Human iPSC-derived macrophages for efficient Staphylococcus aureus clearance in a murine pulmonary infection model

Primary or secondary immunodeficiencies are characterized by disruption of cellular and humoral immunity. Respiratory infections are a major cause of morbidity and mortality among immunodeficient or immunocompromised patients, with Staphylococcus aureus being a common offending organism. We propose here an adoptive macrophage transfer approach aiming to enhance impaired pulmonary immunity against S aureus. Our studies, using human-induced pluripotent stem cell-derived macrophages (iM phi s), demonstrate efficient antimicrobial potential against methicillin-sensitive and methicillin-resistant clinical isolates of S aureus. Using an S aureus airway infection model in immunodeficient mice, we demonstrate that the adoptive transfer of iM phi s is able to reduce the bacterial load more than 10-fold within 20 hours. This effect was associated with reduced granulocyte infiltration and less damage in lung tissue of transplanted animals. Whole transcriptome analysis of iM phi S compared with monocyte-derived macrophages indicates a more profound upregulation of inflammatory genes early after infection and faster normalization 24 hours postinfection. Our data demonstrate high therapeutic efficacy of iM phi-based immunotherapy against S aureus infections and offer an alternative treatment strategy for immunodeficient or immunocompromised patients.

Automated summary

Primary or secondary immunodeficiencies disrupt cellular and humoral immunity, leading to increased susceptibility to respiratory infections. Adoptive transfer of macrophages can enhance pulmonary immunity against Staphylococcus aureus, reducing bacterial load and tissue damage. Studies demonstrate that induced pluripotent stem cell-derived macrophages are more effective in combating S aureus infections compared to monocyte-derived macrophages.