Introduction: The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. Most individuals carry S. aureus asymptomatically, but only a minority develop life-threatening disease. Severe staphylococcal disease can result from single-gene inborn errors of immunity (IEIs). We aim to elucidate the human genetic etiologies of life-threatening staphylococcal disease.
Methods: A 1.5-year-old boy from a consanguineous family was hospitalized for sepsis due to a necrotizing pneumonia and concurrent bacteremia with S. aureus. His disease was clinically accompanied by a macrophage-activating-like syndrome. Because of a suspicion of an IEI, whole-exome sequencing (WES) was performed.
Results: A panel-based analysis for known IEIs was negative, but an open analysis of the patient’s WES-data revealed two homozygous, ultra-rare and predicted deleterious missense variants in macrophage expressed gene 1 (MPEG1). MPEG1 encodes for perforin-2, a pore forming protein. Perforin-2 is involved in endosomal antigen leakage by cross-presenting cells. In humans, heterozygous MPEG1 variants are associated with relatively mild skin and pulmonary infections, but MPEG1-population genetics metrices are within the range of genes underlying IEIs with autosomal recessive inheritance. We hypothesize that autosomal recessive MPEG1 deficiency may underlie life-threatening S. aureus infections in humans. We aim to characterize the patient’s alleles using a gene-editing strategy in THP-1 cells and by functionally characterizing the wild-type MPEG1 and the patient-derived variants in overexpression. Next, we will validate the defect using the patient’s cells.
Conclusion: The study of IEIs can serve as a compass for the clarification of human-specific host-pathogen interactions, such as is the case for S. aureus. This study may reveal MPEG1 as a new gene underlying a previously unknown inborn error of antistaphylococcal immunity.