ZIP8 loss impairs macrophage-mediated phagolysosomal removal of bacteria and is overcome by butyrate supplementation.

Zinc deficiency impacts billions of people and contributes significantly to the increased incidence of community-acquired pneumonia worldwide. Myeloid cells require the zinc transporter ZIP8 for proper host defense. Previously, we observed that infection with S.pneumoniae in myeloid-specific Zip8 knockout mice (Zip8KO) results in increased bacterial burden and mortality despite increased recruitment of macrophages into the lung. Here, we reveal that the lungs of infected Zip8KO mice generate a unique population of dysfunctional macrophages with defects in phagolysosomal function and cell survival. In particular, Zip8KO bone marrow-derived macrophages have increased bacterial accumulation due to deficits in lysosomal number and function via defective mTORC1/TFEB signaling. Knowing that labile Zn cannot enter the cytosol through ZIP8 and that ZIP8 loss impairs butanoate synthesis by the gut microbiome, both previously reported by our group, we reveal an alternative treatment strategy via extended oral phenylbutyrate supplementation. Despite ongoing ZIP8-mediated impairment of lung host defense, phenylbutyrate restored macrophage-mediated bacterial clearance and improved host outcomes. Given the high incidence of diet-induced Zn deficiency and the rs13107325 ZIP8 defective variant allele in humans, future investigations that foster preventive, patient-centered treatment strategies that counter immune dysfunction due to Zn dyshomeostasis are warranted.