{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T09:47:05Z","timestamp":1770284825573,"version":"3.49.0"},"posted":{"date-parts":[[2026,2,2]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Primary amoebic meningoencephalitis (PAM) is a rapidly progressive and often fatal central nervous system infection caused by\n                    <jats:italic>Naegleria fowleri<\/jats:italic>\n                    . Despite widespread environmental exposure to this free-living amoeba, clinical disease is rare, suggesting that it requires not only exposure to the amoeba but also a host vulnerability. Yet, the immune mechanisms controlling protection vs. susceptibility to\n                    <jats:italic>N. fowleri<\/jats:italic>\n                    remain poorly understood.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted comprehensive clinical, immunological, and genetic investigations in one of the few survivors of PAM. We performed high-dimensional immune profiling using Cytometry by Time-Of-Flight (CyTOF) to assess immune cell composition and activation state. We employed whole-exome sequencing (WES) to identify rare genetic variants that affect host responses. Functional immune assays were used to assess serum-mediated amoebicidal activity\n                    <jats:italic>in vitro<\/jats:italic>\n                    and to characterize key host defense pathways.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    A previously healthy pediatric patient was diagnosed with PAM. Contrary to other cases, her clinical course lasted for more than 2 months before she recovered with miltefosine treatment. Immunologic evaluation showed this patient had normal numbers and frequencies of major lymphoid and myeloid immune cells. WES revealed a homozygous deletion in the complement component 2 (C2) gene, resulting in a complete absence of circulating C2 protein and abolishing classical complement pathway activity. Normal human serum induced complement-mediated lysis of\n                    <jats:italic>N. fowleri<\/jats:italic>\n                    trophozoites in vitro, whereas complement-depleted normal human serum and serum from our patient both failed to deposit membrane attack complex (MAC) or kill\n                    <jats:italic>N. fowleri<\/jats:italic>\n                    . MAC deposition and amoebicidal activity were restored by supplementing the patient\u2019s serum with purified human C2 protein.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    Our study demonstrates that PAM can be caused by a monogenic inborn error of immunity (IEI) and that the complement system is critical for human immunity against\n                    <jats:italic>Naegleria fowleri<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.31.26345168","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:35:18Z","timestamp":1770060918000},"source":"Crossref","is-referenced-by-count":0,"title":["Primary Amoebic Meningoencephalitis caused by Complement C2 Deficiency"],"prefix":"10.64898","author":[{"given":"Jian","family":"Cui","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen M.","family":"Roark","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"name":"Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nerea","family":"Dom\u00ednguez-Pinilla","sequence":"additional","affiliation":[{"name":"Pediatric Hematology and Oncology Unit. University Hospital 12 de Octubre. Research Institute Hospital 12 Octubre (imas12). Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8981-4312","authenticated-orcid":false,"given":"Pilar","family":"Nozal Aranda","sequence":"additional","affiliation":[{"name":"Department of Immunology, La Paz University Hospital, Madrid, Spain"},{"name":"Complement Alterations in Human Pathology Group, La Paz Institute of Biomedical Research, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bego\u00f1a","family":"Losada","sequence":"additional","affiliation":[{"name":"Pediatric Unit, University Hospital of Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Zamarr\u00f3n","sequence":"additional","affiliation":[{"name":"Microbiology service, Hospital Virgen de la Salud, Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"Lorenzo-Morales","sequence":"additional","affiliation":[{"name":"University Institute of 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