The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification

Abstract

SummaryMacrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization. Loss of SLC4A7 resulted in increased cytoplasmic acidification during phagocytosis, suggesting that SLC4A7-mediated, bicarbonate-driven maintenance of cytoplasmic pH is necessary for phagosome acidification. Altogether, we identify SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages.

In or out: Phagosomal escape ofStaphylococcus aureus

“…A THP‐1 macrophage mutant in the bicarbonate transporter SLC4A7 demonstrated impaired phagosomal acidification yet subsequently killed S . aureus USA300 more efficiently (Sedlyarov et al, ), thus corroborating the importance of an acidic pH for survival and proliferation of this staphylococcal strain within macrophages (Flannagan et al, ). Also, a study on murine alveolar macrophages indicated that acidic phagosomal pH was not detrimental for S .…”

“…Aside from bacterial proteins, host cell factors also influence staphylococcal survival and proliferation within macrophages. A THP-1 macrophage mutant in the bicarbonate transporter SLC4A7 demonstrated impaired phagosomal acidification yet subsequently killed S. aureus USA300 more efficiently (Sedlyarov et al, 2018), thus corroborating the importance of an acidic pH for survival and proliferation of this staphylococcal strain within macrophages (Flannagan et al, 2018). Also, a study on murine alveolar macrophages indicated that acidic phagosomal pH was not detrimental for S. aureus survival because bacteria were recovered in decreased numbers from cells treated with the v-ATPase inhibitor bafilomycin (Lacoma et al, 2017).…”

“…For instance, USA300‐type S . aureus required phagosomal acidification for intracellular survival (Flannagan et al, ), whereas strain Newman was also reported to be acid‐sensitive and was cleared in an intracellular infection (Sedlyarov et al, ). This versatility of S .…”

“…To what extent the observations are caused by strain differences remains to be determined. For instance, USA300-type S. aureus required phagosomal acidification for intracellular survival (Flannagan et al, 2018), whereas strain Newman was also reported to be acid-sensitive and was cleared in an intracellular infection (Sedlyarov et al, 2018). This versatility of S. aureus strains and isolates and the resulting differences in infection outcomes may reflect adaptations to host species, tissue, or cell type niches.…”

The transporters SLC35A1 and SLC30A1 play opposite roles in cell survival upon VSV virus infection

“…In order to identify solute carriers affecting viral infection and cell survival, we performed unbiased genetic screens using a SLC-focused CRISPR knockout (KO) lentiviral library targeting 388 SLC genes with multiple sgRNAs per gene 15 (Fig 1a). To test the ability of this library to identify factors affecting viral infection, we screened for transporters affecting survival of the lung adenocarcinoma cell line A549 upon influenza A virus (IAV, strain A/WSN/33) infection.…”