Respiratory syncytial virus (RSV) and adenoviral pulmonary infections can be severe and even life-threatening. Unfortunately, there are no fully effective prophylactic or therapeutic measures. A constitutively active oxidative host defense mechanism has been recently described in the conducting airways. This host defense mechanism generates reactive antimicrobial molecules towards the airway lumen and consists of: 1) the airway epithelial enzymes dual oxidase (Duox) 1 and 2 that produce hydrogen peroxide on the mucosal surface, 2) lactoperoxidase (LPO) which is secreted by submucosal glands, and 3) a pseudohalide ion (thiocyanate, SCN-) that is secreted by epithelia. The Duox enzymes generate H2O2 into the apical extracellular space where H2O2 reacts with SCN- in a LPO-catalyzed reaction to form the antibacterial molecule hypothiocyanite (OSCN-). In contrast to its potent antibacterial activity, OSCN- is not effective against respiratory viruses. Our preliminary data suggest that following the delivery of iodide (I-) to the apical side of airway epithelia, the Duox/LPO enzymes will oxidize I- and generate hypoiodous acid (HOI) instead of OSCN-. We have found that HOI is effective against respiratory viruses including adenovirus (Ad) and RSV. Although Iis normally not present in the airway surface liquid, our experiments in human subjects and sheep indicate that the SCN- transporters of airway epithelia accumulate I- in the airway surface liquid following administration of Ibolus by either oral ingestion of KI or intravenous administration of NaI. Furthermore, our pilot experiments suggest that administration of I- bolus may convert the Duox/LPO enzymes into an HOI-generating antiviral mechanism in vivo. Based on our preliminary data we propose the overall hypothesis that the Duox/LPO system can be exploited to enhance pulmonary mucosal immunity against viral pathogens. To test this hypothesis we will use lambs as an animal model because ovine airways (in contrast to that of rodents) express Duox and LPO, and are susceptible to RSV and Ad infection.
In Aim 1 of this proposal, we will explore the mechanism(s) of RSV and Ad inactivation by the Duox/LPO system in primary cultures of human and ovine cells.
In Aim 2, we will evaluate I- secretion and HOI production in the airway following I- administration. The obtained pharmacokinetic data will be used to generate a computational model that predicts HOI production in the airway based on the serum levels of the two LPO substrates I- and SCN-. Experiments of Aim 3 will test the extent to which the Duox/LPO/I- mechanism can be exploited for prophylaxis or treatment of viral respiratory tract infections through delivery of NaI. Our expectation is that the above proposed studies will define the mechanistic basis of the antiviral activity by the Duox/LPO system, and interventions will be established that may prevent or reduce infections caused by respiratory viruses.
. Pulmonary infection by respiratory viruses is a major cause of morbidity and mortality around the word. New therapeutic approaches that could reduce the severity or frequency of viral infections in the respiratory tract are needed. The proposed project will explore the possibility that the antiviral activity of an innate immune mechanism of airways can be enhanced to protect against frequent respiratory pathogens such as respiratory syncytial virus (RSV) and adenovirus (Ad).
|Derscheid, R J; Ackermann, M R (2013) The innate immune system of the perinatal lung and responses to respiratory syncytial virus infection. Vet Pathol 50:827-41|
|Derscheid, Rachel J; van Geelen, Albert; McGill, Jodi L et al. (2013) Human respiratory syncytial virus Memphis 37 grown in HEp-2 cells causes more severe disease in lambs than virus grown in Vero cells. Viruses 5:2881-97|
|Derscheid, Rachel J; Ackermann, Mark R (2012) Perinatal lamb model of respiratory syncytial virus (RSV) infection. Viruses 4:2359-78|