Understanding Severe Staphylococcus aureus Infections: Recalibration of the Focus Towards Host Genetic Factors

Abstract

Staphylococcus aureus is the human pathogen causing the most infections in the world today. While most of these infections are rapidly neutralized by immunity, severe infections can occur and lead to death. Furthermore, various S. aureus antibiotic resistant strains have emerged which are now challenging the main treatment method. The alternatives to antibiotic treatments are slim: Despite decades of research, there are no vaccines against this pathogen. Host immunomodulation remains an attractive option for treatment development. However, while the bacterial virulence factors contributing to severe infection have been extensively researched, there is still much to learn about host factors affecting S. aureus infection to start treatment development. Inborn errors of Immunity are mutations which affect immune responses, and several were proven to predispose patients to severe S. aureus infections. Their study offers a powerful tool to assess the importance of specific immune genes in anti-S. aureus immunity, which directly nourishes research into novel therapies against Staphylococcus aureus. In this review, all evidence of human genetic predispositions to S. aureus have been assembled and examined. A majority of the identified IEIs predisposing patients to severe staphylococcal disease highlighted the importance of neutrophil recruitment in preventing bacterial dissemination and thus severe infection. These IEIs were found to affect mainly the development and function of neutrophils themselves, the TLR and IL-1R – NF-kB signaling pathway and T helper 17 immunity. Interestingly, non-traditional and non-haematopoietic IEIs were also identified – which urges researchers to discuss the approach to take in the coming years.