Infectious disease
Abstract
Studies with a candidate vaccine deleted in glycoprotein D (ΔgD-2) for herpes simplex virus (HSV) prevention uncovered a role for herpes virus entry mediator (HVEM) in mediating antibody-dependent cell-mediated killing (ADCK) of virally-infected cells. Antibodies elicited by ΔgD-2 passively protect wild-type but not Fc gamma receptor (FcγR) or HVEM knockout (KO) mice. The goals of this study were to identify which cells mediate ADCK and the role of HVEM signaling. Using HVEM ligand and conditional cell-type specific HVEM KO mice combined with in vitro mouse and human cytolytic assays, we demonstrate that ADCK of HSV-infected cells is mediated primarily by neutrophils and requires their expression of HVEM and its ligand, LIGHT. Cytolysis is not associated with granzyme and perforin production but occurs by a trogocytosis-like pathway. Pharmacological inhibition of myosin light-chain kinase (MLCK), which mediates trogocytosis, inhibits cytolysis. Similar results were obtained when human neutrophils were cocultured with HSV-infected cells opsonized with ADCK-containing human immune serum or with breast cancer cells treated with an anti-HER2 trogocytosis mediating antibody. Killing was significantly reduced when an MLCK inhibitor or blocking antibodies to CD16a, HVEM, or LIGHT were added. Together these results define a mechanism of HVEM-enhanced FcγR-mediated neutrophil-dependent ADCK of targets cells.
Authors
Matthew S. Gromisch, Masayuki Kuraoka, Carl F. Ware, Steven C. Almo, Betsy C. Herold
Abstract
Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical knowledge gap, we first performed scRNA-seq on gated cell populations and validated CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNγ during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNγ, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.
Authors
Jason Nideffer, Florian Bach, Steven Strubbe, Luis Lopez, Maato Zedi, Felistas Nankya, Jessica Briggs, Kattria van der Ploeg, Kenneth Musinguzi, Soyeon Kim, Aracely Garcia Romero, Arefin Keya, Kylie Camanag, Savannah Lewis, Muhammad Abdelbasset, Bing Wang, Allison Boss, Evelyn Nansubuga, Joaniter I. Nankabirwa, Emmanuel Arinaitwe, Saki Takahashi, Grant Dorsey, Bryan Greenhouse, Isabel Rodriguez-Barraquer, Moses R. Kamya, Rosa Bacchetta, Isaac Ssewanyana, Ashraful Haque, Maria Grazia Roncarolo, Prasanna Jagannathan
Abstract
Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.
Authors
Michihiro Takahama, Krysta S. Wolfe, Gabriella Richey, Madison Plaster, Anna Czapar, Fabian Hernandez, Denis Cipurko, Tatsuki Ueda, Yoshimi Miki, Yuki Nagasaki, Yoshitaka Taketomi, Tatsuya Saitoh, Tadafumi Kawamoto, Steven M. Dudek, Makoto Murakami, Nicolas Chevrier
Abstract
Bacteria-modulated gastric epithelial cells (GECs) play key roles in Helicobacter pylori–associated pathology. Here, we demonstrate both procolonization and proinflammation roles of GEC-derived PPFIA4 in H. pylori infection. PPFIA4 was elevated in GECs from gastric mucosa of H. pylori–infected patients and mice. PPFIA4 could be synergistically induced by H. pylori and IL-33 via the CagA/AP1 pathway. Human gastric PPFIA4 correlated with H. pylori colonization and the severity of gastritis, and H. pylori colonization and inflammation were attenuated in Ppfia4ΔGEC mice. Mechanistically, PPFIA4’s SAM1 domain bound domains from CaMK to the first L27 of CASK and subsequently formed a PPFIA4/CASK/AKT1 complex to activate AKT1, resulting in NF-κB activation and MMP1/CXCL3 secretion. This not only led to decreased E-cadherin and ZO-1 by MMP1, thereby promoting gastric mucosal damage to foster H. pylori colonization, but also resulted in increased gastric influx of G-MDSCs via CXCL3-dependent migration, thereby promoting gastritis and impairing H. pylori–specific IFN-γ–producing CD4+ T cell responses to foster H. pylori colonization. Furthermore, we identified a PPFIA4 inhibitor, kira6, which effectively inhibited GEC’s MMP1/CXCL3 production and ameliorated gastric H. pylori colonization and gastritis. Overall, PPFIA4 could be a promising therapeutic target, as it collectively ensures H. pylori persistence and promotes gastritis.
Authors
Pan Wang, Nan You, Yong-Sheng Teng, Yi-Pin Lv, Wen-Qing Tian, Jing-Yu Xu, Rui Xie, Jiang-Bo Wu, Geng-Yu Yue, Ping Cheng, Jin-Yu Zhang, Liu-Sheng Peng, Fang-Yuan Mao, Shou-Lu Luo, Shi-Ming Yang, Yong-Liang Zhao, Hong Zhou, Weisan Chen, Bin Wang, Yuan Zhuang
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to two glycoproteins: 1) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and 2) the glycoprotein 38 (GP38). By antibody variable gene analysis, we identified genetic diversity in the B cell response to CCHFV within a single donor for both Gc- and GP38-specific responses. Protection against most bunyavirus-associated diseases is mediated principally by neutralizing antibodies, but here, we found that neutralization activity was not associated with protection. Gc-specific antibodies to diverse antigenic sites neutralized only weakly and did not protect against heterologous virus challenge. GP38-specific antibodies bound to two dominant antigenic sites on the glycoprotein. Although GP38-specific antibodies did not neutralize the virus, one mediated protection against heterologous virus challenge in an experimental model of infection in mice primarily by complement-mediated activity. These studies support the model of development of CCHFV countermeasures that induce protection against GP38 in vivo.
Authors
Nathaniel S. Chapman, Viktoriya Borisevich, Nurgun Kose, Luke Myers, Stephen Priest, Éric Bergeron, Elena Trigo Esteban, María Paz Sanchez-Seco, Jose Melero, Thomas Geisbert, Robert W. Cross, James E. Crowe Jr.
Abstract
Despite the success of antiretroviral therapy in controlling HIV replication, latent viral reservoirs persist, presenting a major barrier to a cure. Current treatment approaches that aim to reactivate latent virus and eliminate infected cells, termed “shock and kill,” hold promise but have yet to demonstrate meaningful reservoir reduction in vivo. In this study, we explored combining ciapavir, a Smac mimetic latency-reversing agent, with adeno-associated virus–delivered (AAV-delivered) eCD4-Ig to treat antiretroviral therapy–suppressed, SHIV-infected rhesus macaques. We could demonstrate that a Smac mimetic can induce modest reactivation of the latent SHIV reservoir, as evidenced by transient increases in plasma viremia. However, while AAV-expressed eCD4-Ig conferred partial protection against intrarectal SHIV challenge in uninfected animals, neither eCD4-Ig nor ciapavir reduced the viral reservoir in SHIV-infected rhesus macaques, as determined by total SHIV DNA and a 5-target intact provirus detection assay. Animals treated with the combination showed no significant differences in viral rebound kinetics post–analytical treatment interruption compared with controls. Additionally, repeated ciapavir dosing resulted in adverse effects in some animals, suggesting potential toxicity with repeat administration. These findings highlight the challenges in reducing viral reservoirs using this shock-and-kill approach, particularly in SHIV-infected models, and suggest that further optimization of both latency-reversing agent and immune-mediated clearance strategies is required.
Authors
Lars Pache, John K. Bui, Lindsay M. Klouser, Christine M. Fennessey, Alexander C. Noyola, Teresa Einhaus, Haiying Zhu, Laurence Stensland, Isai Leguizamo, Abubakarr A. Koroma, Peter Teriete, W.L. William Chang, Ollivier Hyrien, Natasha N. Duggan, Dominik Heimann, Ailyn C. Pérez-Osorio, Katharine J. Bar, Nicholas D.P. Cosford, Brandon F. Keele, Dennis J. Hartigan-O’Connor, Michael Farzan, Matthew R. Gardner, Keith R. Jerome, Sumit K. Chanda, Hans-Peter Kiem, Christopher W. Peterson
Abstract
BACKGROUND Sepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes (“hyperinflammatory” and “hypoinflammatory”) have been consistently identified within sepsis via latent class analysis. These phenotypes differ in their biological features, clinical outcomes, and therapeutic responses to interventions. Prior studies of sepsis heterogeneity have focused primarily on the host response. Here, we investigate the potential influence of the causative pathogen on sepsis heterogeneity and pathobiology.METHODS We performed a retrospective observational analysis of 8,280 critically ill patients with sepsis to identify associations between pathogen characteristics and the hyperinflammatory and hypoinflammatory patient phenotypes. We also performed controlled murine and swine modeling of sepsis and lung injury and a secondary analysis of 449 patients enrolled in the EUPHRATES randomized controlled trial.RESULTS Pathogen characteristics (pathogen identity, burden, virulence, and anatomic site of infection) were strongly and independently associated with the previously reported phenotypes. In a cohort of critically ill patients with sepsis, infection with gram-negative pathogens, primarily Enterobacterales spp. (e.g., Escherichia coli, Klebsiella pneumoniae), was strongly associated with the hyperinflammatory phenotype. The hyperinflammatory phenotype was also independently associated with increased pathogen burden, virulence, and initial anatomic site of infection. In controlled murine and swine modeling, both the identity and burden of the pathogen provoked key biological features of the hyperinflammatory phenotype. Among patients with sepsis, the prognostic value of lactate clearance varied substantially by phenotype. In a secondary analysis of a randomized trial of polymyxin B hemoadsorption (which removes circulating endotoxin), hypoinflammatory patients experienced worse survival.CONCLUSIONS Our results demonstrate the central importance of pathogen features in the clinical and biological heterogeneity of sepsis. Future studies of sepsis pathobiology and heterogeneity should expand their scope beyond the host response, as understanding pathogen-host interactions will be crucial in the development of precision therapeutic strategies to improve patient outcomes.TRIAL REGISTRATION EUPHRATES trial NCT01046669.FUNDING 5P30AG024824, IK2CX002766, R01HL144599, K24HL159247, R01HL158626, R01HL173531, R35GM142992, R35GM145330, R35GM136312, K23HL166880, R35HL140026.
Authors
Rishi Chanderraj, Brian Bartek, Kathleen A. Stringer, Mohamad H. Tiba, Michael W. Sjoding, Ying He, Mark Nuppnau, Kale S. Bongers, Mark D. Adame, Sunny S. Lou, V. Eric Kerschberger, Matthew M. Churpek, Carolyn S. Calfee, Sandhya Tripathi, Debra M. Foster, John A. Kellum, Robert P. Dickson, Pratik Sinha
Abstract
Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor–deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN–dependent (IFN-I–dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.
Authors
Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang
Abstract
BACKGROUND. Susceptibility to human immunodeficiency virus type 1 (HIV-1) infection varies between individuals, but the biological determinants of acquisition risk remain poorly defined. METHODS. We conducted a case-control study nested within a high-risk cohort in Kenya. We compared the plasma extracellular RNA collected before HIV-1 acquisition with matched uninfected controls to identify immunological processes linked to infection risk. RESULTS. Individuals who later acquired HIV-1 exhibited upregulation of immune processes that facilitate viral infection, including T cell suppression, type II interferon and Th2 immune responses. In contrast, processes associated with antiviral defence and tissue repair, such as neutrophil and natural killer cell responses, type I interferon responses, wound healing, and angiogenesis, were downregulated. CONCLUSION. These findings highlight dampened antiviral immunity prior to exposure as a correlate of increased risk for subsequent HIV-1 acquisition. TRIAL NUMBERS. Not applicable. FUNDING. This work was supported by a Wellcome Trust Award (209289/Z/17/Z) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through the DELTAS Africa programme [Del-22-007], supported by the Science for Africa Foundation, Wellcome Trust, the UK Foreign, Commonwealth & Development Office, and the European Union. Additional support was provided by the Bill & Melinda Gates Foundation, Gilead Sciences Inc., Aidsfonds, and the Ragon Institute of Mass General, MIT, and Harvard. The cohort study was supported by PEPFAR through USAID. The views expressed are those of the authors.
Authors
Mwikali Kioko, Shaban Mwangi, Lynn Fwambah, Amin S. Hassan, Jason T. Blackard, Philip Bejon, Eduard J. Sanders, Thumbi Ndung'u, Eunice W. Nduati, Abdirahman I. Abdi
Abstract
Prion diseases are a family of transmissible, neurodegenerative conditions caused by mis-folded proteins called prions. Human cerebral organoids can be infected with prions from sporadic Creutzfeldt-Jakob Disease (sCJD) brain tissue. Initial experiments indicated that the cerebral organoids may be able to differentiate biological properties of different sCJD subtypes and, if so, it would be possible to investigate the pathogenic similarities and differences. Herein, we investigated multiple infections of cerebral organoids with two sCJD subtypes, comparing hallmark features of disease as well as neuronal function and health. Our results show that while all infections produced seeding capable PrP, which increased from 90-180 days post infection, a sCJD subtype preference for protease resistant PrP deposition was observed. Both subtypes caused substantial electrophysiological dysfunction in the infected organoids, which appeared uncoupled from PrP deposition. Neuronal dysfunction was associated with changes in neurotransmitter receptors that differed between the subtypes but produced the same outcome of a shift from inhibitory toward excitatory neurotransmission. Further changes indicated shared deficits in mitochondrial dynamics, and subtype influenced alterations in intracellular signaling pathways, cytoskeletal structure, and the extracellular matrix. We conclude that cerebral organoids demonstrate both common mitochondrial deficits and sCJD subtype specific changes in neurotransmission and organoid architecture.
Authors
Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Arielle Hay, Ryan O. Walters, Tina Thomas, Gianluigi Zanusso, James A. Carroll, Cathryn L. Haigh
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ISSN: 0021-9738 (print), 1558-8238 (online)