Dr Sarhad Alnajjar

Respiratory syncytial virus is a major cause of acute lower respiratory tract infection in young children, immunocompromised adults, and the elderly. Intervention with small-molecule antivirals specific for respiratory syncytial virus presents an important therapeutic opportunity, but no such compounds are approved today. Here we report the structure of JNJ-53718678 bound to respiratory syncytial virus fusion (F) protein in its prefusion conformation, and we show that the potent nanomolar activity of JNJ-53718678, as well as the preliminary structure–activity relationship and the pharmaceutical optimization strategy of the series, are consistent with the binding mode of JNJ-53718678 and other respiratory syncytial virus fusion inhibitors. Oral treatment of neonatal lambs with JNJ-53718678, or with an equally active close analog, efficiently inhibits established acute lower respiratory tract infection in the animals, even …

Many animal models have been established for respiratory syncytial virus (RSV) infection of infants with the purpose of studying the pathogenesis, immunological response, and pharmaceutical testing and the objective of finding novel therapies and preventive measures. This review centers on a neonatal lamb model of RSV infection that has similarities to RSV infection of infants. It includes a comprehensive description of anatomical and immunological similarities between ovine and human lungs along with comparison of pulmonary changes and immune responses with RSV infection. These features make the newborn lamb an effective model for investigating key aspects of RSV infection in infants. The importance of RSV lamb model application in preclinical therapeutic trials and current updates on new studies with the RSV-infected neonatal lamb are also highlighted.

Respiratory syncytial virus (RSV) is the main cause of viral bronchiolitis resulting in hospitalization and a frequent cause of secondary respiratory bacterial infection especially by Streptococcus pneumoniae (Sp) in infants. While murine studies have demonstrated enhanced morbidity during a viral/bacterial co-infection, human meta-studies have been mixed. Moreover, less is known about pathogenesis of Sp serotype 22 and especially the co-pathologies between RSV and Sp dual infections.

Here, we sought to examine mechanisms contributing to co-pathogen-induced morbidity using a large neonatal lamb animal model naturally permissive to infection by both pathogens.

Colostrum deprived lambs (aged 3–5 days) were randomly divided into four groups. Two of the groups were nebulized with RSV M37 (1.27 × 107 IFFU/mL), and the other two group nebulized with cell–conditioned mock media. At day 3 post-infection, one RSV group (RSV/Sp) and one mock-nebulized group (Sp only) were infected with (2×106 cfu of Sp) intratracheally. At day 6 post-infection all lambs were humanely euthanized and bacterial/viral pathogeneses were assessed by culture, focus forming unit, qPCR, IHC, and histopathology.

Lambs dually infected with RSV and Sp had higher RSV titers by qPCR but lower Sp than the other comparable groups. Additionally, lung lesions were more intense in the RSV/Sp group as characterized by increased interalveolar wall thickness with neutrophils and lymphocyte infiltration.

Despite lower Sp in lungs, lambs co-infected with RSV exhibited greater morbidity and tissue histopathology. Thus, enhanced disease severity may be due more to elevated immunopathogenesis than elevated bacterial pathogenesis

In order to study the pathogenesis of the Pasteurella multocida in its natural rout of infection, this study was done to investigate and compare its pathogenesis after intranasal and intraocular infection. Thirty (30) rabbits were divided into three groups, the 1 st group (n= 12) infected with 240 CFU of Pasteurella multocida intra-nasal, the 2 nd (n= 12) infected with 240 CFU of P. multocida intra-ocular (eye drop), and the 3 rd group (n= 6) served as control negative. The animals were sacrificed if they did not die naturally at 24-48hr, 3, 6, 9, 30 day post-infection (pi). The results showed dullness of the animals with nasal and ocular discharge and some animals dead at 48hr and 72 hr pi (two animals from the 1 st group and four animals from the 2 nd group). The gross examination of the dead and sacrificed animals showed hemorrhage in the upper respiratory tract with fibrinous pleuropericaditis and emphysematous lung in the 1 st group, while the 2 nd group showed eye opacity and in some animal’s eye swelling in addition to the feature noticed in the 1 st group. Pasteurella multocida was isolated from the organs of all the infected animals. The histopathological changes in the 1 st group were more intense than the 2 nd group and concenterated at the upper and lower respiratory tract as acute hemorrhagic treacheatis with fibrinous pneumonia, while the kidney showed hypercellularity of the glomeruli with cellular degeneration of renal tubule and lymphocytic hepatitis, also there is focal gliosis. Conclusion, intranasal infection was the effective route and the main pathological changes observed in the respiratory system characterized by fibrinous …

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable “muco-trapping” variant of motavizumab (Mota-MT), a potent neutralizing mAb against RSV F is engineered. Mota-MT traps RSV in AM via polyvalent Fc-mucin bonds, reducing the fraction of fast-moving RSV particles in both fresh pediatric and adult AM by ≈20–30-fold in a Fc-glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota-MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota-MT to RSV-infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000-fold and 100 000-fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota-MT-treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco-trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.