Human iPSC-derived macrophages for efficientStaphylococcus aureusclearance in a murine pulmonary infection model

Abstract

Primary or secondary immunodeficiencies are characterized by disruption of the 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 here propose an adoptive macrophage transfer approach aiming to enhance impaired pulmonary immunity against S. aureus. Our studies, using human induced pluripotent stem cells (iPSC)-derived macrophages (iMφ) 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 iMφ 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 iMφ compared to monocyte-derived macrophages indicates a more profound upregulation of inflammatory genes early after infection and faster normalization 24 hours post-infection. Our data demonstrate high therapeutic efficacy of iMφ-based immunotherapy against S. aureus infections and offers an alternative treatment stratgey for immunodeficient or immunocompromised patients.

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

“…iMph infectability with various pathogens has been documented and used to study the molecular basis of macrophage-pathogen interactions. Future developments will likely include the elaboration of approaches to infectious disease treatment based on the use of “native” [ 46 , 96 , 98 ] or genetically engineered [ 96 ] iMphs. Drug screening.…”

“…Previously, Ackermann and co-authors demonstrated that human iMphs co-administered with P. aeruginosa to immunodeficient humanized mice prevented the development of P. aeruginosa infection; when injected shortly after the pathogen, iMphs rescued mice from severe infection [ 46 ]. More recently, the same group reported that intrapulmonary injection of human iMphs significantly reduced bacterial load and local pulmonary inflammation in immunodeficient mice challenged with Staphilococcus aureus 4 h prior to cell transfer [ 98 ]. Of note, iMphs responded to S. aureus infection by a profound upregulation of inflammatory genes soon after the infection, but quickly restored their stationary state, which is considered as a feature important for future iMph therapeutic use.…”

“…As a proof of principle, Lachmann’s group documented the anti-bacterial effect of unmodified human iMphs (EB-S) intratracheally administered to mice simultaneously with or shortly after their infection with P. aerugenosa or S. aureus [ 46 , 98 ]. Taylor and co-authors [ 96 ] reported an increased restriction of HIV-1 replication by iMphs (EB-S) with depleted USP18 gene (discussed above).…”

Macrophage-based Cell Strategies: A Novel Approach in Immunotherapy

“…Considering the unmet clinical need and the high morbidity and mortality of S. aureus in immunodeficient patients, Hashtchin et al 2 recently explored the applicability of a macrophage-based immunotherapy against pulmonary S. aureus infections in immunodeficient condition. Using a scalable production platform, the authors generated a highly pure population of macrophages derived from human-induced pluripotent stem cells (iPSCs).…”

“…While immunodeficient mice infected via intratracheal instillation of S. aureus developed extensive pulmonary infection, infected immunodeficient mice treated with iPSC-derived macrophages showed sign of a significantly less severe infection, with reduced pulmonary bacterial load, decreased monocyte and granulocyte infiltration, and overall less edema and tissue damage (Figure 1 ). 2 Interestingly, the authors compared iPSC-derived versus peripheral blood monocyte-derived macrophages as potential source of cell immunotherapy. A significantly stronger antimicrobial response was provided by iPSC-derived macrophages, as suggested by the higher secretion of IL-6, a crucial pro-inflammatory cytokine driver of immunity against S. aureus .…”