Immunology
Abstract
Rationale: Persistent monocyte activation contributes to HIV-associated neurocognitive disorders (HAND), yet biomarkers that predict neurocognitive impairment before and after antiretroviral therapy (ART) remain incompletely defined. Objectives: We evaluated monocyte subsets and activation markers in participants from the SEARCH007 cohort prior to ART initiation and at 6 and 12 months following treatment. Methods and Results: Increased frequencies of CD14+CD16+ monocytes and elevated CD163 expression were associated with worsening neurocognitive performance and HAND severity. Plasma soluble CD163 levels increased with neurocognitive impairment and correlated with plasma HIV RNA levels, while CCR2 expression was associated with NPZ Global scores. Notably, CD169 expression was elevated across all monocyte subsets and demonstrated a stepwise increase with worsening neurocognitive impairment. Although ART reduced overall monocyte activation, elevated CD169 expression persisted in some individuals despite virologic suppression. Bayesian kernel machine regression and random forest analyses identified CD169 expression as one of the strongest predictors of cognitive impairment, surpassing plasma viral load, CD4+ T-cell count, and several established monocyte activation markers. Conclusions: These findings identify monocyte CD169 expression as a biomarker of neurocognitive dysfunction before and during the first year of ART and support further investigation of its role in HAND pathogenesis.
Authors
Hai Duc Nguyen, Andrew K. Ding-Su, Caroline Soulas, Tricia H. Burdo, Patrick Autissier, Pasiri Sithinamsuwan, Nitiya Chomchey, Jintanat Ananworanich, Victor Valcour, Silvia Ratto-Kim, Woong-Ki Kim, Kenneth C. Williams
Abstract
Authors
Xiao Yang, Sameen Fatima, Salvador Sampere-Birlanga, Akshay Ware, Mariana Shumliakivska, Lukas Zanders, Srisurekha Radhakrishnan, Guillermo Luxán, David John, Stefan Günther, Silvia Mas-Peiro, Stefanie Dimmeler, Andreas M. Zeiher, Wesley T. Abplanalp
Abstract
Authors
Allen Duong, Sajad Moshkelgosha, Tereza Martinu, Stephen Juvet
Abstract
Mycobacteriumtuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1 (PLWH). This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are not completely understood. To address this knowledge gap, using pleural effusion samples from PLWH and TB, we investigated how the HIV-1 genetic landscape and the anti-HIV-1 immune response are impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell-mediated antiviral response at this site of HIV-1/Mtb coinfection. Moreover, efficient CD8+ T cell activation was inhibited by lipids present in the TB-associated pleural effusion. These findings indicate that this immune microenvironment induced by TB promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in PLWH and TB.
Authors
Samantha Cronin, Jennifer Simpson, Andrea Pereyra-Casanova, Yuchen Li, Josefina Marín-Rojas, Freja A. Warner van Dijk, Katie Fisher, Daniel J. Buffa, Hafsa Rana, Zoï Vahlas, Joaquina Barros, Mariano Maio, Thomas R. O'Neil, Kirstie M. Bertram, Eunok Lee, Najla Nasr, Andrew N. Harman, Gabriela Turk, Maria Florencia Quiroga, Anthony D. Kelleher, Christel Vérollet, Luciana Balboa, Sarah Palmer, Gabriel Duette
Abstract
Plasmodium falciparum sporozoite (PfSPZ) vaccines, comprised of aseptic, purified, live parasites that arrest during or just after liver stage development, show excellent safety and efficacy in humans. They can induce complete protection against Pf infection, mediated primarily by cellular immune responses against parasite antigens expressed in hepatocytes. Current PfSPZ vaccines rely on the West African PfNF54 parasite, which uniquely produces high numbers of PfSPZ in mosquitoes, facilitating manufacturing efficiency. However, PfNF54 has relatively low hepatocyte infectivity, limiting potency. We created hybrid pan-African Pf strains by genetically crossing PfNF54 with East African Pf strains. The hybrid, AV27, was selected for development based on balanced contribution of parental genomes, high PfSPZ production and high liver stage infectivity. As compared to NF54-based PfSPZ vaccines, we expect AV27-based vaccines will have greater and broader efficacy at lower doses due to higher liver stage infectivity and inclusion of unique East African CD8+ T cell epitopes.
Authors
Lucia Pazzagli, Bethany Jenkins, Ankit Dwivedi, Asha Patil, Yonas Abebe, Tales V. Pascini, Urvashi Rai, Priya Gupta, Nastaran Rezakhani, Chakshu Gandhi, Yiwei Yang, Sudhir Kumar, Mohd Kamil, Gigliola Zanghí, Manuel Llinás, Stephen L. Hoffman, Joana C. Silva, Ashley M. Vaughan, B. Kim Lee Sim
Abstract
The glymphatic-meningeal pathway, important for brain homeostasis, depends on the drainage function of the cervical lymphatic system. Although new therapies aim to modulate this pathway, a lack of methods for quantifying lymphatic drainage function hinders our ability to understand how targeting the cervical lymph nodes may benefit brain health. To address this, we developed and applied a fluid transport model to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data to visualize and quantify tracer-tagged lymph through the deep cervical lymph nodes (dcLN). The model incorporated physical principles of solute transport to provide a biologically interpretable framework for analyzing microflows in real-time. We applied this model to investigate the effects of chronic hypertension on dcLN drainage by comparing normotensive Wistar-Kyoto rats with spontaneously hypertensive stroke-prone (SHRSP) rats. In normal rats, the model revealed complex and tortuous lymph streams, of a 200 kDa tracer transported through the sinus system of the dcLN. In contrast, SHRSP rats exhibited significantly altered fluid dynamics, characterized by simpler stream patterns and reduced flow through the dcLN. These findings demonstrated that untreated chronic hypertension adversely affects lymph node drainage function. This provides new insight into impaired lymphatic drainage as a mechanism linking systemic disease to brain health.
Authors
Kaiming Xu, Ankita Bhardwaj, Sunil Koundal, Qin Ren, Chenyu You, Xenophon Papademetris, Helene Benveniste, Tryphon T. Georgiou
Abstract
Bone marrow-derived circulating monocytes continuously replenish intestinal macrophages, which become dysregulated in inflammatory bowel disease (IBD) and contribute to disease pathology. The origins of this dysregulation remain poorly understood. Here, we investigate the reprogramming of circulating monocytes in IBD prior to tissue recruitment using single-cell transcriptomic, epigenomic and functional approaches. We characterise blood monocyte heterogeneity in newly diagnosed, treatment-naïve IBD patients and healthy controls and show that monocytes in Crohn’s disease (CD) display a distinct transcriptional profile and altered distributions across inferred developmental trajectories; less pronounced changes are observed in ulcerative colitis (UC). We link CD-associated transcriptional changes to alterations in chromatin accessibility and identify NFB, EGR, KLF and AP-1 family transcription factors as putative regulators of an inflammatory gene program in blood monocytes from CD patients. We uncover a potential role for IFN- in priming blood monocytes for inflammatory function in CD by limiting their capacity to be regulated by IL-10. Finally, we show that the transcriptional and functional alterations in monocytes from CD patients are maintained in monocyte-derived cells from the intestine. Together these data suggest that intestinal macrophage dysfunction in CD is, at least in part, pre-established by systemic signals prior to tissue recruitment.
Authors
Eve Hornsby, Radha Gadhok, Inva Hoti, Eva Wozniak, James R. Boot, Emma Connick, Paul A Stevens, Holly Creed, Amy Lewis, Andrew Silver, James O Lindsay, Andrew J. Stagg
Abstract
The NF-κB signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-κB subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying previously unreported heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-κB signaling was intact, but induction of inhibitory regulators such as IκBα and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-κB activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-κB feedback control to unchecked inflammation and inflammatory cell death.
Authors
Nadja Lucas, Sophia Weidler, Antonia A. Eicher, Baerbel Keller, Özlem Satirer, Adam Desrochers, Timothy J.S. Ramnarine, Mohammad Mokhtari, Sophie Elstner, Timmy Strauss, Simon W. Mages, Arek Kendirli, Oana Cristina Buzoianu, Tobias B. Haack, Lina Igel, Tim Niehues, Sandra von Hardenberg, Maria Fasshauer, Rami Abou Jamra, Hagen Ott, Ulrike Hüffmeier, Catharina Schütz, Marisa Bijwaard, Susan Wagner, Paulina Switala, Sarah Koss, Jurek Schultz, Stefanie Kretschmer, Jasmin Kümmerle-Deschner, Christine Wolf, Johanna Klughammer, Min Ae Lee-Kirsch
Abstract
Authors
Yudai Miyashita, Taisuke Kaiho, Yuriko Yagi, Taichi Nagano, Xin Wu, Yuanqing Yan, Haiying Sun, Carl Atkinson, GR Scott Budinger, Ankit Bharat, Chitaru Kurihara
Abstract
BACKGROUND Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), but the diagnosis may be missed as kidney biopsies are rarely obtained when acute tubular injury (ATI) is suspected.METHODS The Kidney Precision Medicine Project is a cohort study that obtains kidney biopsies from individuals with AKI, which undergo pathologic and molecular interrogation. We compared ATI and AIN cases among the first 60 AKI participants.RESULTS On clinicopathologic adjudication, 30 patients (50%) had a primary adjudicated diagnosis of ATI, 13 (22%) patients had AIN, 9 (15%) had diabetic nephropathy, and 3 (5%) had other conditions. There were increased interstitial white blood cells and tubulitis (P < 0.05 for both) in AIN compared with ATI. Prior to biopsy, the treating clinician suspected ATI in 83% of the cases with adjudicated ATI, while the treating clinician suspected AIN in 54% of the cases with AIN. Tissue transcriptomic signatures showed enrichment of proinflammatory signaling and increased expression of CXCL9, a chemokine induced by IFN-γ, in myeloid cells of participants with AIN. CXCL9 localized to inflammatory infiltration in spatial transcriptomic data.CONCLUSION Adjudication of kidney biopsies revealed distinct pathologic and molecular profiles between ATI and AIN. Kidney biopsy should be considered more frequently in AKI, as AIN is clinically underrecognized.TRIAL REGISTRATION ClinicalTrials.gov NCT04334707.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937.
Authors
Jennifer A. Schaub, Rajasree Menon, Ricardo Melo Ferreira, Elizabeth Kiernan, Insa M. Schmidt, Christine P. Limonte, Soumya Yennapureddy, Ying-Hua Cheng, Leal Herlitz, Avi Z. Rosenberg, Joel M. Henderson, Kelly D. Smith, Jeffrey B. Hodgin, Edgar Otto, Gilbert W. Moeckel, Lloyd G. Cantley, Suman Setty, Ulysses G.J. Balis, Dawit Demeke, Agnes B. Fogo, Andrew S. Bomback, Vivette D. D’Agati, Isaac E. Stillman, Jose R. Torrealba, Allen R. Hendricks, Erika Bracamonte, Vanessa Moreno, Pavan Bhatraju, Amy K. Mottl, Frank C. Brosius, Bijin Thajudeen, Steven G. Coca, Paul M. Palevsky, Parmjeet S. Randhawa, Raghavan Murugan, Laura Barisoni, Charles E. Alpers, Steven Menez, F. Perry Wilson, Dennis G. Moledina, Michael T. Eadon, Matthias Kretzler, Jonathan Himmelfarb, Chirag R. Parikh, the Kidney Precision Medicine Project
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