Long COVID is increasingly understood as a disease that can persist beyond the respiratory phase of SARS-CoV-2 infection, affecting multiple organs and, in some patients, producing prolonged neurological symptoms. A new study by Tan, Verma, Lowery and colleagues examines how myeloid cells may contribute to neuroPASC—the neurological form of post-acute sequelae of SARS-CoV-2 infection—in mice. Published in Nature Communications, the work uses a longitudinal approach to investigate how immune-cell activity changes over time during the development of virus-associated neurological disease.
NeuroPASC is a broad term covering symptoms such as impaired concentration, memory problems, persistent fatigue, sleep disturbances, headaches, altered sensory processing and mood changes. Although these symptoms are frequently reported after COVID-19, their biological origins remain difficult to define. Researchers have proposed several, potentially overlapping mechanisms, including persistent immune activation, damage to the blood–brain barrier, altered vascular function, viral remnants and disturbances in communication between the nervous and immune systems. The new study focuses on myeloid cells, a major branch of the innate immune system that includes monocytes, macrophages, microglia and related cell populations.
Myeloid cells are among the first immune responders to infection or tissue injury. In the central nervous system, resident microglia continuously survey the environment, remove cellular debris and help regulate neuronal networks. Circulating monocytes and macrophages can also enter or influence the brain when inflammatory signals alter the normally restrictive blood–brain barrier. These cells are essential for host defense, but prolonged or improperly controlled activation can produce inflammatory mediators, reactive oxygen species and other signals capable of disrupting neuronal function. Their effects may therefore depend not only on their abundance, but also on their origin, state and timing.
The longitudinal design is particularly important because immune responses after viral infection are dynamic rather than static. A single examination can show that inflammation is present, but it cannot easily distinguish between an early protective response, a delayed reaction to tissue damage and a persistent process that helps sustain chronic symptoms. By following disease-associated changes over time in a murine model, the investigators sought to track how myeloid-cell populations and their behavior relate to the progression of neuroPASC-like pathology. This type of analysis can reveal whether particular immune states emerge before neurological abnormalities, accompany them or persist after the initial infection has subsided.
In experimental models, researchers can examine tissues and cell populations in considerably greater detail than is usually possible in patients. Techniques such as flow cytometry, immunohistochemistry, transcriptomic profiling and analysis of inflammatory mediators can distinguish resident microglia from infiltrating monocytes and other myeloid subsets. These approaches may also identify changes in gene-expression programs associated with antigen presentation, phagocytosis, interferon signaling, chemokine production or tissue repair. Such molecular signatures are valuable because two myeloid populations that appear similar under a microscope may have very different effects on neural tissue.
The study’s emphasis on myeloid contributions addresses a central question in post-viral neurological disease: whether ongoing symptoms are driven primarily by direct viral damage or by the immune response that follows infection. SARS-CoV-2 can affect tissues outside the lungs, but neurological complications do not require large quantities of replicating virus to remain in the brain. In some circumstances, immune cells may continue responding to residual viral material, damaged tissue or altered signals from peripheral organs. Myeloid cells could act as intermediaries in this process, translating systemic inflammation into changes within the nervous system.
A better understanding of these mechanisms could influence the search for biomarkers and treatments. If specific myeloid-cell states consistently accompany neuroPASC-like disease, their surface markers, secreted molecules or gene-expression profiles might help identify biologically distinct patient groups. Therapeutic strategies could then be designed to reduce harmful inflammation without eliminating the protective functions of microglia and macrophages. Potential approaches might include selectively blocking chemokine pathways, modulating innate immune signaling or promoting the transition from inflammatory activity toward tissue repair. However, findings from mice must be interpreted carefully, because murine immune systems, brain structure and infection responses do not fully reproduce human disease.
The longitudinal perspective also reinforces the possibility that neuroPASC is not a single, uniform condition. Different patients may experience symptoms through different combinations of immune, vascular, metabolic and neurological mechanisms. A myeloid-cell-centered pathway could be especially relevant for some individuals, while other cases may involve autoantibodies, autonomic dysfunction or persistent changes in brain energy metabolism. By defining when and where myeloid responses arise in relation to neurological changes, the research may help clarify why symptoms can continue long after the acute viral illness has ended.
As the scientific community works to explain the long-term consequences of COVID-19, studies that connect immune-cell behavior with disease progression are becoming increasingly important. Tan and colleagues’ analysis places myeloid cells at the center of a timeline linking viral infection, persistent inflammation and neurological dysfunction in a mouse model. The work does not by itself establish that the same cellular sequence occurs in every person with neuroPASC, but it offers a framework for testing that possibility in human samples and clinical studies. Ultimately, mapping the immune events that sustain post-viral brain dysfunction could help move long COVID research from symptom description toward mechanism-based diagnosis and treatment.
Subject of Research: Myeloid cell contributions to murine neuroPASC pathogenesis
Article Title: Longitudinal analysis reveals myeloid cell contributions to murine neuroPASC pathogenesis
Article References: Tan, L., Verma, A.K., Lowery, S. et al. “Longitudinal analysis reveals myeloid cell contributions to murine neuroPASC pathogenesis.” Nature Communications (2026). https://doi.org/10.1038/s41467-026-76156-5
Image Credits: AI Generated
DOI: 10.1038/s41467-026-76156-5
Keywords: neuroPASC, long COVID, SARS-CoV-2, myeloid cells, microglia, neuroinflammation, murine model, post-acute sequelae of COVID-19
Tags: blood-brain barrier damage in COVID-19immune system and nervous system communication disruptioninnate immune response in neurological sequelaeLong COVID neurological symptomslongitudinal immune response in post-viral neurological diseasemicroglia and monocyte involvement in neuroPASCneuroPASC pathogenesis in micepersistent immune activation after SARS-CoV-2 infectionrole of myeloid cells in neuroinflammationSARS-CoVvascular dysfunction in long COVIDviral remnants and neurological symptoms
