Ontogeny of the Immune Response in the Ovine Lung

Ackermann

2012

Viruses

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Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term) lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO) oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation) and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines.

Section: Lambs As a Model Of Rsv Infection Of Infantsmentioning

confidence: 99%

“…These lambs are not premature; however, innate immune gene responses, cellular differentiation, and responses to RSV by preterm lambs have significant differences from term lambs [71,79]. In contrast, rodents do not survive preterm birth.…”

Section: Lambs As a Model Of Rsv Infection Of Infantsmentioning

confidence: 99%

Perinatal Lamb Model of Respiratory Syncytial Virus (RSV) Infection

Ackermann

2012

Viruses

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“…Error bars = SEM. *P , 0.05; ***P , 0. time points during gestation and compared with adult expression levels as described previously (41,42). Expression of LPO and Duox1 was low preterm, at gestational Days 115 and 130, and at birth, whereas expression was markedly increased in adults ( Figures 5A and 5B).…”

Section: Ontologic Expression Of Duox1 Duox2 and Lpo Genes In Lamb mentioning

confidence: 99%

Increased Concentration of Iodide in Airway Secretions Is Associated with Reduced Respiratory Syncytial Virus Disease Severity

Am J Respir Cell Mol Biol

Geelen

Berkebile³

et al. 2014

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Recent studies have revealed that the human and nonrodent mammalian airway mucosa contains an oxidative host defense system. This three-component system consists of the hydrogen peroxide (H 2 O 2 )-producing enzymes dual oxidase (Duox)1 and Duox2, thiocyanate (SCN 2 ), and secreted lactoperoxidase (LPO Clinical RelevanceThis study demonstrates that enhancement of dual oxidase/ lactoperoxidase oxidative responses by potassium iodide administration reduces respiratory syncytial virus disease severity in a lamb model that has much similarity to disease condition in human infants. The work is readily translational.Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection in infants and young children and is a leading cause of infantile bronchiolitis worldwide (1, 2). In industrialized countries, human RSV (hRSV) accounts for up to 70% of hospitalized bronchiolitis cases (1-3). Although the antiviral drugs palivizumab and ribavirin have virucidal activity against RSV in vivo, there are no fully satisfactory therapeutic regimens or vaccines (4-6). It is estimated that 3% of RSV cases in the United States and 10% of cases worldwide result in hospitalization; the reported number of new cases of lower respiratory infection due to RSV in children under 5 years of age in 2005 was 33.8 million (7,8). Thus, there is a need for new therapies for RSV infection.The host defense activity of the airway epithelium is critical for the continuous inactivation and removal of inhaled microbes from the respiratory tract. Although the role of mucociliary clearance and epithelial host defense proteins and peptidesin lung immunity is well established, the recognition that airway epithelial cells express an oxidative

“…Expression of SP-A and SP-D increases throughout fetal lung development in lambs. 91,133 RSV infection of lambs enhances expression of SP-A and SP-D and is associated with viral clearance. 44,61,101,102 Drugs, such as ethanol exposure in utero, reduce SP-A production in lungs of newborns and may explain, at least in part, why ethanol consumption by pregnant mothers is a risk factor for severe RSV disease.…”

mentioning

confidence: 99%

The Innate Immune System of the Perinatal Lung and Responses to Respiratory Syncytial Virus Infection

Ackermann

2013

Vet Pathol

The response of the preterm and newborn lung to airborne pathogens, particles, and other insults is initially dependent on innate immune responses since adaptive responses may not fully mature and require weeks for sufficient responses to antigenic stimuli. Foreign material and microbial agents trigger soluble, cell surface, and cytoplasmic receptors that activate signaling cascades that invoke release of surfactant proteins, defensins, interferons, lactoferrin, oxidative products, and other innate immune substances that have antimicrobial activity, which can also influence adaptive responses. For viral infections such as respiratory syncytial virus (RSV), the pulmonary innate immune responses has an essential role in defense as there are no fully effective vaccines or therapies for RSV infections of humans and reinfections are common. Understanding the innate immune response by the preterm and newborn lung may lead to preventive strategies and more effective therapeutic regimens.