Primary Amoebic Meningoencephalitis caused by Complement C2 Deficiency

BackgroundPrimary 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. MethodsWe 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. ResultsA 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 patients serum with purified human C2 protein. ConclusionOur 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.