Browsing by Subject "Adaptive immunity"
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Item Co-recognition of β-glucan and chitin and programming of adaptive immunity to Aspergillus fumigatus(Frontiers Media S.A., 2015-04-21) Amarsaikhan, Nansalmaa; Templeton, Steven P.; Department of Microbiology and Immunology, IU School of MedicineThe prevalence of fungal infections has increased concurrently with increases in immune suppressive therapies and susceptible individuals. Opportunistic fungal pathogens such as Aspergillus fumigatus may exhibit invasive growth and dissemination resulting in a high mortality rate. Herein, we discuss how immune sensing of germination directs innate immune responses and programs adaptive responses that could promote or impair immune protection during periods of heightened susceptibility. In infected individuals, Th1 responses are the most protective, while Th2 responses lead to poor disease outcomes. In particular, the roles of β-glucan and chitin co-recognition in shaping Th1- and Th2-type immunity to fungal infection are explored. We discuss how fungal responses to environmental stresses could result in decreased immune protection from infection, particularly in response to anti-fungal drugs that target β-glucan synthesis. Furthermore, we consider how experimental modulation of host-pathogen interactions might elucidate the mechanisms of protective and detrimental immunity and the potential of current and future studies to promote the development of improved treatments for patients that respond poorly to existing therapies.Item Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort(Research Square, 2023-12-06) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of MedicineBackground: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.Item The gut microbiome, immunity, and Plasmodium severity(Elsevier, 2020-12) Waide, Morgan L.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.Item Immune Response Mechanisms against AAV Vectors in Animal Models(Elsevier, 2020-06) Martino, Ashley T.; Markusic, David M.; Pediatrics, School of MedicineEarly preclinical studies in rodents and other species did not reveal that vector or transgene immunity would present a significant hurdle for sustained gene expression. While there was early evidence of mild immune responses to adeno-associated virus (AAV) in preclinical studies, it was generally believed that these responses were too weak and transient to negatively impact sustained transduction. However, translation of the cumulative success in treating hemophilia B in rodents and dogs with an AAV2-F9 vector to human studies was not as successful. Despite significant progress in recent clinical trials for hemophilia, new immunotoxicities to AAV and transgene are emerging in humans that require better animal models to assess and overcome these responses. The animal models designed to address these immune complications have provided critical information to assess how vector dose, vector capsid processing, vector genome, difference in serotypes, and variations in vector delivery route can impact immunity and to develop approaches for overcoming pre-existing immunity. Additionally, a comprehensive dissection of innate, adaptive, and regulatory responses to AAV vectors in preclinical studies has provided a framework that can be utilized for development of immunomodulatory therapies to overcome or bypass immune responses and for developing strategic approaches toward engineering stealth AAV vectors that can circumvent immunity.Item Immune Responses to Viral Gene Therapy Vectors(Elsevier, 2020-03-04) Shirley, Jamie L.; de Jong, Ype P.; Terhorst, Cox; Herzog, Roland W.; Pediatrics, School of MedicineSeveral viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, with many more in pre-clinical testing. Efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive. In fact, viral vector gene therapy has been able to treat or even cure diseases for which there had been no or only suboptimal treatments. However, innate and adaptive immune responses to these vectors and their transgene products constitute substantial hurdles to clinical development and wider use in patients. This review provides an overview of the type of immune responses that have been documented in animal models and in humans who received gene transfer with one of three widely tested vector systems, namely adenoviral, lentiviral, or adeno-associated viral vectors. Particular emphasis is given to mechanisms leading to immune responses, efforts to reduce vector immunogenicity, and potential solutions to the problems. At the same time, we point out gaps in our knowledge that should to be filled and problems that need to be addressed going forward.Item Immune System, Friend or Foe of Oncolytic Virotherapy?(Frontiers, 2017-05-23) Filley, Anna C.; Dey, Mahua; Neurological Surgery, School of MedicineOncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune-mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus-expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies.Item Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine(American Society for Clinical Investigation, 2024-04-30) Senkpeil, Leetah; Bhardwaj, Jyoti; Little, Morgan R.; Holla, Prasida; Upadhye, Aditi; Fusco, Elizabeth M.; Swanson, Phillip A., II; Wiegand, Ryan E.; Macklin, Michael D.; Bi, Kevin; Flynn, Barbara J.; Yamamoto, Ayako; Gaskin, Erik L.; Sather, D. Noah; Oblak, Adrian L.; Simpson, Edward; Gao, Hongyu; Haining, W. Nicholas; Yates, Kathleen B.; Liu, Xiaowen; Murshedkar, Tooba; Richie, Thomas L.; Sim, B. Kim Lee; Otieno, Kephas; Kariuki, Simon; Xuei, Xiaoling; Liu, Yunlong; Polidoro, Rafael B.; Hoffman, Stephen L.; Oneko, Martina; Steinhardt, Laura C.; Schmidt, Nathan W.; Seder, Robert A.; Tran, Tuan M.; Medicine, School of MedicineA systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.Item The JAK inhibitor ruxolitinib reduces inflammation in an ILC3-independent model of innate immune colitis(Springer Nature, 2018-09) Overstreet, A.M.; LaTorre, D.L.; Abernathy-Close, L.; Murphy, S.F.; Rhee, L.; Boger, A.M.; Adlaka, K.R.; Iverson, A.M.; Bakke, D.S.; Weber, C.R.; Boone, D.L.; Microbiology and Immunology, School of MedicineInnate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune-mediated IBD.Item Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection(American Society for Clinical Investigation, 2020-05-19) Obeng-Adjei, Nyamekye; Larremore, Daniel B.; Turner, Louise; Ongoiba, Aissata; Li, Shanping; Doumbo, Safiatou; Yazew, Takele B.; Kayentao, Kassoum; Miller, Louis H.; Traore, Boubacar; Pierce, Susan K.; Buckee, Caroline O.; Lavstsen, Thomas; Crompton, Peter D.; Tran, Tuan M.; Medicine, School of MedicineBACKGROUND Malaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum–infected erythrocytes to the microvasculature mediated via specific interactions between P. falciparum erythrocyte membrane protein (PfEMP1) variant domains and host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria. METHODS We evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission. RESULTS Using longitudinal data, we found that IgG antibodies against the pathogenic domain variants CIDRα1.7 and CIDRα1.8 were acquired the earliest. Furthermore, IgG antibodies against CIDRγ3 were associated with reduced prospective risk of febrile malaria and recurrent malaria episodes. CONCLUSION This study provides evidence that acquisition of IgG antibodies against PfEMP1 variants is ordered and demonstrates that antibodies against CIDRα1 domains are acquired the earliest in children residing in an area of intense, seasonal malaria transmission. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant–specific antibodies. TRIAL REGISTRATION ClinicalTrials.gov NCT01322581.Item Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine(Springer Nature, 2022) Li, Chunfeng; Lee, Audrey; Grigoryan, Lilit; Arunachalam, Prabhu S.; Scott, Madeleine K.D.; Trisal, Meera; Wimmers, Florian; Sanyal, Mrinmoy; Weidenbacher, Payton A.; Feng, Yupeng; Adamska, Julia Z.; Valore, Erika; Wang, Yanli; Verma, Rohit; Reis, Noah; Dunham, Diane; O’Hara, Ruth; Park, Helen; Luo, Wei; Gitlin, Alexander D.; Kim, Peter; Khatri, Purvesh; Nadeau, Kari C.; Pulendran, Bali; Microbiology and Immunology, School of MedicineDespite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.