ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf013
Caitlin M Tilsed, Joshua Brotman, Shaun O'Brien, Brennan Lee, Edmund Moon, Steven M Albelda
{"title":"Identification and characterization of tissue resident memory T cells in malignant pleural effusions associated with non-small cell lung cancer.","authors":"Caitlin M Tilsed, Joshua Brotman, Shaun O'Brien, Brennan Lee, Edmund Moon, Steven M Albelda","doi":"10.1093/immhor/vlaf013","DOIUrl":"https://doi.org/10.1093/immhor/vlaf013","url":null,"abstract":"<p><p>Tissue resident memory T cells (TRM) play a critical role in cancer immunity and their presence in solid tumors is associated with improved prognosis and response to therapy. Although TRM have been identified and their function characterized in lung cancers, little is known regarding TRM outside of a tissue context, such as within malignant pleural effusions (MPE). As MPE are routinely drained and collected to manage symptoms, analysis of this fluid can provide an insight into the peri-tumoral environment. In this study, we performed flow cytometry and single cell RNAseq (scRNAseq) on MPE associated with non-small lung cancer and examined the phenotype and function of TRM. We found that 14% of CD8+ T cells and 6% of CD4+ T cells were TRM, as defined by the phenotype of CD45RO+CCR7-CD62L- and expressing 1 or both of CD69 and CD103. The scRNAseq revealed distinct clusters expressing TRM-associated genes including ITGAE and CD49A and lacking expression of SELL, CCR7, and IL7RA. TRM did not differ from other memory T cell subsets, such as T central memory (TCM) and T effector memory (TEM) cells, in expression of the inhibitory markers PD-1, TIGIT, and CD39. When TRM function was assessed by measuring the production of IFN-γ, TNF-α, and CD107a after stimulation with αnti-CD3 antibodies in vitro, TRM had comparable function to T effector cells (TE), indicating that despite expression of exhaustion markers these cells retained effector function. Finally, we found that CD69 expression, and not CD103 expression, on TRM was associated with production of effector cytokines.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"STAP-1-derived peptide suppresses TCR-mediated T cell activation and ameliorates immune diseases by inhibiting STAP-1-LCK binding.","authors":"Yuto Sasaki, Kota Kagohashi, Shoya Kawahara, Yuichi Kitai, Ryuta Muromoto, Kenji Oritani, Jun-Ichi Kashiwakura, Tadashi Matsuda","doi":"10.1093/immhor/vlaf015","DOIUrl":"https://doi.org/10.1093/immhor/vlaf015","url":null,"abstract":"<p><p>Signal-transducing adaptor protein-1 (STAP-1) is an adaptor protein specifically expressed in immune cells, such as T cells. We previously demonstrated that STAP-1 positively upregulates T cell receptor (TCR)-mediated T cell activation by interacting with LCK and phospholipase C-γ1 and affecting autoimmune demyelination and airway inflammation. In this study, we aimed to generate a new STAP-1-derived peptide, iSP1, to inhibit the STAP-1-LCK interaction. We also analyzed its function in vitro and in vivo. iSP1 successfully interfered with STAP-1-LCK binding and suppressed TCR-mediated signal transduction, interleukin-2 production, and human and murine T cell proliferation. Additionally, iSP1 prevented the progression of experimental autoimmune encephalomyelitis by inhibiting Th1 and Th17 cell infiltration. Our findings suggest iSP1 as a new therapeutic immunomodulatory agent for T cell-mediated autoimmune diseases.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf014
Sasha E Larsen, Maham Rais, Valerie A Reese, Debora Ferede, Tiffany Pecor, Suhavi Kaur, Deepika Nag, Thomas Smytheman, Sean A Gray, Darrick Carter, Susan L Baldwin, Rhea N Coler
{"title":"Characterizing TLR4 agonist EmT4™ as an anti-Mycobacterium tuberculosis vaccine adjuvant.","authors":"Sasha E Larsen, Maham Rais, Valerie A Reese, Debora Ferede, Tiffany Pecor, Suhavi Kaur, Deepika Nag, Thomas Smytheman, Sean A Gray, Darrick Carter, Susan L Baldwin, Rhea N Coler","doi":"10.1093/immhor/vlaf014","DOIUrl":"https://doi.org/10.1093/immhor/vlaf014","url":null,"abstract":"<p><p>Tuberculosis (TB) is again the deadliest infectious disease globally, and more efficacious vaccines are needed to reduce this mortality. Successful subunit TB vaccines need antigens and adjuvants that are immunogenic, inexpensive, and accessible. Here we evaluated the potential of synthetically produced Monophosphoryl lipid A (SyMLP), a TLR4-agonist, formulated in an oil-in-water emulsion (EmT4™) in combination with selected fusion proteins, to drive an effective vaccine-mediated immunogenic response in C57BL/6 mice against Mycobacterium tuberculosis (M.tb) HN878 and H37Rv challenge. We first observed that EmT4™ enhances activation of C57BL/6 bone-marrow derived macrophages and dendritic cells measured by CD40, CD86, and MHCII expression by flow cytometry. EmT4™ did not induce safety signals in a scaled tolerability study. In immunogenicity studies, mice immunized 3 times 3 weeks apart with ID93 antigen + EmT4™ produced a significantly higher magnitude of circulating proinflammatory cytokines and ID93-specific immunoglobulin G (IgG) antibodies pre- and post-challenge with M.tb than saline control animals. Ex vivo ID93 restimulated splenocytes and lung cells elicited significant polyfunctional CD4+ T-helper 1 responses. Importantly, ID93 + EmT4™ immunizations significantly reduced bacterial burden in C57BL/6 mice 4 weeks post-challenge. Interestingly, EmT4™ paired with a next generation protein fusion ID91 also afforded prophylactic protection against M.tb HN878 challenge in both young (6 to 8 wk) and aged (20 mo) immunocompromised Beige mice. These protection and immunogenicity findings suggest that synthetically derived EmT4™ adjuvant is not only suitable to help backfill the preclinical TB vaccine candidate pipeline but is also suitable for the needs of the global community.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf020
{"title":"Correction to: Comprehensive immune profiling of dengue and chikungunya viral responses using a novel miniaturized automated whole blood cellular analysis system and mass cytometry in a pediatric cohort in Msambweni, Kenya.","authors":"","doi":"10.1093/immhor/vlaf020","DOIUrl":"https://doi.org/10.1093/immhor/vlaf020","url":null,"abstract":"","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf017
Piu Saha, Ahmed Abokor, Matam Vijay-Kumar
{"title":"Dynamics of antimicrobial proteins' expression and their bactericidal activity in mouse milk.","authors":"Piu Saha, Ahmed Abokor, Matam Vijay-Kumar","doi":"10.1093/immhor/vlaf017","DOIUrl":"https://doi.org/10.1093/immhor/vlaf017","url":null,"abstract":"<p><p>Mother's milk is considered as \"complete edible immune system.\" It contains macro- and micronutrients required to maintain infant growth and provides an excellent source for innate and adaptive immune proteins that not only protects infants from enteropathogens but also aid in the initial colonization of gut microbiota. In this study, we analyzed the milk of C57BL/6J dams and found significant changes in the composition of antimicrobial and immune proteins throughout the lactation period. Innate immune proteins, serum amyloid A, soluble CD14, and notably lipocalin-2 were detected in milk at high quantities. These proteins were substantially reduced in the milk from MyD88-deficient dams. Further, adaptive immune proteins, specifically IgA and IgG, exhibit a distinct shift during postpartum lactation stages. While IgG is the dominant immunoglobulin in milk at day 5 postpartum, by day 15 its levels were surpassed by IgA whose levels increased over time. The administration of TLR4 ligand LPS to WT dams significantly increased the aforementioned milk innate and adaptive proteins. Surprisingly, the milk from WT dams suppressed E. coli growth more effectively than milk collected from LPS-treated mice; such suppression, however, was completely lost upon boiling. Intriguingly, IgA, but not Lcn2, serves as a predominant factor in inhibiting E. coli proliferation, suggesting the critical role of IgA in regulating microbial colonization in the neonatal gut. Collectively, our findings provide insight into the dynamics of various immune proteins present in breast milk and highlight their pivotal roles in determining neonatal immune responses and microbial colonization at early stage.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf011
Eden E Faneuff, Min Joo Kim, Amondrea Blackman, Kirti A Karunakaran, Jackie E Bader, Xin Zhen, Kaitlyn S Gallagher, Tanner J Durst, James A Connelly, Jeffrey C Rathmell, Ana Salina, Ruben Martinez-Barricarte, Carlos Henrique Serezani
{"title":"PTEN inhibits scavenger receptor-mediated phagocytosis of methicillin-resistant Staphylococcus aureus.","authors":"Eden E Faneuff, Min Joo Kim, Amondrea Blackman, Kirti A Karunakaran, Jackie E Bader, Xin Zhen, Kaitlyn S Gallagher, Tanner J Durst, James A Connelly, Jeffrey C Rathmell, Ana Salina, Ruben Martinez-Barricarte, Carlos Henrique Serezani","doi":"10.1093/immhor/vlaf011","DOIUrl":"https://doi.org/10.1093/immhor/vlaf011","url":null,"abstract":"<p><p>Phagocytosis requires the coordination of various classes of receptors and the activation of multiple signaling programs, culminating in actin cytoskeletal rearrangement and ingestion. Given the pleiotropic nature of the events necessary for proper microbial ingestion, identifying molecules that control distinct steps of phagocytosis could reveal potential strategies to enhance microbial clearance. PTEN is a lipid/protein phosphatase traditionally recognized as a tumor suppressor. While PTEN inhibits various arms of the innate immune response, its role during Staphylococcus aureus infection remains unclear. We hypothesize that PTEN inhibits the functions of scavenger receptors (SRs) and the actin cytoskeleton during methicillin-resistant S. aureus (MRSA) infection in macrophages. RNAseq analysis of PTEN KO immortalized bone marrow-derived macrophages (iBMDMs) unveiled increased expression of genes involved in actin polymerization, pathogen recognition, and SRs, which leads to enhanced MRSA phagocytosis in both iBMDMs and primary peritoneal macrophages lacking PTEN. PTEN is physically associated with 2 SRs, MARCO and CD36, and blocking these receptors prevents the increased phagocytosis seen in PTEN KO macrophages. PTEN binds to the actin depolymerizing factor cofilin-1 during infection, inhibiting F-actin (the essential form of actin for phagocytosis) while increasing G-actin pools. Cytometry by time of flight (CyTOF) analysis of human myeloid cell populations from a PTEN-haploinsufficient patient suggests that PTEN is necessary for generating specific monocyte and dendritic subclasses. This study identifies the role of PTEN in macrophage phagocytosis of a gram-positive pathogen and in the development of monocyte subsets. This highlights the spectrum of PTEN importance in host defense mechanisms in both murine and human phagocytes.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-04-26DOI: 10.1093/immhor/vlaf016
Joel Guertin, Pavel Chrobak, Clémence Meunier, Cassandra M Thomson, Zaher Hanna, Paul Jolicoeur
{"title":"HIV Nef disrupts Lck signaling by inducing aberrant phosphorylation of its substrates.","authors":"Joel Guertin, Pavel Chrobak, Clémence Meunier, Cassandra M Thomson, Zaher Hanna, Paul Jolicoeur","doi":"10.1093/immhor/vlaf016","DOIUrl":"https://doi.org/10.1093/immhor/vlaf016","url":null,"abstract":"<p><p>Human in vitro studies of HIV Nef on TcR proximal signaling have been controversial and have not provided an integrated picture of its impact. Tyrosine (Y) phosphorylation (pY) of Lck and its substrates (CD3ζ, Zap-70) was investigated in vivo, in Nef-expressing transgenic (Tg) thymocytes. In Tg cells, Lck was mis-localized and activated, but the pY-CD3ζ levels were unexpectedly lower, both constitutively and after anti-CD3ε Ab stimulation. Nef also favors the hyperphosphorylation of the Lck Y505 site and the accumulation of doubly phosphorylated (Y394, Y505) Lck. In contrast, after anti-CD3ε+anti-CD4 Ab stimulation, Nef decreased Lck activity and Lck was deprived of its pY partners. In Nef and LckY505F Tg thymocytes, Lck had similar activity but distinct LckY505 levels, Zap-70 pY phosphorylation, and Zap-70 activity, suggesting a different mode of Lck activation. Western blot analysis of Zap-70 with pY site-specific mAb showed modest enhanced levels of Zap-70pY292 and Zap-70pY493 (the latter required for its full activation) constitutively and after anti-CD3ε Ab stimulation, consistent with elevated Tg LATpY and suggesting a semiactive kinase. In fact, phenotypes of Nef Tg mice are very similar to those of mice harboring semiactive Zap-70 mutants. After anti-CD3ε+anti-CD4 stimulation, Tg Zap-70 activity and Zap-70pY493 levels were severely decreased, but Zap-70pY292 and Zap-70pY319 levels were barely affected, suggesting qualitative Lck defect. Rescue of Nef-mediated CD4+ T-cell loss with LckY505F in double (Nef × LckY505F) Tg mice correlated with greatly enhanced levels of Zap-70pY and Zap-70 activity. Thus, Nef impacts Lck in a unique way, triggering it to mis-phosphorylate its substrates.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-03-26DOI: 10.1093/immhor/vlaf005
Johannes F Scheid, Kiki Cunningham-Bussel, Nancy Kim, Shiuli Agarwal, Garrett Nieddu, Josee Cote, Lieselotte Lemoine, Tatjana Decaesteker, Luis Mendez, Erina Paul, Latisha Love-Gregory, Alejandra Virginia Contreras, Xuemei Zhao, Lucia Franco-Dilone, Ling Pang, Gretchen A Baltus, Maribel Beaumont, Ketal Shah, Nathan Higginson-Scott, Katalin Kis-Toth, Kevin L Otipoby, Joanne L Viney, Eric Sicard, Sylvie Rottey, John S Sundy, Kristien Van Dyck, Tine Laethem, Patrick Larson, Santosh Sutradhar, Richard Wnek, Tjerk Bueters, Eseng Lai, S Aubrey Stoch, Marian Iwamoto, Jonathan A Robbins
{"title":"Safety, pharmacokinetics, and pharmacodynamics of MK-6194, an IL-2 mutein designed to selectively activate regulatory T cells: single ascending dose and multiple ascending dose trial data.","authors":"Johannes F Scheid, Kiki Cunningham-Bussel, Nancy Kim, Shiuli Agarwal, Garrett Nieddu, Josee Cote, Lieselotte Lemoine, Tatjana Decaesteker, Luis Mendez, Erina Paul, Latisha Love-Gregory, Alejandra Virginia Contreras, Xuemei Zhao, Lucia Franco-Dilone, Ling Pang, Gretchen A Baltus, Maribel Beaumont, Ketal Shah, Nathan Higginson-Scott, Katalin Kis-Toth, Kevin L Otipoby, Joanne L Viney, Eric Sicard, Sylvie Rottey, John S Sundy, Kristien Van Dyck, Tine Laethem, Patrick Larson, Santosh Sutradhar, Richard Wnek, Tjerk Bueters, Eseng Lai, S Aubrey Stoch, Marian Iwamoto, Jonathan A Robbins","doi":"10.1093/immhor/vlaf005","DOIUrl":"10.1093/immhor/vlaf005","url":null,"abstract":"<p><p>MK-6194, an interleukin-2 mutein designed to selectively activate regulatory T cells (Tregs), was evaluated for safety, pharmacokinetics (PK), immunogenicity, and pharmacodynamics in healthy participants. In a single ascending dose trial (N = 56), participants received subcutaneous MK-6194 or placebo (3:1 ratio) across dose levels ranging from 1 to 10 mg. In a multiple ascending dose trial (N = 54), participants received subcutaneous MK-6194 or placebo (3:1 ratio) at dose levels ranging from 0.5 to 5 mg every 2 wk (total 3 doses) as well as 5 mg every 4 wk (total 2 doses). Baseline characteristics were comparable between trials, with participants mostly male with a mean age of 36 yr. There were no serious adverse events or dose-limiting toxicities. The most common adverse events were injection site erythema and eosinophil count elevations (with no indication of severe eosinophilia or eosinophilia-related organ damage). PK showed dose-proportionality and repeated doses of MK-6194 did not result in accumulation or time-dependent PK. Immunogenicity was low with no impact on PK or safety. Treg expansion as assessed by flow cytometry and Treg-specific demethylation region analysis was observed in a dose-dependent manner during both trials and expanded within about 8 d postdose up to about 5-fold and returned to baseline by 14 to 29 d postdose. Minimal impact was observed on other lymphocytes including total T lymphocyte and natural killer cell counts. These findings support the further development of MK-6194 as a potential treatment for autoimmune disorders.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"In vitro and in vivo neutralization of Dengue virus by a single domain antibody.","authors":"Surbhi Dahiya, Sudhakar Singh, Gaurav Kumar Bhati, Sharvan Sehrawat","doi":"10.1093/immhor/vlaf012","DOIUrl":"10.1093/immhor/vlaf012","url":null,"abstract":"<p><p>To alleviate the contribution of antibody dependent enhancement in DenV pathogenesis, we obtain a DenV neutralizing single domain antibody (sdAb) from an in-house constructed phage display library of camelid VHH. The anti-DenV sdAb specifically reacts with the envelope (E) protein of DenV with a Kd value of 2x108. Molecular dynamic simulations and docking analysis show that the sdAb interacts with the DenV(E) protein via domain II (EDII) and interferes with the virus internalization process. The anti-DenV(E) sdAb potently inhibits the infectivity of a DenV(E) protein expressing pseudovirus as well as that of a virulent DenV in vitro. A mouse adapted DenV2 induces 100% mortality in the infected IFNRKO mice, but the animals injected with the sdAb neutralized virus remain fully protected. Furthermore, the therapeutically administered anti-DenV(E) sdAb slows down the disease progression and enhances the survival of DenV infected animals. In conclusion, we report an anti-DenV(E) sdAb as a potential therapy to manage DenV pathogenesis.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunoHorizonsPub Date : 2025-03-26DOI: 10.1093/immhor/vlaf009
Elizabeth M Fusco, Layne Bower, Rafael Polidoro, Allen M Minns, Scott E Lindner, Nathan W Schmidt
{"title":"Microbiome-mediated modulation of immune memory to P. yoelii affects the resistance to secondary cerebral malaria challenge.","authors":"Elizabeth M Fusco, Layne Bower, Rafael Polidoro, Allen M Minns, Scott E Lindner, Nathan W Schmidt","doi":"10.1093/immhor/vlaf009","DOIUrl":"10.1093/immhor/vlaf009","url":null,"abstract":"<p><p>Malaria is caused by protozoan parasites in the genus Plasmodium. Over time individuals slowly develop clinical immunity to malaria, but this process occurs at variable rates, and the mechanism of protection is not fully understood. We have recently demonstrated that in genetically identical C57BL/6N mice, gut microbiota composition dramatically impacts the quality of the humoral immune response to Plasmodium yoelii and subsequent protection against a lethal secondary challenge with Plasmodium berghei ANKA in C57BL/6N mice. Here, we utilize this genetically identical, gut microbiome-dependent model to investigate how the gut microbiota modulate immunological memory, hypothesizing that the gut microbiome impacts the formation and functionality of immune memory. In support of this hypothesis, P. yoelii hyperparasitemia-resistant C57BL/6N mice exhibit increased protection against P. berghei ANKA-induced experimental cerebral malaria (ECM) compared to P. yoelii hyperparasitemia-susceptible C57BL/6N mice. Despite differences in protection against ECM, P. yoelii-resistant and -susceptible mice accumulate similar numbers of memory B cells (MBCs) and memory T cells. Following challenge with P. berghei ANKA, P. yoelii-resistant mice generated more rapid germinal center reactions; however, P. yoelii-resistant and -susceptible mice had similar titers of P. yoelii- and P. berghei-specific antibodies. In contrast, P. yoelii-resistant mice had an increased number of regulatory T cells in response to secondary challenge with P. berghei ANKA, which may dampen the immune-mediated breakdown of the blood-brain barrier and susceptibility to P. berghei-induced ECM. These findings demonstrate the ability of the gut microbiome to shape immune memory and the potential to enhance resistance to severe malaria outcomes.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}