2. Academic Validation
  3. Primary Amoebic Meningoencephalitis caused by Complement C2 Deficiency

Primary Amoebic Meningoencephalitis caused by Complement C2 Deficiency

  • medRxiv. 2026 Feb 2:2026.01.31.26345168. doi: 10.64898/2026.01.31.26345168.
Jian Cui 1 2,  Colleen M Roark 1 2,  Nerea Domínguez-Pinilla 3,  Pilar Nozal Aranda 4 5,  Begoña Losada 6,  Pilar Zamarrón 7,  Jacob Lorenzo-Morales 8 9 10,  José Miguel Rubio Muñoz 11,  Megan M Dobrose 1 2,  Ana Van den Rym 12,  Luis M Allende 13 14 15,  Catherine Shelton 2 16,  Dante E Reyna 2 17,  Janet G Markle 1 2 16 18 19,  Santiago Rodríguez de Córdoba 20,  Margarita Lopez-Trascasa 5 21,  Rebeca Pérez de Diego 12,  C Henrique Serezani 2 16 17 18,  Mariana X Byndloss 2 16 22,  Isabel de Fuentes Corripio 23,  Luis Ignacio González-Granado 15 24,  Ruben Martinez-Barricarte 1 2 16 18 19
Affiliations

Affiliations

  • 1 Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2 Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3 Pediatric Hematology and Oncology Unit. University Hospital 12 de Octubre. Research Institute Hospital 12 Octubre (imas12). Madrid, Spain.
  • 4 Department of Immunology, La Paz University Hospital, Madrid, Spain.
  • 5 Complement Alterations in Human Pathology Group, La Paz Institute of Biomedical Research, Madrid, Spain.
  • 6 Pediatric Unit, University Hospital of Toledo, Spain.
  • 7 Microbiology service, Hospital Virgen de la Salud, Toledo, Spain.
  • 8 University Institute of Tropical Diseases and Public Health of the Canary Islands, University of La Laguna, La Laguna, Spain.
  • 9 Department of Pediatric Obstetrics and Gynecology, Pediatrics, Preventive Medicine and Public Health, Toxicology, Legal Medicine, Forensics and Parasitology, University of La Laguna, La Laguna, Spain.
  • 10 CIBER on Infectious Diseases (CIBERINFEC), Carlos III Health Institute, Madrid, Spain.
  • 11 Malaria & Emerging Parasitic Diseases Laboratory, Parasitology Department, National Microbiology Centre, Carlos III Health Institute, Majadahonda, Spain.
  • 12 Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain.
  • 13 Department of Immunology, University Hospital 12 de Octubre, Madrid, Spain.
  • 14 Research Institute Hospital 12 Octubre (imas12), Madrid, Spain.
  • 15 School of Medicine, Complutense University of Madrid, Madrid, Spain.
  • 16 Vanderbilt Institute of Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 17 Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
  • 18 Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 19 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 20 Genetic and Molecular Complement Diagnostic Laboratory, Center for Biological Research Margarita Salas, Madrid, Spain.
  • 21 Department of Medicine, Autonoma University of Madrid, Madrid, Spain.
  • 22 Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 23 Toxoplasmosis and intestinal protozoan unit, Referral and investigation lab in parasitology, National Center of Microbiology, Carlos III Health Institute. Majadahonda, Spain.
  • 24 Department of Pediatrics, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12). Madrid, Spain.
PMID: 41674601 DOI: 10.64898/2026.01.31.26345168
Abstract

Background: Primary amoebic meningoencephalitis (PAM) is a rapidly progressive and often fatal central nervous system Infection caused by Naegleria fowleri. 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. fowleri remain poorly understood.

Methods: 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 in vitro and to characterize key host defense pathways.

Results: 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. fowleri 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. fowleri. MAC deposition and amoebicidal activity were restored by supplementing the patient's serum with purified human C2 protein.

Conclusion: 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 Naegleria fowleri.

Keywords

Inborn error of immunity (IEI); Naegleria fowleri; Primary amoebic meningoencephalitis (PAM); complement C2 deficiency; complement system; innate immunity.

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