Immunology
Abstract
Dengue virus (DENV) vaccines should be designed to induce balanced protective immunity against all four dengue serotype to mitigate the risk of vaccine-mediated enhanced dengue disease. The first tetravalent vaccine (Dengvaxia) tested in humans was efficacious in children who were partially immune to DENV at baseline. In DENV-naive children, the vaccine was not efficacious and placed some naïve children at risk of experiencing more severe wild-type DENV breakthrough infections. To define dengue vaccine responses at the individual subject level and their relationship to mild and severe dengue infections, we prospectively studied a cohort of DENV-naive children who received one dose of Dengvaxia. The vaccine stimulated variable responses that neutralized 0, 1 (monotypic), or 2+ (multitypic) serotypes in individual children. We used a logistic regression model to evaluate whether vaccine status and serotype-specific NAb status at the end of study period 1 influenced the probability of experiencing a virologically confirmed dengue disease (VCD) case thereafter (months 20 - 60). Vaccinated children with NAb response to only one serotype were at greater risk of being a case compared to the DENV-naïve control group (Odds Ratio 5.07). This risk was not observed in vaccinated children with no NAb or NAb to 2 or more serotypes. We propose that individuals with durable NAb to one serotype have an abundance of serotype cross-reactive, non-neutralizing Abs implicated in the enhanced replication of heterologous serotypes. We discuss the implications of our findings for flagging vaccine candidates that are likely to pose a special risk to seronegative subjects.
Authors
Laura J. White, Lindsay D. Hein, Maria Abad Fernandez, Cameron Adams, Elizabeth Adams, Emily Freeman, Ruby Shah, Lakshmanane Premkumar, Kristal An Agrupis, Maria Vinna Crisostomo, Jedas Veronica Daag, Michelle Ylade, Jacqueline Deen, Ana Lena Lopez, Leah Katzelnick, Aravinda M. de Silva
Abstract
Allogeneic islet transplantation is an effective treatment for type 1 diabetes, but its clinical use is limited by rejection involving innate and adaptive immune responses, requiring life-long immunosuppression. We herein engineered islets by transiently display two immunomodulators chimeric with streptavidin (SA), thrombomodulin (SA-TM) and CD47 (SA-CD47) for localized modulation of both innate and adaptive immune responses. The engineering process did not impact islet viability, glucose responsiveness, and metabolic activity. Intraportal transplantation into allogeneic recipients achieved sustained survival, with 8/11 grafts surviving 120-330 days without immunosuppression. In contrast, non-engineered islets were acutely rejected [median survival time (MST) = 12 days], while islets engineered with SA-TM showed delayed rejection [Median survival time (MST) = 13.5 days], and those with SA-CD47 exhibited prolonged survival (MST = 24 days). Double-engineered islets generated a localized tolerogenic immune environment characterized by low frequencies of inflammatory innate immune cells and increased frequencies of M2 macrophages, myeloid-derived suppressor cells, and CD4+FoxP3+ T regulatory cells. The transcriptomic analysis showed downregulation of proinflammatory and upregulation of immune regulatory pathways. Our results demonstrate that transient co-display of immunomodulatory molecules on the islet surface is a versatile platform with significant translational potential for islet transplantation.
Authors
Shadab Kazmi, Mohammad Tarique, Darshan Badal, Vahap Ulker, Ali Turan, Kathleen M. Yee-Flores, Abdalmonam Jadou Nejma, Esma S. Yolcu, Haval Shirwan
Abstract
Introduction: BK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood. Methods: In a cross-sectional study, single-cell RNA sequencing from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and two distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction). Results: Genes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection. Conclusion: These not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.
Authors
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
Abstract
The molecular mechanisms responsible for the “atopic march” of allergic skin disease to allergic airway disease are incompletely understood. Secreted phospholipase A2 group X (sPLA2-X) is implicated in human asthma and modulates airway hyperresponsiveness (AHR) and inflammation in murine models of allergic asthma. We developed a complete proteolytic allergen model of dermal sensitization followed by airway challenge to mimic the “atopic march” and examined the role of sPLA2-X in regulating peripheral allergen sensitization, AHR, and airway inflammation. Pla2g10-/- mice receiving both house dust mite (HDM) peripheral sensitization and airway challenge had attenuated AHR relative to WT mice and lower airway eosinophils. Transgenic C57BL/6 PLA2G10 mice (only expressing the human sPLA2-X gene) receiving treatment with a small molecule inhibitor of sPLA2-X (ROC0929) during the dermal sensitization phase demonstrated attenuated AHR and a reduction in lung tissue dust mite-specific tissue resident memory CD4+ T cells. Thus, sPLA2-X acts as an endogenous adjuvant to facilitate allergic sensitization in the periphery, which leads to AHR and airway inflammation following inhalation of the allergen. These results provide proof of concept that inhibition of sensitization in the periphery with a sPLA2-X inhibitor modulates subsequent allergen-induced airway dysfunction.
Authors
Ryan C. Murphy, Ying Lai, Yu-Hua Chow, Matt Liu, Brian D. Hondowicz, Dowon An, Marion Pepper, William A. Altemeier, Teal S. Hallstrand
Abstract
Macrophages (MΦ), endowed with remarkable phenotypic plasticity are essential for orchestrating injury responses and regulating iron homeostasis. Given the central role of ferritin heavy chain (FtH) as a molecular rheostat linking iron sequestration to redox-dependent signaling, we examined how myeloid FtH governs renal iron trafficking and ensuing oxidative-stress pathways during acute kidney injury (AKI). Transcriptome analysis revealed coupling of FtH deficiency in monocytes and MΦ with ferroptosis activation, a regulated cell death associated with iron accumulation. Moreover, myeloid FtH deletion worsened AKI, increasing leukocyte infiltration and iron deposition, together with ferroptosis‐associated gene induction, oxidative stress, and lipid peroxidation. Notably, ⍺-synuclein (SNCA), an iron-binding protein and the main pathological driver of Parkinson’s disease, was robustly induced by both FtH deficiency and following AKI. Mechanistic studies showed that monomeric SNCA exhibits ferrireductase activity, amplifying redox cycling and promoting ferroptotic cell death. Furthermore, SNCA expression was elevated in kidney pathologies characterized by leukocyte expansion in both mouse models and human cohorts, suggesting that inflammatory microenvironments promote SNCA accumulation and redox imbalance. These findings define a MΦ FtH-SNCA regulatory axis as a key driver of ferroptosis in AKI, implicating SNCA as a pathological nexus between iron dyshomeostasis and inflammatory kidney injury.
Authors
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary E. Miller, Bronte Johnson, Yanfeng Zhang, Laura A. Volpicelli-Daley, Lauren A. Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, Jozsef Balla, Christian Faul, Abolfazl Zarjou
Abstract
Heterogeneity in disease severity and treatment response in inflammatory bowel disease (IBD) likely evolve from individual differences in host-microbiota-immune interactions. Histological evaluation of intestinal biopsies is central to diagnosis, but histological parameters that define underlying immune mechanisms are limited. We investigated histological features that distinguish individual patient immune profiles in therapy-naive paediatric IBD patients (age 6‒18-years-old) using biopsy immunohistochemistry and transcriptomics and plasma proteomics across two cohorts. High colonic epithelial expression of Secretory Leukocyte Protease Inhibitor (SLPI), a microbiota-induced regulator of epithelial function, occurred in IBD patients with high clinical disease activity and more severe endoscopic and microscopic disease activity. SLPI expression related to increased neutrophil infiltration, transcriptomic signatures of activation and genes known to associate with therapeutic resistance. High SLPI co-localized with high densities of IL-17-secreting cells and was associated with high plasma concentrations of Th17-related immune proteins. Additionally, patients with high intestinal SLPI had an intrinsically different immunotype, in which circulating neutrophils exhibited altered transcription of genes involved in neutrophil granule formation, phagocytosis, oxidative phosphorylation, and interferon signalling. Thus, high colonic SLPI expression at diagnosis associates with severe IBD, increased IL-17A-neutrophil pathway responses and altered transcriptomic wiring of circulating neutrophils.
Authors
Sandrine Nugteren, Beatriz Calado, Ytje Simons-Oosterhuis, Daniëlle H. Hulleman-van Haaften, Willem K. Smits, Renz C.W. Klomberg, Bastiaan Tuk, Mohammed Charrout, Dicky J. Lindenbergh-Kortleve, Michail Doukas, Mathijs A. Sanders, Gregory van Beek, Johanna C. Escher, Lissy de Ridder, Maria Fernanda Pascutti, Janneke N. Samsom
Abstract
Viral lower respiratory tract infections are common early in life and are associated with long-term development of asthma, a chronic condition defined by reversible airflow obstruction secondary to inflammation. Understanding the immunologic mechanism connecting these two pathologies observed early in life becomes imperative to guide therapeutic measures. To investigate this connection, neonatal (day of life 4-6) or adult mice were infected with human metapneumovirus (HMPV) followed by a secondary HMPV infection 6 weeks later. Mice initially infected as neonates demonstrate increased mucus production, eosinophil recruitment, airway hyperresponsiveness, and Th2 T-cell differentiation following re-challenge compared to adult mice rechallenged with HMPV. Neonatal HMPV infection led to formation of Th2 clonally expanded tissue resident memory (TRM) T cells that were absent after adult HMPV. FTY720-mediated disruption of lymphocyte circulation demonstrated TRMs contribute to pathology. Local depletion of lung CD4+ T cells and JAK2-inhibition mitigated pathology. These findings suggest TRMs uniquely generated after early life viral infection can contribute to Th2-driven asthma pathology.
Authors
Emma E. Brown, Jie Lan, Olivia B. Parks, Li Fan, Dequan Lou, Alysia McCray, Lisa Mathews, Alexander J. Wardropper, Anna Shull, Michelle L. Manni, Hēth R. Turnquist, Kong Chen, Taylor Eddens
Abstract
Next-generation sequencing technologies are increasingly used to diagnose genetic disorders, particularly immunological diseases with broad and overlapping immune dysregulation. Cryopyrin-associated periodic syndromes (CAPS) are caused by gain-of-function mutations in NLRP3 and include 3 autoinflammatory diseases spanning a continuum of severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Linking NLRP3 variants to protein dysfunction and clinical phenotype remains challenging because of genetic modifiers and environmental factors. We report the generation and phenotyping of 5 mouse lines expressing either the common human NLRP3 allele or 1 of 4 CAPS mutations spanning the disease spectrum from FCAS to NOMID. In these lines, the murine Nlrp3 locus is replaced by syntenic integration of the human NLRP3 locus, yielding 1 line with the common allele and 4 lines each carrying a distinct CAPS mutation. Unlike models in which a human mutation is introduced into the mouse protein, these lines recapitulate the spectrum of disease severity observed in humans. These findings support a model in which evaluation of nonsynonymous mutations in mice is optimized when introduced in the context of the human gene. This suggests that species-specific regulation and/or intramolecular epistasis may impact modeling of disease-associated variants.
Authors
John N. Snouwaert, MyTrang Nguyen, Christopher A. Gabel, Ivona Aksentijevich, Jenny P.-Y. Ting, Beverly H. Koller
Abstract
Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.
Authors
Yu Gu, Dongmei Zuo, Qi-Xin Hu, Virginie Sanguin-Gendreau, Alain Pacis, Marie-Christine Guiot, Alexander Chih-Chieh Chang, Tarek Taifour, Chen Ling, Adrian V. Lee, Steffi Oesterreich, William J. Muller
Abstract
Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.
Authors
Adam S. Krebs, Tomi Lazarov, Anthony T. Reynolds, Kimberly A. Dill-McFarland, Abigail Xie, James M. Bean, Muxue Du, Olivier Levy, John A. Buglino, Aaron Zhong, Anna-Lena Neehus, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E. Kroon, Marlo Möller, Thomas R. Hawn, Ting Zhou, Lydia W.S. Finley, Marc Antoine Jean Juste, Dan W. Fitzgerald, Frederic Geissmann, Michael S. Glickman
No posts were found with this tag.
