Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal Pneumonia Virus of Mice.

Abstract

Respiratory syncytial virus (RSV) is the major causative agent of acute lower respiratory tract infections in infants and young children. Unfortunately, there are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Thus, the development of effective vaccines and therapeutic interventions against RSV is a preeminent public health priority. Pneumonia virus of mice (PVM) causes similar clinical symptoms and disease in mice to those observed in RSV-infected patients, and therefore is used as a model for pathogenesis studies. Lethal PVM infection (i.e. 3000 pfu) in Balb/c mice is characterized by 20% weight loss in total body weight, rough coats, abnormal posture, nasal discharge, and difficulty breathing due to neutrophilia, edema and alveolitis in the lower airways. Also, these mice will succumb to the infection between days 6 and 7 p.i. Immunomodulation mediated by a novel formulation composed of the toll-like receptor 3 agonist poly I:C, an innate defense regulator peptide and a polyphosphazene (i.e. P-I-P) was first assessed in healthy adult Balb/c mice. Subsequently, the protective potential of P-I-P was further investigated in the context of a lethal PVM infection. P-I-P induced highest mRNA and protein expression of chemokines and cytokines in the lung milieu between 6 and 24 hr post-treatment. In addition, a single dose of P-I-P protected adult mice against PVM when given 24 hr prior to challenge. These animals displayed minimal body weight changes, no clinical disease, 100% survival, as well as reduced lung virus titers and pathology. P-I-P pre-treatment induced early mRNA and protein expression of key chemokine and cytokines, and decreased neutrophil and eosinophil numbers in the lungs, resulting in an overall modulation of the delayed exacerbated nature of PVM disease without short-term side effects. It was determined that the protective effects of P-I-P prophylaxis were maintained if administered up to 3 days prior to lethal PVM infection. On day 14 post-infection, P-I-P-treated survivor mice were confirmed to be PVM-free. These results demonstrate the capacity of this formulation to prevent PVM and possibly other viral respiratory infections.