In the relentless quest to understand COVID-19’s complex pathology, a groundbreaking study published recently in Nature Microbiology uncovers a pivotal role played by lung macrophages in disease progression and long-term tissue damage. While much attention has been dedicated to the hyperinflammatory states and cytokine storms accompanying severe SARS-CoV-2 infection, this new research reveals that the virus’s ability to induce the formation of lipid-engorged immune cells known as foam cells significantly contributes to pulmonary fibrosis and thrombosis in affected patients.
Macrophages are frontline defenders in the lungs, acting as scavengers that engulf pathogens and coordinate immune responses. This study marks a significant advance by demonstrating that SARS-CoV-2 infection triggers a marked increase in macrophage populations within the lung tissue, coupled with their differentiation into foam cells, a phenomenon typically associated with chronic inflammatory diseases but previously unlinked to coronavirus infections. These foam cells become engorged with lipids, altering their functional state and driving pathological changes in lung microenvironments.
Leveraging a robust experimental design, the researchers utilized an array of models—including humanized mice genetically engineered to mimic human immune function, rhesus macaques, and analyses of post-mortem human lung samples—to provide a comprehensive picture of macrophage dynamics during and after infection. This trio of investigative platforms transparently portrays the consistent phenotypic shift in lung macrophages solely in response to SARS-CoV-2, distinguishing it starkly from infections by closely related viruses such as SARS-CoV-1, MERS-CoV, and even bat-derived coronaviruses like SHC014-CoV or WIV1-CoV.
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Interestingly, traditional beta-coronaviruses with genetic and structural similarities did not incite the macrophage proliferation or foam cell formation observed in SARS-CoV-2 infection, highlighting a unique pathogenic signature. This specificity suggests that particular viral-host interactions exclusive to SARS-CoV-2 drive these aberrant macrophage behaviors, possibly explaining why the lung damage and long-term consequences witnessed in COVID-19 differ fundamentally from other respiratory viral diseases.
At a molecular level, the foam cells identified exhibited a transcriptional profile characterized by upregulation of genes involved in pro-fibrotic and pro-thrombotic pathways. Genes associated with platelet activation, aggregation, extracellular matrix (ECM) organization, and collagen synthesis were notably enriched within these cells. This implies that foam cells directly contribute to the excessive tissue remodeling and clot formation observed in severe COVID-19 cases, thereby establishing a mechanistic link between immune dysfunction and the vascular and fibrotic sequelae that complicate patient recovery.
The persistence of these foam cells in lung tissue post-viral clearance provides key insight into the lingering symptoms experienced by patients suffering from long COVID. Even after the virus is no longer detectable, the elevated numbers of macrophages and ongoing collagen deposition sustain a pro-inflammatory environment, leading to chronic lung fibrosis and microvascular thrombosis. Such findings shine a light on the immune system’s role not only in acute disease but also in mediating long-term pulmonary compromise.
Importantly, the study assessed therapeutic interventions targeting this macrophage-driven pathology. Administration of EIDD-2801, an antiviral agent also known as molnupiravir, either prior to infection or during early stages of disease, effectively curtailed macrophage expansion and foam cell formation. This early antiviral intervention also mitigated markers of fibrosis within lung tissues, underscoring the value of prompt viral suppression not just for controlling virus replication but also for preventing deleterious immune-driven tissue remodeling.
This integrative approach emphasizes that beyond curbing viral load, therapeutic strategies should prioritize modulation of macrophage activity and lipid metabolism within lung immune cells. The pronounced shift in macrophage phenotype toward foam cells appears to be a hallmark of SARS-CoV-2 pathogenesis and a driving force behind fibrotic and thrombotic complications. Thereby, targeted interruption of these processes could form the basis for novel adjunct therapies aimed at reducing morbidity and enhancing recovery in COVID-19 and long COVID patients.
The discovery of foam cell involvement in COVID-19 also opens new avenues for biomarker development. Since these cells express gene signatures linked to ECM remodeling and platelet function, their detection or quantification might serve as a prognostic tool to identify patients at risk of progressing to severe lung fibrosis or thrombosis. Early identification of such patients could inform clinical decisions and tailor interventions more effectively.
Beyond the immediate implications for SARS-CoV-2 research, this phenomenon prompts a reevaluation of macrophage roles in viral pneumonias more broadly. The absence of foam cell formation following infection with other coronaviruses suggests that subtle viral genetic differences may drive distinct immune responses. This indicates a complex interplay between viral proteins, host lipid metabolism, and immune signaling cascades that warrant further investigation to unravel the precise molecular triggers.
The study also has ramifications for understanding post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as long COVID. The sustained presence of foam cells and fibroproliferative signals in lung tissue provide a pathological substrate that likely underpins chronic respiratory symptoms, including breathlessness and reduced lung capacity. This insight stresses the need for monitoring and potentially targeting these immune cell populations in the clinical management of long COVID to alleviate persistent symptoms.
Furthermore, the findings challenge earlier assumptions that the primary culprit in COVID-19 lung pathology is a transient hyperinflammatory cytokine storm. Instead, they highlight a sustained immune cell dysfunction involving altered macrophage lipid metabolism as a core driver of long-term tissue injury. This refined understanding could reshape future research priorities, directing attention toward immunometabolic pathways and their role in disease chronicity.
Notably, the integration of diverse models—humanized mice, macaques, and human tissue—fortifies the translational relevance of these results. The humanized mouse model, in particular, underscores the feasibility of dissecting viral-immune cell interactions in a controlled setting, while the non-human primate and human post-mortem data affirm these findings’ real-world applicability.
The research further underscores the critical window in early infection during which antiviral interventions exert their maximal protective effect. Delayed treatment may fail to prevent foam cell formation and subsequent fibrotic consequences, stressing the urgency of early diagnosis and medical intervention to forestall chronic lung damage.
Looking forward, these discoveries pave the way for potential combination therapies that pair antivirals with agents targeting foam cell formation or macrophage lipid handling. Modulators of lipid metabolism, antifibrotic drugs, or antiplatelet therapies might synergize with antiviral drugs to diminish both viral replication and immune-mediated tissue injury, offering hope for improved outcomes.
In summary, the elucidation of pro-fibrotic and pro-thrombotic foam cell formation in SARS-CoV-2 infection reframes our understanding of COVID-19 pathogenesis. It spotlights macrophages not merely as immune sentinels but as active mediators of disease progression and tissue remodeling. By mapping the cellular and molecular landscapes of these foam cells, this study provides a vital foundation for next-generation interventions designed to mitigate the long-term pulmonary consequences of SARS-CoV-2 infection and combat the growing global burden of long COVID.
Subject of Research: The role of macrophages and foam cell formation in SARS-CoV-2 infection and their contribution to pulmonary fibrosis and thrombosis.
Article Title: SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation.
Article References:
Battaglia, D.M., Post, C.E., Yao, W. et al. SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation. Nat Microbiol (2025). https://doi.org/10.1038/s41564-025-02090-9
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Tags: chronic inflammation and COVID-19experimental models in COVID-19 researchfoam cell formation in COVID-19immune response to coronavirus infectionlipid metabolism in lung macrophageslong-term tissue damage from COVID-19macrophage differentiation in lung tissueNature Microbiology research findingspulmonary fibrosis and thrombosisSARS-CoV-2 effects on macrophagesstudy of COVID-19 pathologyunderstanding COVID-19 immune dynamics
