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.
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 (Sigmodon 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.
Boukhvalova
Marina S
MS
Virion Systems, Inc., Rockville, Maryland 20850, USA. marinab@virionsystems.com
Sotomayor
Talia B
TB
Point
Ryan C
RC
Pletneva
Lioubov M
LM
Prince
Gregory A
GA
Blanco
Jorge C G
JC
D000818:Animals; D018893:Bronchoalveolar Lavage; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D011014:Pneumonia / Q000276:immunology / Q000821:virology; D011070:Poly I-C / Q000494:pharmacology; D011107:Polylysine / Q000031:analogs & derivatives / Q000494:pharmacology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000276:immunology; D016205:Sigmodontinae / Q000276:immunology* / Q000821:virology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D019562:Viral Load / Q000187:drug effects
D018925:Chemokines; D051196:Toll-Like Receptor 3; D011107:Polylysine; C019531:poly ICLC; D007372:Interferons; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C