opportunity to facilitate the development of safe immunotherapeutic agents, such as vaccine adjuvants. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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20 pages, 4870 KiB

Open AccessArticle

Diversity of HLA-A2-Restricted and Immunodominant Epitope Repertoire of Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Protein: Novel Insights among N-Terminal, Central and C-Terminal Regions

by Thaiza Aline Pereira-Santos, Anderson Santos da Rocha, Ágata Lopes-Ribeiro, Laura Cardoso Corrêa-Dias, Patrícia Melo-Oliveira, Erik Vinicius de Sousa Reis, Flávio Guimarães da Fonseca, Edel Figueiredo Barbosa-Stancioli, Moriya Tsuji and Jordana Grazziela Alves Coelho-dos-Reis

Biomolecules 2023, 13(3), 545; https://doi.org/10.3390/biom13030545 - 16 Mar 2023

Viewed by 2319

Abstract

The present study sought to search for the immunodominance related to the N-terminal, Central and C-terminal regions of HTLV-1 Tax using novel, cutting-edge peptide microarray analysis. In addition, in silico predictions were performed to verify the presence of nine amino acid peptides present along Tax restricted to the human leukocyte antigen (HLA)-A2.02*01 haplotype, as well as to verify the ability to induce pro-inflammatory and regulatory cytokines, such as IFN-γ and IL-4, respectively. Our results indicated abundant dose-dependent reactivity for HLA-A*02:01 in all regions (N-terminal, Central and C-terminal), but with specific hotspots. Furthermore, the results of fold-change over the Tax^11–19 reactivity obtained at lower concentrations of HLA-A*02:01 reveal that peptides from the three regions contain sequences that react 100 times more than Tax^11–19. On the other hand, Tax^11–19 has similar or superior HLA-A*02:01 reactivity at higher concentrations of this haplotype. The in silico analysis showed a higher frequency of IFN-γ-inducing peptides in the N-terminal portion, while the C-terminal portion showed a higher frequency of IL-4 inducers. Taken together, these results shed light on the search for new Tax immunodominant epitopes, in addition to the canonic Tax^11–19, for the rational design of immunomodulatory strategies for HTLV-1 chronic diseases. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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14 pages, 2928 KiB

Open AccessArticle

Cysteine Residues in Region 6 of the Plasmodium yoelii Erythrocyte-Binding-like Ligand That Are Related to Its Localization and the Course of Infection

by Hitoshi Otsuki, Osamu Kaneko, Daisuke Ito, Yoko Kondo, Hideyuki Iriko, Tomoko Ishino, Mayumi Tachibana, Takafumi Tsuboi and Motomi Torii

Biomolecules 2023, 13(3), 458; https://doi.org/10.3390/biom13030458 - 2 Mar 2023

Viewed by 2043

Abstract

Plasmodium malaria parasites use erythrocyte-binding-like (EBL) ligands to invade erythrocytes in their vertebrate host. EBLs are released from micronemes, which are secretory organelles located at the merozoite apical end and bind to erythrocyte surface receptors. Because of their essential nature, EBLs have been studied as vaccine candidates, such as the Plasmodium vivax Duffy binding protein. Previously, we showed through using the rodent malaria parasite Plasmodium yoelii that a single amino acid substitution within the EBL C-terminal Cys-rich domain (region 6) caused mislocalization of this molecule and resulted in alteration of the infection course and virulence between the non-lethal 17X and lethal 17XL strains. In the present study, we generated a panel of transgenic P. yoelii lines in which seven of the eight conserved Cys residues in EBL region 6 were independently substituted to Ala residues to observe the consequence of these substitutions with respect to EBL localization, the infection course, and virulence. Five out of seven transgenic lines showed EBL mislocalizations and higher parasitemias. Among them, three showed increased virulence, whereas the other two did not kill the infected mice. The remaining two transgenic lines showed low parasitemias similar to their parental 17X strain, and their EBL localizations did not change. The results indicate the importance of Cys residues in EBL region 6 for EBL localization, parasite infection course, and virulence and suggest an association between EBL localization and the parasite infection course. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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11 pages, 1222 KiB

Open AccessArticle

The Immunogenicity of a VLP-based Malaria Vaccine Targeting CSP in Pregnant and Neonatal Mice

by Lucie Jelínková, Bryce Roberts, Diane T. Ajayi, David S. Peabody and Bryce Chackerian

Biomolecules 2023, 13(2), 202; https://doi.org/10.3390/biom13020202 - 19 Jan 2023

Cited by 1 | Viewed by 2794

Abstract

Maternal antibodies are passively transferred to the fetus via the placenta during gestation and can play an important role in protecting the newborn from infection. For example, in malaria-endemic regions, maternal antibodies likely provide substantial protection against Plasmodium falciparum malaria in the first 6 months of life. However, circulating maternal antibodies can also interfere with vaccine efficacy. Here, we used a mouse maternal transfer model to evaluate whether maternal antibodies interfere with the responsiveness to a virus-like particle (VLP)-based vaccine targeting the CIS43 epitope of the malaria circumsporozoite protein (CSP). We found immunized dams passively transfer to pups high levels of anti-CSP IgG antibodies that steadily decline as the animals age. We also found that the neonatal offspring of immunized mice do not respond to de novo immunization with the CIS43-targeted VLP vaccine until maternal antibody titers decline below an inhibitory threshold. These findings may have important implications for delineating the delicate balance between protection conferred by maternal antibodies and the offspring’s ability to respond to immunization. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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8 pages, 1141 KiB

Open AccessArticle

Sex-Specific Differences in Cytokine Induction by the Glycolipid Adjuvant 7DW8-5 in Mice

by Felicia N. Watson, Caroline J. Duncombe, Anya C. Kalata, Ethan Conrad, Sumana Chakravarty, B. Kim Lee Sim, Stephen L. Hoffman, Moriya Tsuji, Melanie J. Shears and Sean C. Murphy

Biomolecules 2023, 13(1), 8; https://doi.org/10.3390/biom13010008 - 21 Dec 2022

Cited by 1 | Viewed by 2246

Abstract

7DW8-5 is a potent glycolipid adjuvant that improves malaria vaccine efficacy in mice by inducing IFN-γ and increasing protective CD8⁺ T cell responses. The addition of 7DW8-5 was previously shown to improve the efficacy of a CD8⁺ T cell-mediated heterologous ‘prime-and-trap’ malaria vaccine against Plasmodium yoelii sporozoite challenge in inbred female mice. Here, we report significant differential sex-specific responses to 7DW8-5 in inbred and outbred mice. Male mice express significantly less IFN-γ and IL-4 compared to females following intravenous 7DW8-5 administration. Additionally, unlike in female mice, 7DW8-5 did not improve the vaccine efficacy against sporozoite challenge in prime-and-trap vaccinated male mice. Our findings highlight the importance of including both female and male sexes in experimental adjuvant studies. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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21 pages, 1253 KiB

Open AccessEditor’s ChoiceReview

The Need for Novel Asexual Blood-Stage Malaria Vaccine Candidates for Plasmodium falciparum

by Eizo Takashima, Hitoshi Otsuki, Masayuki Morita, Daisuke Ito, Hikaru Nagaoka, Takaaki Yuguchi, Ifra Hassan and Takafumi Tsuboi

Biomolecules 2024, 14(1), 100; https://doi.org/10.3390/biom14010100 - 12 Jan 2024

Cited by 7 | Viewed by 2698

Abstract

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective RTS,S/AS01 pre-erythrocytic vaccine has been recommended by the WHO for use in sub-Saharan Africa against Plasmodium falciparum in children residing in moderate to high malaria transmission regions. A second pre-erythrocytic vaccine, R21/Matrix-M, was also recommended by the WHO on 3 October 2023. However, the paucity and limitations of pre-erythrocytic vaccines highlight the need for asexual blood-stage malaria vaccines that prevent disease caused by blood-stage parasites. Few asexual blood-stage vaccine candidates have reached phase 2 clinical development, and the challenges in terms of their efficacy include antigen polymorphisms and low immunogenicity in humans. This review summarizes the history and progress of asexual blood-stage malaria vaccine development, highlighting the need for novel candidate vaccine antigens/molecules. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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16 pages, 1358 KiB

Open AccessReview

Natural Killer T and Natural Killer Cell-Based Immunotherapy Strategies Targeting Cancer

by Tomonori Iyoda, Satoru Yamasaki, Shogo Ueda, Kanako Shimizu and Shin-ichiro Fujii

Biomolecules 2023, 13(2), 348; https://doi.org/10.3390/biom13020348 - 10 Feb 2023

Cited by 11 | Viewed by 3719

Abstract

Both natural killer T (NKT) and natural killer (NK) cells are innate cytotoxic lymphoid cells that produce inflammatory cytokines and chemokines, and their role in the innate immune response to tumors and microorganisms has been investigated. Especially, emerging evidence has revealed their status and function in the tumor microenvironment (TME) of tumor cells. Some bacteria producing NKT cell ligands have been identified to exert antitumor effects, even in the TME. By contrast, tumor-derived lipids or metabolites may reportedly suppress NKT and NK cells in situ. Since NKT and NK cells recognize stress-inducible molecules or inhibitory molecules on cancer cells, their status or function depends on the balance between inhibitory and activating receptor signals. As a recent strategy in cancer immunotherapy, the mobilization or restoration of endogenous NKT or NK cells by novel vaccines or therapies has become a focus of research. As a new biological evidence, after activation, effector memory-type NKT cells lasted in tumor-bearing models, and NK cell-based immune checkpoint inhibition potentiated the enhancement of NK cell cytotoxicity against cancer cells in preclinical and clinical trials. Furthermore, several new modalities based on the characteristics of NKT and NK cells, including artificial adjuvant vector cells, chimeric antigen receptor-expressing NK or NKT cell therapy, or their combination with immune checkpoint blockade have been developed. This review examines challenges and future directions for improving these therapies. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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