Immunology
Abstract
Post-acute sequelae of SARS-CoV-2 (PASC) occurs in subsets of individuals, including those with pre-existing lung disease. To investigate PASC pathogenesis and therapeutics in a chronic bronchitis mouse model (Scnn1b-Tg), Scnn1b-Tg and WT mice were inoculated with a mouse adapted SARS-CoV-2 virus (SARS-CoV-2MA10) and followed for 60 days. Viral titer, histology, immunohistochemistry (IHC), single-cell RNA sequencing, RNA in situ hybridization, and spatial transcriptomic profiling characterized disease pathologies. Scnn1b-Tg mice inoculated with SARS-CoV-2MA10 exhibited lower viral titers and less weight loss than WT mice. Airway epithelia of Scnn1b-Tg mice were less infected than epithelia of WT mice, reflecting increased airway mucus and enhanced epithelial antiviral activities in Scnn1b-Tg mice. However, Scnn1b-Tg mice subsequently exhibited heterogeneous airway and parenchymal disease with elevated Il33 expression characteristic of human eosinophilic pneumonia. Cohorts of infected mice were administered a monoclonal antibody targeting the IL-33 receptor (ST2) or enteral prednisone. Administration of an anti-ST2 monoclonal antibody mitigated development of eosinophilic pneumonia while enteral prednisone suppressed IL33 expression and disease. The eosinophilic pneumonia in Scnn1b-Tg mice after SARS-CoV-2MA10 infection mimics reports of eosinophilic pneumonia in humans post-SARS-CoV-2, suggesting targeting of IL-33 may be beneficial in treating post-viral eosinophilic pneumonia in humans.
Authors
Padraig E. Hawkins, Sarah R. Leist, Hong Dang, Minako Saito, Lisa C. Morton, Rodney C. Gilmore, Stephen A. Schworer, Ella F. Burns, Jason R. Rock, Robert S. Hagan, James J. Pestka, Alexandra Schäfer, Kenichi Okuda, Lauren K. Heine, Jack R. Harkema, Wanda K. O'Neal, Alessandra Livraghi-Butrico, Raymond J. Pickles, Ralph S. Baric, Richard C. Boucher
Abstract
Extracellular vesicles (EVs)-mediated inter-organ communication represents a promising frontier in transplant immunology; however, its role in cardiac allograft rejection remains poorly characterized. We performed proteomic profiling of plasma-derived EVs in a rat heterotopic heart transplantation model and identified a distinct liver-predominant protein signature during acute rejection, with Antithrombin III (ATIII) emerging as a top candidate. Functional validation revealed that pharmacological EV inhibition intensified systemic and intragraft inflammation, whereas adeno-associated virus (AAV)-mediated silencing of hepatic ATIII directly accelerated allograft rejection. Conversely, AAV-mediated hepatocyte-specific ATIII overexpression attenuated rejection pathology, reduced immune cell recruitment, and markedly prolonged median graft survival. This protective effect was achieved without evidence of coagulopathic complications, indicating an immunomodulatory mechanism beyond ATIII’s canonical anticoagulant function. Mechanistically, ATIII overexpression was associated with upregulation of heme oxygenase-1 (HO-1) in the liver and suppression of proinflammatory cytokine expression in the graft. These findings highlight hepatocyte-derived EVs as important mediators of a liver-heart signaling axis in transplant rejection, and further implicate the protein ATIII as a contributor to this axis. Our study reveals a therapeutically targetable liver-heart signaling axis in transplant rejection, whereby enhancing liver-derived ATIII or its downstream pathways (such as HO-1) could attenuate acute cardiac allograft rejection.
Authors
Shiyu Dai, Wei Zhou, Fangyu Chen, Huanyu Zhang, Zhenchun Ji, Xuejing Zong, Wanruo Zhang, Jie Hu, Shumin Jiang, Fei Wang, Zhenya Shen
Abstract
Vaccine development for tuberculosis is a global priority. Our studies using Collaborative Cross (CC) mice show that genetic diversity influences the efficacy of BCG, the most widely used TB vaccine. BCG vaccination of CC042 mice reduced their lung bacillary burden and increased their survival following low-dose aerosol Mycobacterium tuberculosis infection (MTBI), despite impaired T cell trafficking due to a defective Itgal gene. BCG vaccination conferred early bacillary control which appeared to be independent of B cell or T cell recall responses following MTBI. In contrast, long term survival of BCG-vaccinated CC042 mice after MTBI required T cells. Thus, CC042 mice reveal two phases of immunity induced by BCG: an early phase mediated by innate immunity or innate-like T cells and a later phase mediated by conventional memory CD4 and/or CD8 T cells. Although measurement of vaccine-induced protection 30 days after MTBI is a standard measure of vaccine efficacy in the TB model, this time point might be independent of memory T cells in CC042 mice. Our results suggest that vaccine-elicited innate/innate-like responses could have a larger role in protection than previously considered. The concordance between lung CFU, pathology, and survival make CC042 mice useful for mechanistic studies on vaccine-induced immunity.
Authors
Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Anthony V. Tran, Gillian L. Beamer, Samuel M. Behar
Abstract
It is necessary for naïve CD8 T cells to be actively maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation during homeostasis. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection, and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is decreased. In mice, this is associated with a loss of metabolic quiescence and reduced capacity to accumulate following infection. Our data highlight the role of metabolic regulation in CD8 T cell quiescence and identifies a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.
Authors
Molly E. Lumnitzer, Stefanie F. Valbon, Stephanie A. Condotta, Allison E. Norlander, Sheng Liu, Jun Wan, Martin J. Richer
Abstract
Polymorphonuclear neutrophils (PMNs) serve as frontline defenders against injury and infection, eliminating pathogens and initiating mucosal tissue repair. However, excessive PMN transepithelial migration (TEpM) contributes to chronic mucosal inflammatory disorders, including inflammatory bowel disease. PMN pro-inflammatory and pro-repair functions are regulated by incompletely defined signaling cascades involving kinases and phosphatases. Here, we determined how the protein tyrosine phosphatase CD45/PTPRC regulates PMN trafficking and effector functions in the gut. Pharmacologic inhibition of CD45 significantly reduced PMN colonic TEpM in vitro and in vivo and decreased intestinal PMN trafficking was observed in transgenic mice with PMN-specific deletion of CD45 (MRP8-Cre;Cd45fl/fl). Beyond limiting TEpM, CD45 depletion impaired key antimicrobial functions, including degranulation and phagocytosis, indicating broader effects on PMN effector activity. Importantly, recovery from dextran sodium sulfate (DSS)–induced colitis and biopsy-induced colonic wounding was delayed in MRP8-Cre;Cd45fl/fl mice, linking altered PMN function to defective mucosal healing. Mechanistically, CD45 depletion reduced surface expression of the β2 integrin CD11b/CD18 and inactivated the Src family kinase member Lyn. Together, data highlight an important CD45–CD11b–Lyn signaling axis that regulates PMN trafficking and effector functions in the intestine and identify CD45 as a promising target for modulating PMN function to promote mucosal tissue repair.
Authors
Jael Miranda, Dylan J. Fink, Zachary S. Wilson, Roland Hilgarth, Asma Nusrat, Charles A. Parkos, Jennifer C. Brazil
Abstract
Authors
Aneri Shethji, Theresa Hutchins, Anwesha Sanyal, Tianhao Liu, Wei Chen, Kathryn S. Torok
Abstract
Authors
Erin M. Dickey, Harper M. Marsh, Camilla Rydberg-Millrud, Haleh Amirian, Karthik Rajkumar, Manan Patel, Andrew Adams, Anuroop Allena, Kevin Van der Jeught, Nipun Merchant, Peter J. Hosein, Anna Bianchi, David Liberg, Jashodeep Datta
Abstract
The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type–specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.
Authors
Abhijeet S. Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily Dale, Flavia Goche, Thanh Thanh Le Nguyen, Mastura Akter, FangFang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A. Jewanee, Anthony D. Umpierre, Dale B. Bosco, Koichiro Haruwaka, Rajan Sah, Long-Jun Wu
Abstract
Authors
Peter Dimitrion, Jesse Veenstra, Deangelo Ferguson, Ping Wang, Jeffrey Cruz, Tasneem F. Mohammad, Ian Loveless, Aamir Siddiqui, Iltefat H. Hamzavi, Li Zhou, Indra Adrianto, Qing-Sheng Mi
Abstract
Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8+ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP (Slc10a1), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1, Slco1a4, and Slco1b2, responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8+ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8+ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.
Authors
Felix Clemens Richter, Zsofia Keszei, Csilla Viczenczova, Maximilian Baumgartner, Henrique G. Colaço, Magdalena Siller, Lisa Holnsteiner, Hatoon Baazim, Anna Hofmann, Aubrey Burrett, Anna Schönbichler, Lukas Endler, Joel Xu En Wong, Laura Antonio-Herrera, Oleksandr Petrenko, Fabian Amman, Jakob-Wendelin Genger, Claudia D. Fuchs, Hubert Scharnagl, Hanns-Ulrich Marschall, Thomas Reiberger, Karl S. Lang, Clarissa Campbell, Michael Trauner, Andreas Bergthaler
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