Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent
© 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the meta...
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American Chemical Society (ACS)
2021
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Online Access: | https://hdl.handle.net/1721.1/135317 |
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author | Rosen, Tomer Nolan, Elizabeth M |
author2 | Massachusetts Institute of Technology. Department of Chemistry |
author_facet | Massachusetts Institute of Technology. Department of Chemistry Rosen, Tomer Nolan, Elizabeth M |
author_sort | Rosen, Tomer |
collection | MIT |
description | © 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the metal-sequestering ability of CP is based on biochemical and functional studies performed at neutral or near-neutral pH. Nevertheless, CP can be present throughout the human body and is expressed at infection and inflammation sites that tend to be acidic. Here, we evaluate the metal binding and antimicrobial properties of CP in the pH range of 5.0-7.0. We show that Ca(II)-induced tetramerization, an important process for the extracellular functions of CP, is perturbed by acidic conditions. Moreover, a low pH impairs the antimicrobial activity of CP against some bacterial pathogens, including Staphylococcus aureus and Salmonella enterica serovar Typhimurium. At a mildly acidic pH, CP loses the ability to deplete Mn from microbial growth medium, indicating that Mn(II) sequestration is attenuated under acidic conditions. Evaluation of the Mn(II) binding properties of CP at pH 5.0-7.0 indicates that mildly acidic conditions decrease the Mn(II) binding affinity of the His6 site. Lastly, CP is less effective at preventing capture of Mn(II) by the bacterial solute-binding proteins MntC and PsaA at low pH. These results indicate that acidic conditions compromise the ability of CP to sequester Mn(II) and starve microbial pathogens of this nutrient. This work highlights the importance of considering the local pH of biological sites when describing the interplay between CP and microbes in host-pathogen interactions. |
first_indexed | 2024-09-23T08:59:32Z |
format | Article |
id | mit-1721.1/135317 |
institution | Massachusetts Institute of Technology |
language | English |
last_indexed | 2024-09-23T08:59:32Z |
publishDate | 2021 |
publisher | American Chemical Society (ACS) |
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spelling | mit-1721.1/1353172023-10-05T19:27:40Z Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent Rosen, Tomer Nolan, Elizabeth M Massachusetts Institute of Technology. Department of Chemistry © 2020 American Chemical Society. Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the metal-sequestering ability of CP is based on biochemical and functional studies performed at neutral or near-neutral pH. Nevertheless, CP can be present throughout the human body and is expressed at infection and inflammation sites that tend to be acidic. Here, we evaluate the metal binding and antimicrobial properties of CP in the pH range of 5.0-7.0. We show that Ca(II)-induced tetramerization, an important process for the extracellular functions of CP, is perturbed by acidic conditions. Moreover, a low pH impairs the antimicrobial activity of CP against some bacterial pathogens, including Staphylococcus aureus and Salmonella enterica serovar Typhimurium. At a mildly acidic pH, CP loses the ability to deplete Mn from microbial growth medium, indicating that Mn(II) sequestration is attenuated under acidic conditions. Evaluation of the Mn(II) binding properties of CP at pH 5.0-7.0 indicates that mildly acidic conditions decrease the Mn(II) binding affinity of the His6 site. Lastly, CP is less effective at preventing capture of Mn(II) by the bacterial solute-binding proteins MntC and PsaA at low pH. These results indicate that acidic conditions compromise the ability of CP to sequester Mn(II) and starve microbial pathogens of this nutrient. This work highlights the importance of considering the local pH of biological sites when describing the interplay between CP and microbes in host-pathogen interactions. 2021-10-27T20:22:56Z 2021-10-27T20:22:56Z 2020 2021-07-14T17:47:03Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135317 en 10.1021/ACS.BIOCHEM.0C00359 Biochemistry Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Chemical Society (ACS) PMC |
spellingShingle | Rosen, Tomer Nolan, Elizabeth M Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title | Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title_full | Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title_fullStr | Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title_full_unstemmed | Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title_short | Metal Sequestration and Antimicrobial Activity of Human Calprotectin Are pH-Dependent |
title_sort | metal sequestration and antimicrobial activity of human calprotectin are ph dependent |
url | https://hdl.handle.net/1721.1/135317 |
work_keys_str_mv | AT rosentomer metalsequestrationandantimicrobialactivityofhumancalprotectinarephdependent AT nolanelizabethm metalsequestrationandantimicrobialactivityofhumancalprotectinarephdependent |