Infectious disease
Abstract
Allergen-specific monoclonal antibodies (mAbs) that block IgE binding to allergens are emerging as new therapeutics for treating allergies to pollen, peanuts, and cats. Alpha-Gal syndrome (AGS) is an allergy to galactose-α-1,3-Galactose (α-Gal), which is present in mammalian meat and tissue-derived products. Initially aiming to identify mAbs targeting α-Gal on malaria parasites, we isolated 42 α-Gal–specific mAbs from B cells of individuals who had been exposed to malaria but found that they bound weakly to the Plasmodium falciparum parasite. These mAbs predominantly used the IGHV3 gene family and had a wide range of mutation frequencies. We then screened these mAbs for their ability to bind α-Gal on AGS allergens and to block the binding of serum IgE of patients with AGS to AGS allergens. Thirteen mAbs bound to the AGS allergens angiotensin-I-converting enzyme (ACE), aminopeptidase-N (AP-N), and cetuximab, and 2 mAbs— AG028 as both IgA2 and IgM, and AG050 IgA1 — blocked the binding of serum IgE from patients with AGS to ACE and AP-N. Additionally, AG028 IgA2 and AG028 IgM suppressed ACE-mediated activation of basophils sensitized with serum of patients with AGS. This study supports the development of α-Gal–specific mAbs as a new intervention to prevent α-Gal allergy.
Authors
Hyeseon Cho, Youngsil Seo, Haewon Sohn, Shailesh K. Choudhary, Jeff Skinner, Ming Zhao, Ludmila Krymskaya, Weizhi Zhong, Justin Lack, Shanping Li, Boubacar Traore, Joshua Tan, Scott P. Commins, Peter D. Crompton
Abstract
Authors
S. Marina Casalino-Matsuda, Vijeeth Guggilla, Catherine A. Gao, Kaitlyn E. DeMeulenaere, Luisa Cusick, Samuel W. Fenske, Zhan Yu, Ziyan Lu, Suchitra Swaminathan, Rogan A. Grant, Maxwell J. Schleck, Murali Prakriya, Sudarshan Hebbar, Kenneth Stauderman, Helen K. Donnelly, Chiagozie I. Pickens, Luisa Morales-Nebreda, The NU SCRIPT Study Investigators, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer, G.R. Scott Budinger
Abstract
Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
Authors
Fang R. Zhao, Maksim Kleverov, Emma S. Winkler, Russell B. Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T. Baldridge, Thaddeus S. Stappenbeck, Larissa B. Thackray, Chyi-Song Hsieh, Scott A. Handley, Chun-Jun Guo, Michael A. Fischbach, Maxim N. Artyomov, Michael S. Diamond
Abstract
Cerebral malaria (CM) from Plasmodium falciparum is a major cause of death in African children. Since bradykinin (BK) is a mediator of vasogenic edema, we hypothesized that it contributes to the pathogenesis of CM in Kenyan children and Plasmodium berghei ANKA (PbA) infected C57BL/6J mice in experimental cerebral malaria (ECM). Cleaved plasma high molecular weight kininogen (cHK) is a marker for BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA-infected mice with ECM had circulating cHK, elevated BK levels, and reduced HK and prekallikrein activity/antigen levels. HK null (Kng1–/–), combined BK B1 and B2 receptor null (Bdkrb1–/–/Bdkrb2–/–), BK B2 (Bdkrb2–/–) or BK B1 (Bdkrb1–/–) receptor null mice were protected significantly from neurologic deterioration and brain edema compared to wild-type mice. F12–/– mice were not protected from neurological deterioration. Prekallikrein null (Klkb1–/–), prolylcarboxypeptidase hypomorphs (Prcpgt/gt), and brain endothelial cell conditional knockout of PRCP (Prcpfl/fl Cre) mice with ECM had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment in PbA-infected mice reversed neurologic deterioration and brain edema and significantly prolonged survival over artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.
Authors
Alessandro S. de Sa Pinheiro, Douglas E. Teixeira, Rodrigo P. Silva-Aguiar, Young Jun Shim, Alona A. Merkulova, Sadiq Silbak, Yelenna Skomorovska-Prokvolit, David Midem, Sidney Ogolla, Bjoern B. Burckhardt, Tanja Gangnus, Julio Scharfstein, Celso Caruso-Neves, Owen J.T. McCarty, David Gailani, Michael Bader, Philip J. Rosenthal, Arlene E. Dent, Chris J. Janse, Keith R. McCrae, Ana Acacia de Sa Pinheiro, James W. Kazura, Alvin H. Schmaier
Abstract
Background. CIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase 2 trial showed that a single dose of CIS43LS conferred >85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other anti-malaria mAbs. Methods. Using 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for anti-drug antibodies and target-mediated drug disposition. A two-compartment, non-linear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy. Results. The median CIS43LS t1/2 was 63.2 days (95%CI 59.4–67.2 days). Serum concentrations ≥64 μg/mL (95%CI 49–93 μg/mL) corresponded to ≥80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations >64 µg/mL in >97.5% of individuals for 4 months, the timeframe for the World Health Organization preferred product characteristics for anti-malaria mAbs. There was no evidence of anti-drug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed. Conclusion. This study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of anti-malaria mAbs in malaria-endemic populations. Trial registration. NCT04329104. Funding. National Institutes of Health and Gates Foundation.
Authors
Tuan M. Tran, Zonghui Hu, Kassoum Kayentao, Aissata Ongoiba, Sam Jones, Nada Abla, Sara A. Healy, Hamidou Cisse, Bickey H. Chang, Jeff Skinner, Leonid Serebryannyy, Sandeep R. Narpala, Robin Schlesinger, Kwang Huei Low, Rachel Kazmierski, Bob C. Lin, Joana Dias, Safiatou Doumbo, Didier Doumtabe, Anne C. Preston, Shanping Li, Mary E. Peterson, Amit Oberai, Adam D. Shandling, Joseph J. Campo, Sean C Murphy, Shinyi Telscher, Emily E. Coates, Edmund V. Capparelli, Amagana Dolo, Boubacar Traore, Robert A. Seder, Peter D. Crompton
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.
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)