{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:15:24Z","timestamp":1782836124163,"version":"3.54.5"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Long-term COVID-19 syndrome (LTCS) or \u201clong COVID\u201d is a debilitating post-viral condition affecting approximately 2%\u20138% of individuals after SARS-CoV-2 infection. It manifests typically \u22653 months post-infection with symptoms persisting for at least 2 months, including fatigue, pulmonary dysfunction, and cognitive impairment, in the absence of alternative diagnoses. The biological mechanisms underlying LTCS remain poorly defined, yet emerging evidence implicates immune dysregulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We profiled plasma antibodies and cytokines from healthy controls (HC,\n                      <jats:italic>N<\/jats:italic>\n                      = 66), convalescents (CONV,\n                      <jats:italic>N<\/jats:italic>\n                      = 24), and LTCS patients (\n                      <jats:italic>N<\/jats:italic>\n                      = 94), followed by multiparametric 14-color flow cytometry of PBMCs from HC (\n                      <jats:italic>N<\/jats:italic>\n                      = 9), CONV (\n                      <jats:italic>N<\/jats:italic>\n                      = 6), and LTCS (\n                      <jats:italic>N<\/jats:italic>\n                      = 23) participants. To gain mechanistic insight, we performed single-cell transcriptomic profiling (scRNA-seq) on PBMCs from HC (\n                      <jats:italic>N<\/jats:italic>\n                      = 8), CONV (\n                      <jats:italic>N<\/jats:italic>\n                      = 6), and LTCS (\n                      <jats:italic>N<\/jats:italic>\n                      = 32) individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LTCS patients exhibited elevated anti-SARS-CoV-2 IgG (spike S1\/RBD\/N) titers compared with HC, but displayed significantly reduced systemic cytokine levels, including IFN-\u03b3, TNF-\u03b1, IL-6, and IL-10. Flow cytometry revealed marked depletion of CD56\n                      <jats:sup>+<\/jats:sup>\n                      CD16\n                      <jats:sup>+<\/jats:sup>\n                      NK cells and CD56\n                      <jats:sup>+<\/jats:sup>\n                      CD3\n                      <jats:sup>+<\/jats:sup>\n                      NKT cells, accompanied by altered T-cell activation states. scRNA-seq confirmed NK type I cell loss and uncovered broad transcriptional reprogramming with upregulation of\n                      <jats:italic>PDCD4<\/jats:italic>\n                      ,\n                      <jats:italic>CHD1<\/jats:italic>\n                      ,\n                      <jats:italic>CXCR4<\/jats:italic>\n                      , and\n                      <jats:italic>SLC7A5<\/jats:italic>\n                      and downregulation of\n                      <jats:italic>TGFBR3<\/jats:italic>\n                      ,\n                      <jats:italic>RIPOR2<\/jats:italic>\n                      , and\n                      <jats:italic>MBNL1<\/jats:italic>\n                      . Gene set enrichment analyses indicated activation of circadian and translational programs and suppression of olfactory receptor, neurotransmitter receptor, and GABA-gated ion-channel pathways. Functional assays validated reduced NK-cell inflammatory capacity in LTCS participants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>LTCS is characterized by systemic cytokine attenuation and a quantitative and functional NK-cell deficit coupled to neurosensory pathway suppression. These findings identify NK cells as key sentinels of LTCS pathophysiology and highlight an NK-centric neuroimmune axis as a promising target for biomarker discovery and therapeutic intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1720551","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:23:06Z","timestamp":1773033786000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulated NK-cell gene expression defines the enduring symptoms of long COVID-19"],"prefix":"10.3389","volume":"17","author":[{"given":"Urvi","family":"Ray","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Research Institute of Women\u2019s Health, University of T\u00fcbingen","place":["T\u00fcbingen, 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