Hypothiocyanite and host–microbe interactions

Abstract

The pseudohypohalous acid hypothiocyanite/hypothiocyanous acid (OSCN − /HOSCN) has been known to play an antimicrobial role in mammalian immunity for decades. It is a potent oxidant that kills bacteria but is non-toxic to human cells. Produced from thiocyanate (SCN − ) and hydrogen peroxide (H 2 O 2 ) in a variety of body sites by peroxidase enzymes, HOSCN has been explored as an agent of food preservation, pathogen killing, and even improved toothpaste. However, despite the well-recognized antibacterial role HOSCN plays in host-pathogen interactions, little is known about how bacteria sense and respond to this oxidant. In this work, we will summarize what is known and unknown about HOSCN in innate immunity and recent advances in understanding the responses that both pathogenic and non-pathogenic bacteria mount against this antimicrobial agent, highlighting studies done with three model organisms, Escherichia coli, Streptococcus spp., and Pseudomonas aeruginosa.

The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in Staphylococcus aureus

“…MPO dismutates superoxide to H 2 O 2 , which is used by MPO for the oxidation of chloride to produce the highly microbicidal hypochlorous acid (HOCl) ( 7 – 10 ). In the presence of the pseudohalide thiocyanate (SCN - ), MPO generates the hypothiocyanous acid (HOSCN), which is a similar powerful oxidant and antimicrobial agent as HOCl ( 7 , 13 ). Although SCN - is the preferred substrate for MPO, the chloride outcompetes SCN - in the neutrophil phagosome, indicating that HOCl is the main oxidant produced by MPO ( 14 ).…”

“…Although SCN - is the preferred substrate for MPO, the chloride outcompetes SCN - in the neutrophil phagosome, indicating that HOCl is the main oxidant produced by MPO ( 14 ). Apart from MPO, two other heme peroxidases, including lactoperoxidase (LPO) and eosinophil peroxidase (EPO) catalyze the reaction of SCN - with H 2 O 2 to produce high levels of 1–3 mM HOSCN in the airways and saliva and 5–50 µM in the blood plasma of the human body ( 13 , 15 – 17 ). Thus, S. aureus encounters HOSCN, especially at the sites of infections and colonization, including the airway mucosa of the upper respiratory tract where high SCN - levels are secreted ( 13 ).…”

The role of metals in hypothiocyanite resistance inEscherichia coli

“…The molecular details of the layered defenses that different bacteria employ to protect themselves against HOSCN are now beginning to be deciphered (11–19, 37), decades after HOSCN was first identified as an antimicrobial compound produced by the immune system (69). This paper now shows that glutathione is a key component in the E. coli HOSCN stress response, distinct from the protection provided by more HOSCN-specific defenses ( e.g.…”

“…For one thing, to my knowledge no studies to date have attempted to quantify HOSCN in the large intestine, although the presence of dedicated HOSCN resistance genes ( e.g. rclABC ) in diverse intestinal bacteria suggests it is present in at least some situations (11, 49). Cu 2+ and Zn 2+ were potent inhibitors of RclA activity in vitro ( Fig 3 ), and while solubility issues in the minimal media I used to grow E. coli prevented me from determining unambiguously whether either of these metals could inhibit RclA in vivo , that does not necessarily mean that it cannot happen in the host environment.…”

“…In contrast, bacterial thioredoxin reductase is inhibited by HOSCN (4), as are a number of central bacterial metabolic enzymes (5)(6)(7). HOSCN has therefore long been considered a specifically antimicrobial product which the innate immune system uses to control bacteria without causing damage to host tissues, a model which has generally assumed that bacteria lack effective defenses against HOSCN (8)(9)(10)(11).…”