Neutrophils, known as the first responders of the innate immune system, rapidly infiltrate infected lung tissue during respiratory viral infections, where they exert both protective and potentially damaging effects. Until now, the scientific consensus predominantly held that these cells either proliferated within the lung microenvironment or were mobilized from the bone marrow. However, Prof. Cao’s team systematically analyzed immune cell kinetics in a SARS-CoV-2-infected golden hamster model, discovering that the spleen plays a critical and previously underappreciated role in neutrophil generation and trafficking.

Extensive single-cell RNA velocity profiling revealed a linear developmental trajectory within the lung neutrophil populations post-infection, beginning from proliferative precursors through immature and mature states to fully activated neutrophils. Yet, local proliferation in the lung failed to produce sufficient neutrophils to account for the marked infiltration observed at the infection peak. Intriguingly, a synchronous rise in splenic neutrophil numbers was recorded around days five to seven post-infection, coinciding tightly with the surge seen in the lung, suggesting a causative link.

To further unravel this inter-organ relationship, the researchers compared transcriptomic profiles of neutrophil subsets across the lung and spleen. They noted three conserved major subpopulations — proliferative, non-activated, and activated neutrophils — exhibiting strikingly similar gene expression signatures in both tissues. This powerful insight hinted strongly that splenic neutrophils, proliferating robustly during infection, were primed to migrate to the lung, replenishing its cellular repertoire and supporting immune function.

The team harnessed spatial transcriptomic techniques alongside the Redeconve deconvolution algorithm to map these neutrophils back to precise lung microenvironments. This innovative spatial analysis demonstrated that between days five and seven post-infection, splenic-origin neutrophils constituted a significant fraction of the lung’s neutrophil population — in some cases matching or surpassing that of locally derived cells. Notably, no similar migratory patterns were identified for other immune cells, underscoring the unique role of the spleen regarding neutrophil trafficking.

Temporal dynamics further illuminated the spleen-lung communication axis. Early-stage proliferative neutrophils emigrated from the spleen to the lung by day five, while subsequent influxes predominantly comprised immature and mildly activated neutrophils by day seven. This sequential migration suggests a continuous splenic contribution, supplying neutrophils at different developmental stages tailored for effective antiviral activities within the inflamed pulmonary tissue.

Mechanistically, this directional trafficking adheres to a complex chemokine-receptor signaling code. The lungs at infection peak overexpressed several neutrophil-attracting chemokines, including CXCL5, CXCL12, and CCL11, secreted respectively by epithelial cells, macrophages, and fibroblasts. Correspondingly, splenic neutrophil subsets exhibited distinct receptor profiles — immature neutrophils expressing CXCR4 primarily respond to CXCL12, while mature neutrophils upregulate CXCR2, CCR1, and CCR3, receptors for CXCL5 and CCL11. This ligand-receptor matching provides a biochemical roadmap facilitating precise, stage-specific recruitment from spleen to lung.

This discovery challenges the orthodox paradigm that views the bone marrow as the exclusive reservoir for neutrophil supply during pulmonary infections. Instead, the spleen emerges as an essential extramedullary niche harboring a dynamic pool of neutrophils ready for deployment. These findings have profound implications for understanding immune mobilization and inter-organ coordination in inflammation and infection.

Professor Cao emphasized that this spleen-lung axis elucidates the intricate systemic orchestration of innate immunity, offering novel conceptual frameworks for immunological research. The inter-organ dialogue between spleen and lung shaped by chemokine signals refines the spatial and temporal dimensions of immune responses and raises important questions about similar mechanisms in other infections and inflammatory conditions.

From a clinical perspective, modulation of this neutrophil trafficking axis may pave the way for innovative therapeutic strategies. Excessive neutrophil recruitment is a hallmark of severe viral pneumonias, including COVID-19, where it contributes to lung injury and respiratory failure. Targeting specific chemokine-receptor interactions involved in spleen-to-lung signaling may provide keener control over inflammatory cell influx, balancing protective immunity with tissue preservation.

Equally significant, this research introduces potential diagnostic biomarkers identifying splenic neutrophil activation states or chemokine gradients that could predict disease progression or therapeutic responses. The integration of single-cell and spatial multi-omics represents a powerful technology platform to discern such immune axes across diseases, offering a path toward precision medicine in infectious and inflammatory lung disorders.

In summary, this pioneering study uncovers a critical spleen-to-lung neutrophil axis instrumental in orchestrating antiviral defense during respiratory infection. The convergence of cutting-edge single-cell transcriptomics, spatial mapping, and functional analysis reshapes the understanding of systemic immune cell trafficking, providing exciting opportunities for both fundamental research and clinical translation in pulmonary medicine.

Subject of Research: Animals

Article Title: Single-cell spatiotemporal mapping reveals a spleen-to-lung neutrophil axis in antiviral defense

News Publication Date: 11-Mar-2026

References: DOI: 10.1007/s44466-026-00030-8

Image Credits: Professor Xuetao Cao, Chinese Academy of Medical Sciences, Beijing, China

Keywords

Neutrophil trafficking, spleen-to-lung axis, antiviral immunity, single-cell RNA velocity, spatial transcriptomics, SARS-CoV-2 infection, chemokine signaling, innate immunity, pulmonary inflammation, immune cell migration, extramedullary hematopoiesis, immunotherapy.

Sorek’s research leverages state-of-the-art bioinformatics tools to scan microbial genomes for genetic signatures indicative of antiviral activity. By meticulously combining these computational predictions with laboratory validation, his team was able to confirm more than fifty distinct bacterial defense systems. These systems operate by detecting and neutralizing viruses known as bacteriophages, which prey upon bacterial cells. This monumental screen not only cataloged an unprecedented number of such systems but also broadened the landscape of microbial immunity, revealing bacteria as a critical reservoir of antiviral innovations.

Central to the significance of Dr. Sorek’s work is the discovery that certain bacterial defense pathways share evolutionary roots with components of the human immune system. Among the most striking findings was the identification of the cGAS-STING pathway, a crucial mammalian antiviral mechanism, as evolutionarily conserved from its original role in bacterial defense against phage infection. This revelation bridges a deep biological connection between prokaryotic defense strategies and the innate immunity of complex organisms, suggesting that the human immune system’s ability to detect viral DNA partly emerged from bacterial ancestors.

The methodology underpinning this discovery involved an iterative process of computational predictions and experimental screenings. The initial genomic scans identified candidate genes with potential antiviral properties. Subsequently, these genes were systematically cloned and expressed in bacterial strains to test their capacity to confer resistance to phage infections. This integrated approach allowed the validation of numerous novel defenses and opened new avenues for understanding microbial immunity’s molecular underpinnings.

Beyond its fundamental biological insights, Sorek’s work has practical implications, particularly in the development of novel antiviral therapeutics. Some of the small molecules and defense proteins characterized by his lab have shown promising antiviral properties and are currently being evaluated in clinical settings. These developments hint at a future where antiviral drugs inspired by bacterial defense systems could combat a variety of human viral diseases, representing a revolutionary translation of bacterial immunity into human medicine.

Esteemed members of the scientific community herald Dr. Sorek’s discoveries as transformative. Geraldine Seydoux, a leading figure in molecular biology, expressed that this research “greatly expanded our understanding of bacterial antiviral immunity” and emphasized how these basic science insights have “paved the way for new antiviral therapies.” Allan Spradling, chair of the Gruber Prize Genetics Selection Board, noted that uncovering the conservation of immune defense systems across domains of life “reshapes our understanding of immune evolution and opens up unprecedented therapeutic possibilities.”

Dr. Sorek’s work epitomizes the power of combining computational and experimental biology to tackle longstanding questions in genetics and immunology. His team’s wide-scale genomic analyses involved processing vast datasets of bacterial sequences, applying machine learning algorithms to detect patterns indicative of defense mechanisms. This integration of big data with bench science epitomizes modern genetics research, demonstrating how interdisciplinary approaches can accelerate discovery.

Moreover, the evolutionary insights gleaned from this research challenge traditional views of immunity. The notion that critical aspects of human antiviral response trace their origins to primitive bacterial systems underscores the deep interconnectedness of life’s evolutionary history. It suggests that the battle between bacteria and their viruses has not only shaped microbial communities but has also influenced the fundamental principles underpinning vertebrate immunity.

The identification of numerous novel bacterial defense pathways also fuels new questions about microbial ecology and evolution. Understanding how these systems function and interact within complex bacterial populations can shed light on how microbial communities maintain resilience against viral predation. This knowledge has implications for a broad range of fields, from biotechnology to infectious disease control.

Dr. Sorek’s recognition with the $500,000 Gruber Genetics Prize honors decades of meticulous work that has peeled back layers of microbial defense complexity. His discoveries highlight the untapped potential residing within bacterial genomes, serving as a testament to the wealth of biological innovation existing beyond traditional model organisms. The prize ceremony later this year will celebrate these achievements and underline the importance of uncovering nature’s antiviral arsenal.

Looking forward, the advancements catalyzed by Dr. Sorek’s research inspire optimism for combating viral diseases through novel mechanisms. By harnessing bacterial defense proteins and molecules, future antiviral strategies might circumvent common viral resistance mechanisms, offering more effective and durable treatments. This promising horizon underscores the vital role fundamental research plays in driving translational medical breakthroughs.

As the scientific world digests the implications of these findings, Dr. Sorek’s work stands as a beacon of modern genetic research’s capacity to reveal hidden biological connections across life’s domains. His discoveries provide not only a deeper comprehension of bacterial and human immunity but also open expansive prospects for innovative approaches to viral defense, with far-reaching impact on human health.

Subject of Research: Immune defense mechanisms in bacteria and their evolutionary connection to human innate immunity

Article Title: Not specified

News Publication Date: 2025

Web References: www.gruber.yale.edu

Keywords: Molecular biology, bacterial immunity, antiviral defense, cGAS-STING pathway, phage infection, innate immunity, computational genomics, experimental microbiology

At the heart of this discovery is the protein Argonaute 2 (AGO2), a key effector in the RNAi pathway that normally modulates gene expression post-transcriptionally in the cytoplasm. Intriguingly, the influenza virus manipulates AGO2 to relocate into the cell nucleus—a location where this protein rarely operates under normal physiological conditions. This nuclear relocalization enables the virus to strategically silence genes essential for the activation of type I interferons, molecules critical for initiating antiviral defense signals in neighboring uninfected cells.

Type I interferons act as alarm substances, orchestrating the immune system’s preparedness to viral invasion by enhancing the antiviral state of cells. By dampening the expression of interferon-related genes through AGO2’s aberrant activity within the nucleus, the influenza virus effectively muffles these alarm signals, blunting the host’s immune alert system and facilitating unchecked viral replication. This finding unveils a previously unanticipated nuclear function of AGO2 exploited by the virus, challenging traditional views of RNAi localization and immune modulation.

Key experiments demonstrated that AGO2 is ferried into the nucleus alongside the tumor suppressor protein p53, which is well-known for its role in DNA damage responses and transcriptional regulation. Once inside the nucleus, AGO2 associates directly with chromatin regions that regulate interferon gene expression, functioning as a repressive factor. This interaction effectively turns off critical immune genes, thereby sabotaging the cellular defense mechanisms at a genetic level.

The implications of this study extend beyond virology into the broader understanding of RNAi dynamics, as it reveals that RNAi effectors like AGO2 can be co-opted to influence nuclear gene transcription under pathological stress. The influenza A virus ingeniously manipulates this dual role of AGO2 to subvert host immunity, highlighting the sophistication of viral-host interactions evolved over millennia.

Prompted by these insights, the team investigated whether disrupting the virus’s ability to commandeer AGO2 would restore immune function and inhibit viral propagation. Encouragingly, the researchers employed arsenic trioxide (ATO), a drug already in clinical use for acute promyelocytic leukemia, hypothesizing that it could interfere with AGO2’s nuclear functions. Treatment with ATO in both cultured cells and infected mice resulted in a marked increase in type I interferon production and a concomitant decrease in viral load within the lungs, underscoring the therapeutic potential of targeting host pathways rather than viral components alone.

This approach signifies a paradigm shift in antiviral strategies, focusing on reinforcing endogenous cellular defenses instead of directly attacking the virus—a tactic that could circumvent common issues of antiviral resistance. By modulating RNAi machinery, specifically AGO2’s nuclear activity, it may be possible to develop broad-spectrum antivirals effective not only against influenza but potentially other RNA viruses with similar immune evasion strategies.

One of the senior authors, Aishe Sarshad, an associate professor of cellular and molecular biology at the University of Gothenburg’s Sahlgrenska Academy, emphasized the novelty of these findings: “It was astonishing to observe how influenza virus hijacks such a fundamental and finely tuned system as RNA interference—especially within the nucleus where AGO2’s regulatory roles have been largely uncharted until now.”

Beyond the molecular discoveries, the study expands the landscape of immunological research by demonstrating a novel viral mechanism that suppresses innate immune signaling pathways at the transcriptional level. This adds a critical piece to the puzzle of how influenza A evades immune detection and persists within the host environment, contributing to its global burden of seasonal epidemics and pandemics.

The collaborative work, much of which was conducted by postdoctoral researcher Hsiang-Chi Huang, delineates the detailed molecular interplay between AGO2, p53, and interferon-related genes, revealing a complex network exploited by viral infection. This intricate interplay not only suppresses antiviral responses but may also influence viral pathogenicity and disease severity.

Looking forward, the research team intends to explore whether similar nuclear hijacking of AGO2 or related RNAi components occurs in infections by other RNA viruses, which could open avenues for a universal antiviral therapy approach. The possibility of manipulating the host’s own RNAi mechanisms to augment immunity against diverse viral pathogens underscores the significance of this discovery.

In conclusion, this study pioneers a novel understanding of influenza A virus-host interactions, identifying nuclear AGO2 as a critical player in viral immune evasion and demonstrating the therapeutic promise of arsenic trioxide in restoring immune function. These findings could revolutionize antiviral treatment paradigms, shifting the focus toward modulation of host gene regulatory systems in the battle against viral diseases.

Subject of Research: Animals

Article Title: Nuclear AGO 2 Supports Influenza A Virus Replication through type-I interferon regulation

News Publication Date: 12-Apr-2025

Web References: http://dx.doi.org/10.1093/nar/gkaf268

Image Credits: Photo: Johan Wingborg (Aishe Sarshad and Davide Angeletti, Sahlgrenska Academy at the University of Gothenburg)

Keywords: Influenza A virus, AGO2, RNA interference, type I interferons, immune evasion, arsenic trioxide, antiviral therapy, nuclear gene regulation, p53, RNA viruses, host-pathogen interaction