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Dual oxidase 1 (DUOX1) is an NADPH oxidase that is highly expressed in respiratory epithelial cells and produces H₂O₂ in the airway lumen. While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN⁻) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1 −/− mice have enhanced mortality, morbidity, and impaired lung viral clearance. Duox1 increases the airway levels of several cytokines (IL-1β, IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. In primary human tracheobronchial epithelial cells, OSCN⁻ is generated by LPO using DUOX1-derived H₂O₂ and inactivates several influenza strains in vitro. We also show that OSCN⁻ diminishes influenza replication and viral RNA synthesis in infected host cells that is inhibited by the H₂O₂ scavenger catalase. Binding of the influenza virus to host cells and viral entry are both reduced by OSCN⁻ in an H₂O₂-dependent manner in vitro. OSCN⁻ does not affect the neuraminidase activity or morphology of the influenza virus. Overall, this antiviral function of Duox1 identifies an in vivo role of this gene, defines the steps in the infection cycle targeted by OSCN⁻, and proposes that boosting this mechanism in vivo can have therapeutic potential in treating viral infections.

Mammalian heme peroxidases are fascinating due to their unique peculiarity of oxidizing (pseudo)halides under physiologically relevant conditions. These proteins are able either to incorporate oxidized halides into substrates adjacent to the active site or to generate different oxidized (pseudo)halogenated species, which can take part in multiple (pseudo)halogenation and oxidation reactions with cell and tissue constituents. The present article reviews basic biochemical and redox mechanisms of (pseudo)halogenation activity as well as the physiological role of heme peroxidases. Thyroid peroxidase and peroxidasin are key enzymes for thyroid hormone synthesis and the formation of functional cross-links in collagen IV during basement membrane formation. Special attention is directed to the properties, enzymatic mechanisms, and resulting (pseudo)halogenated products of the immunologically relevant proteins such as myeloperoxidase, eosinophil peroxidase, and lactoperoxidase. The potential role of the (pseudo)halogenated products (hypochlorous acid, hypobromous acid, hypothiocyanite, and cyanate) of these three heme peroxidases is further discussed.

The influenza virus has a large clinical burden and is associated with significant mortality and morbidity. The development of effective drugs for the treatment or prevention of influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs in which resistance has developed; thus, there is an urgent need to explore new therapeutic options. Boosting antiviral innate immune mechanisms in the airways represents an attractive approach. Hypothiocyanite (OSCN − ) is produced by the airway epithelium and is effective in reducing the replication of several influenza A virus strains in vitro . It remains, however, largely unexplored whether OSCN − has such an antiviral effect in vivo . Here we determined the therapeutic potential of OSCN − , alone or in combination with amantadine (AMT), in preventing lethal influenza A virus replication in mice and in vitro . Mice intranasally infected with a lethal dose of A/Puerto Rico/8/1934 (H1N1) or A/Hong Kong/8/1968 (H3N2) were cured by the combination treatment of OSCN − and AMT. Monotherapy with OSCN − or AMT alone did not substantially improve survival outcomes. However, AMT+OSCN − treatment significantly inhibited viral replication, and in vitro treatment inhibited viral entry and nuclear transport of different influenza A virus strains (H1N1 and H3N2) including the AMT-resistant strain A/WSN/33 (H1N1). A triple combination treatment consisting of AMT, oseltamivir, and OSCN − was also tested and further inhibited in vitro viral replication of the AMT-resistant A/WSN/33 strain. These results suggest that OSCN − is a promising anti-influenza treatment option when combined with other antiviral drugs.

SARS-CoV-2 replicates efficiently in the upper airways during the prodromal stage, resulting in environmental viral shedding from patients with active COVID-19 as well as from asymptomatic individuals. There is a need to find pharmacological interventions to mitigate the spread of COVID-19. Hypothiocyanite and lactoferrin are molecules of the innate immune system with a large spectrum cidal activity. The Food and Drug Administration and the European Medicines Agency designated the hypothiocyanite and lactoferrin combination as an orphan drug. We report an in vitro study showing that micromolar concentrations of hypothiocyanite exhibit dose- and time-dependent virucidal activity against SARS-CoV-2 and that the latter is slightly enhanced by the simultaneous presence of lactoferrin.

Saliva substitutes and/or lubricants are commonly employed to lessen dry mouth symptoms by stimulating and/or substituting for the secretion of saliva. In this study, a novel artificial saliva containing inorganic salts, including sodium chloride and potassium chloride, and bactericidal agents, including potassium thiocyanate and lactoperoxidase, was formulated in the form of a solution (DM-sol) or gel (DM-gel). Those in vivo therapeutic efficacies were assessed in terms of saliva secretion and anti-inflammatory activity in rats and mice, respectively. Salivary secretion was promoted by mucosal application of DM-formulations in normal rats. In particular, DM-gel resulted in 2.5- and 1.9-fold greater salivary flow rates compared to normal saline and DM-sol, respectively. In an in vivo efficacy evaluation in diabetic mice with salivary hypofunction, repeated application of DM-formulations alleviated histopathological changes in the buccal mucosa in terms of atrophy and thinning of the epithelium, compared to vehicle, after 4 weeks. Moreover, the DM-sol and DM-gel were comparably effective for relieving periodontal gingivitis, reducing infiltration of inflammatory cells, and normalizing the neutrophil level in the gingival gingiva, after 4 weeks. Therefore, the novel artificial saliva is expected to facilitate salivary secretion and restore physiological conditions in the mouth of patients with salivary hypofunction.

Sialoperoxidase and myeloperoxidase are the two main peroxidase enzymes found in the oral cavity. Sialoperoxidase is present in salivary secretions and in the biofilms that line the oral surfaces, while myeloperoxidase is abundant in the dento-gingival sulcus area. In the presence of hydrogen peroxide (H2O2), oral peroxidases catalyze the oxidation of the pseudohalide anion thiocyanate (SCN−) to hypothiocyanite (OSCN−), a strong oxidant that serves an antimicrobial role. Furthermore, oral peroxidases consume bacteria-produced H2O2 and could help inactivate toxic carcinogenic and genotoxic substances. Numerous in vitro studies have reported the antibacterial, antimycotic and antiviral role of peroxidases, suggesting possible applications in oral therapy. However, the use of oral hygiene products incorporating peroxidase systems has not yet been shown to be beneficial for the treatment or prevention of oral infections. This paradox reflects our incomplete knowledge of the physiological role of peroxidases in a complex environment, such as the oral region. While hygiene is crucial for restoring oral microbiota to a symbiotic state, there are no data to suggest that the addition of a peroxidase per se can create a dysbiotic state. Recent investigations have associated the presence of peroxidase activity with gram-positive cocci microbial flora, and its insufficiency with dysbiosis has been linked to pathologies, such as caries, periodontitis or infections of the oral mucosa. Therefore, oxidants generated by oral peroxidases appear to be an essential ecological determinant for oral health through the selection of a symbiotic microbiota capable of resisting oxidative stress. The objective of the present review was to update the current knowledge of the physiological aspects and applications of oral peroxidases in clinical practice.

Cystic fibrosis (CF) is a pleiotropic disease, originating from mutations in the CF transmembrane conductance regulator (CFTR). Lung injuries inflicted by recurring infection and excessive inflammation cause [almost equal to]90% of the morbidity and mortality of CF patients. It remains unclear how CFTR mutations lead to lung illness. Although commonly known as a Cl⁻ channel, CFTR also conducts thiocyanate (SCN⁻) ions, important because, in several ways, they can limit potentially harmful accumulations of hydrogen peroxide (H₂O₂) and hypochlorite (OCl⁻). First, lactoperoxidase (LPO) in the airways catalyzes oxidation of SCN⁻ to tissue-innocuous hypothiocyanite (OSCN⁻), while consuming H₂O₂. Second, SCN⁻ even at low concentrations competes effectively with Cl⁻ for myeloperoxidase (MPO) (which is released by white blood cells), thus limiting OCl⁻ production by the enzyme. Third, SCN⁻ can rapidly reduce OCl⁻ without catalysis. Here, we show that SCN⁻ and LPO protect a lung cell line from injuries caused by H₂O₂; and that SCN⁻ protects from OCl⁻ made by MPO. Of relevance to inflammation in other diseases, we find that in three other tested cell types (arterial endothelial cells, a neuronal cell line, and a pancreatic β cell line) SCN⁻ at concentrations of greater-than-or-equal100 μM greatly attenuates the cytotoxicity of MPO. Humans naturally derive SCN⁻ from edible plants, and plasma SCN⁻ levels of the general population vary from 10 to 140 μM. Our findings raise the possibility that insufficient levels of antioxidant SCN⁻ provide inadequate protection from OCl⁻, thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis, neurodegeneration, and certain cancers.

In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme peroxidases lactoperoxidase (LPO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO) contribute to immune protection at epithelial surfaces and in secretions. Whereas LPO is secreted from epithelial cells and maintains microbes in surface linings on low level, MPO and EPO are released from recruited neutrophils and eosinophils, respectively, at inflamed mucous surfaces. Activated heme peroxidases are able to oxidize (pseudo)halides to hypohalous acids and hypothiocyanite. These products are involved in the defense against pathogens, but can also contribute to cell and tissue damage under pathological conditions. This review highlights the beneficial and harmful functions of LPO, MPO, and EPO at unperturbed and inflamed mucous surfaces. Among the disorders, special attention is directed to cystic fibrosis and allergic reactions.

The innate host response system is comprised of various mechanisms for orchestrating host response to microbial infection of the oral cavity. The heterogeneity of the oral cavity and the associated microenvironments that are produced give rise to different chemistries that affect the innate defense system. One focus of this review is on how these spatial differences influence the two major defensive peroxidases of the oral cavity, salivary peroxidase (SPO) and myeloperoxidase (MPO). With hydrogen peroxide (H2O2) as an oxidant, the defensive peroxidases use inorganic ions to produce antimicrobials that are generally more effective than H2O2 itself. The concentrations of the inorganic substrates are different in saliva vs. gingival crevicular fluid (GCF). Thus, in the supragingival regime, SPO and MPO work in unison for the exclusive production of hypothiocyanite (OSCN−, a reactive inorganic species), which constantly bathes nascent plaques. In contrast, MPO is introduced to the GCF during inflammatory response, and in that environment it is capable of producing hypochlorite (OCl−), a chemically more powerful oxidant that is implicated in host tissue damage. A second focus of this review is on inter-person variation that may contribute to different peroxidase function. Many of these differences are attributed to dietary or smoking practices that alter the concentrations of relevant inorganic species in the oral cavity (e.g.: fluoride, F−; cyanide, CN−; cyanate, OCN−; thiocyanate, SCN−; and nitrate, NO3−). Because of the complexity of the host and microflora biology and the associated chemistry, it is difficult to establish the significance of the human peroxidase systems during the pathogenesis of oral diseases. The problem is particularly complex with respect to the gingival sulcus and periodontal pockets (where the very different defensive stratagems of GCF and saliva co-mingle). Despite this complexity, intriguing in vitro and in vivo studies are reviewed here that reveal the interplay between peroxidase function and associated inorganic chemistry.

Infections caused by Streptococcus pneumoniae (pneumococcus, Spn) manifest in several forms such as pneumonia, meningitis, sinusitis or otitis media and are associated with severe morbidity and mortality worldwide. While current vaccines and antibiotics are available to treat Spn infections, the rise of antibiotic resistance and limitations of the vaccines to only certain Spn serotypes urge the development of novel treatments against Spn. Hypothiocyanite (OSCN-) is a natural antimicrobial product produced by the body’s own innate immune system to fight a variety of pathogens. We recently showed that OSCN- is also capable of killing Spn in vitro. OSCN- is an oxidative agent attacking microbes in a nonspecific manner, is safe for the host and also has anti-inflammatory effects that make it an ideal candidate to treat a variety of infections in humans. However, OSCN- has a short life span that makes its use, dosage and administration more problematic. This minireview discusses the antimicrobial mechanism of action of OSCN- against Spn and elaborates on the potential therapeutic use of OSCN- against Spn and other infectious agents, either alone or in combination with other therapeutic approaches.