Macrophage peroxisomes guide alveolar regeneration and limit post-acute sequelae of SARS-CoV-2 infection (PASC)

Peroxisomes are essential but often overlooked metabolic organelles. To explore how macrophage peroxisomes protect the lung, we conducted single-cell RNA sequencing (scRNA-seq) on lungs from both naïve and SARS-CoV-2-infected Pex5^flox/flox (WT) and Cd11c-cre Pex5^flox/flox (KO) mice at 7 days post-infection (d.p.i). scRNA-seq revealed an increased proportion of inflammatory monocytes, neutrophils, and monocyte-derived macrophages (MDMs) in the lungs of infected KO mice, alongside a marked reduction in alveolar type 2 (AT2) cells and alveolar macrophages (AMs) compared to infected WT mice. AMs from KO mice showed elevated expression of genes involved in inflammatory responses, innate immunity, and cellular stress signaling, while genes related to wound healing, cell differentiation, and lipid metabolism were downregulated, compared to AMs from WT mice at 7 d.p.i. Cd11c-cre Pex5^flox/flox or Pex5^flox/flox mice were either uninfected (day 0) or infected with 2000 PFU of SARS-CoV-2 MA30 virus. Lung cells were harvested on day 0 and day 7 post infection. For each time point, cells from three individual mice per genotype were pooled and subjected to single-cell RNA sequencing (scRNA-seq) analysis