Year: 2026
Type: preprint
Study design: Case Report
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 .
Source: medRxiv
Authors: Jian Cui, Colleen M. Roark, Nerea Domínguez-Pinilla, Pilar Nozal Aranda, Begoña Losada, Pilar Zamarrón, Jacob Lorenzo-Morales, José Miguel Rubio Muñoz, Megan M. Dobrose, Ana Van den Rym, Luis M. Allende, Catherine Shelton, Dante E. Reyna, Janet G. Markle, Santiago Rodríguez de Córdoba, Margarita Lopez-Trascasa, Rebeca Pérez de Diego, C. Henrique Serezani, Mariana X Byndloss, Isabel de Fuentes Corripio, Luis Ignacio González-Granado, Ruben Martinez-Barricarte
Institutions: Vanderbilt University, Vanderbilt University Medical Center, Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, Hospital Universitario La Paz, Hospital Universitario de Toledo, Hospital Virgen de la Salud, Universidad de La Laguna, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red Enfermedades Infecciosas, Centro Nacional de Microbiologia, Hospital La Paz Institute for Health Research, Universidad Complutense de Madrid, Centro de Investigaciones Biológicas Margarita Salas, Universidad Autónoma de Madrid, Howard Hughes Medical Institute
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: green
Awards: G107554336, G1149166549, Chemistry-Biology Interface Training Grant, Acquisition of a Focused Ion Beam Scanning Electron Microscope with cryo-stage, G3726302789, G3756376927, G3865556588, Vanderbilt Mouse Metabolic Phenotyping Center, G4320917349, G4513176822, G5338990163, G5853943267, G6546324823, Hyperglycemia and increased severity to Staphylococcus aureus infections., G7220527126, G8658404038, G9000002043, G9000060478, G9000081609, G9000106052, G9000159340, Molecular and Cellular Basis for Digestive Diseases, The role of SERPINB1 in T cell function and its contribution to human diseases, Cancer Center Support Grant, Vanderbilt Diabetes Research Center, Core Grant in Vision Research, Gain-of-function complement activators as a new class of immunotherapeutic molecules
OpenAlex ID: W7127138249