Activation of Interferon Response Through Toll-Like Receptor 3 Impacts Viral Pathogenesis and Pulmonary Toll-Like Receptor Expression During Respiratory Syncytial Virus and Influenza Infections in the Cotton Rat Sigmodon hispidus Model

Abstract

Interferon (IFN) therapy in humans often causes flu-like symptoms by an unknown mechanism. Poly ICLC is a synthetic dsRNA and a toll-like receptor 3 (TLR3) agonist with a strong IFN-inducing ability. In this work we analyzed the effect of poly ICLC on pulmonary responses to influenza and Respiratory Syncytial Virus (RSV) infections in the cotton rat (S. hispidus) model. Viral replication, pulmonary inflammation, and expression of IFN, TLR, and chemokines were monitored and compared. Antiviral effect of poly ICLC against influenza virus and RSV was best achieved at high poly ICLC concentrations that, in the absence of virus infection, induced a strong IFN response. The antiviral doses of poly ICLC, however, also increased lung inflammation, an unexpected finding because of the reported poly ICLC safety in BALB/c mice. Similarly, in contrast to murine model, pathology of RSV infection was increased in cotton rats treated with poly ICLC. Augmented lung inflammation was accompanied by an earlier induction of IFN and TLR responses and a stronger chemokine expression. Overall, these findings indicate significant association between antiviral IFN action and pulmonary inflammation and highlight important animal model-specific variations in the potential of IFN to cause pathology.

Animal models of human respiratory syncytial virus disease

“…Histopathological lesions associated with hRSV challenge in cotton rats consist of mild to moderate bronchiolitis or pneumonia, sloughed epithelial cells, and patchy atelectasis (18,93,94). The cellular and biochemical responses to virus challenge are relatively limited, primarily lymphocytes associated with moderate increases in expression of MIP-1␣/CCL3, MCP-1, and IFN-␥ (18,19,94) and no clear evidence of significant clinical signs of URTD of LRTD (18,93). No specific age dependency in the susceptibility to hRSV has been reported although elderly cotton rats exhibit delayed viral clearance (20).…”

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

“…IP-10 is a chemokine that is known to attract T cells and NK cells. In cotton rat treated with a TLR3 agonist then infected with HRSV, it was shown that type I IFN responses can augment lung inflammation in this model (Boukhvalova et al, 2010). …”

Novel Drugs Targeting Toll-Like Receptors for Antiviral Therapy

“…Studies in mice suggest that poly-ICLC and liposome-encapsulated poly-ICLC are safe and provide broad-spectrum protection against seasonal and highly pathogenic avian influenza A viruses, as well as RSV and SARS virus [89]. However, in a cotton rat model of RSV and influenza infection, intranasal administration of antiviral doses of poly-ICLC induced lung inflammation [90]. Comparative transcriptional analysis upon subcutaneous administration of poly-ICLC indicated that it induces innate immune responses of similar magnitude to a live viral vaccine in humans [91].…”

“…RSV-infected BALB/c mice treated with poly-ICLC showed significantly reduced inflammation and clinical scores for the disease [171]. However, in contrast to the murine model, poly-ICLC treatment resulted in increased pathology during RSV infection in cotton rats [90]. In addition, due to important differences in the TLR signaling pathways in animal models and humans, many drugs tested with encouraging results in animal models failed to show much effect in human studies.…”