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How bacteria neutralize hypothiocyanite, an antimicrobial weapon of the innate immune system

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How do a wide variety of bacteria – both pathogenic and commensal – survive antimicrobials released by the mammalian innate immune system?

The answer for one of the antimicrobials: hypothiocyanite/hypothiocyanous acid or OSCN and HOSCN – has been reported by Michael Gray, Ph.D., and colleagues by the discovery of a new role for an enzyme in E. coli. This previously unknown activity is also demonstrated by homologous enzymes found in pathogenic Streptococcus and Staphylococcus bacteria and various commensal gut microbes.

“During inflammation, the human immune system releases a variety of reactive and harmful antimicrobials that are meant to fight off invading pathogens,” said Gray, an assistant professor at the University of Alabama in Birmingham’s Department of Microbiology. “Understanding how bacteria can evade these powerful oxidants, including the hypohalous acids such as HOSCN, is critical to human health.

“By identifying the function of the enzyme RclA in the model organism E. coli – which is notably able to compete with commensal organisms and thrive in an inflamed gut – we have laid the foundation for understanding bacterial survival and the relationship with the human immune system in ways not previously understood,” Gray said.

“E. coli thrives mainly in the chronically inflamed environment found in patients with inflammatory bowel disease, and it is able to compete with and outgrow other important commensal organisms, suggesting that HOSCN may be a relevant antimicrobial agent in the gut.” are, which has not been explored before,” he said.

HOSCN is known to be abundant in saliva and airway secretions as a highly specific antimicrobial agent that is nearly harmless to mammalian cells. However, some microbes, including pathogens, can escape HOSCN damage during inflammation, allowing continued growth and even serious disease.

Report in the journal Proceedings of the National Academy of Sciences, researchers led by Gray and Frederick Stull, assistant professor of chemistry at Western Michigan University, Kalamazoo, explain that the E. coli flavoprotein RclA reduces HOSCN to harmless thiocyanate with near-perfect catalytic efficiency, and this extremely rapid activity protects E. coli strong. against HOSCN toxicity. Thus, HOSCN appears to be the physiologically relevant substrate for RclA, Gray says, rather than the previously described ability to modestly resist reactive chlorine.

The researchers also tested the homologous flavin-dependent oxidoreductases found in Streptococcus pneumonia, Staphylococcus aureus and in Bacteroides thetaiotaomicron. S. pneumonia and S. aureus are pathogens known to colonize tissues during chronic inflammation, especially in the lungs, where they should come into contact with high concentrations of HOSCN. B. thetaiotaomicron is an important human gut commensal.

Their three flavin-dependent oxidoreductases — which exhibit 47 to 49 percent amino acid sequence identity with E. coli RclA — were cloned into E. coli, where they all showed potent activity against HOSCN. The active sites of RclA and the three homologs show close amino acid sequence identity.

HOSCN works by rapidly oxidizing sulfur-containing amino acids in bacterial proteins, especially cysteine. Oxidoreductases such as RclA contain two cysteine ​​residues in their active site. These two cysteines are thought to be important for the function of the enzyme, yet they are a very likely target for HOSCN. The researchers showed that each active-site cysteine ​​in RclA was required for RclA function, and that they work together to rapidly reduce HOSCN, using NAD(P)H.

“Perhaps our most exciting finding is that homologues of RclA, including from the gut commensal species B. thetaiotaomicron and Limosilactobacillus reuteri and from species implicated in severe lung disease, protect against HOSCN damage to the same extent as E. coli RclA,” said RclA. Gray. “This indicates that a wide range of bacteria, both commensal and pathogenic, may have specific defense mechanisms against HOSCN stress. By learning more about the scope of protection this enzyme provides to pathogenic species, we gain better knowledge about potentially a wide range of diseases, including cystic fibrosis, inflammatory bowel disease, and oral disease.”

“While we have not yet directly addressed the effect of this enzyme on host colonization in vivo, we have established an important foundation for future studies with the data collected here,” Gray said.


Varied functionality of an enzyme that breaks down lipids


More information:
Julia D. Meredith et al, Escherichia coli RclA is a highly active hypothiocyanite reductase, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2119368119

Provided by the University of Alabama at Birmingham

Quote: How Bacteria Defuse Hypothiocyanite, An Antimicrobial Weapon of the Innate Immune System (2022, Aug. 10) Retrieved Aug. 10, 2022 from https://phys.org/news/2022-08-bacteria-defuse-hypothiocyanite-antimicrobial-weapon. html

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