Abstract
Sigmodon hispidus or cotton rat is an excellent animal model for studying human infections of respiratory viruses including respiratory syncytial virus (RSV), which is the leading cause of hospitalization in infants and causes high rates of infection in the elderly and immunocompromised patient populations. Despite several decades of research, no vaccine has been licensed whereas inactivated vaccines have been shown to induce severe adverse reaction in a clinical trial, with other forms of RSV vaccine also found to induce enhanced disease in preclinical animal studies. While arguably the cotton rat is the best small animal model for evaluation of RSV vaccines and antivirals, many important genes of the immune system remain to be isolated. Programmed cell death-1 (PD-1) plays an integral role in regulating many aspects of immunity by inducing suppressive signals. In this study, we report the isolation of mRNA encoding the cotton rat PD-1 (crPD-1) and characterization of the PD-1 protein. crPD-1 bound to its cognate ligand on dendritic cells and effectively suppressed cytokine secretion. Moreover, using the newly acquired gene sequence, we observed a decreased level of crPD-1 levels in cotton rats with enhanced respiratory disease induced by inactivated RSV vaccine, unraveling a new facet of vaccine-induced disease.
Highlights
Programmed cell death-1 (PD-1) is a receptor that belongs to the CD28 superfamily[1]
Using the newly identified gene sequence as a probe, we found significantly decreased levels of the PD-1 gene in enhanced respiratory disease (ERD) cotton rats following vaccination with FI-respiratory syncytial virus (RSV), suggesting that downregulation of PD-1 could be associated with excessive pulmonary inflammation
Significant reduction in the percentage of PD-1 positive cells, approximately 50%, was observed at the protein level in formaldehyde-inactivated RSV (FI-RSV) immunized cotton rats compared to RSV (p = 0.0379), formaldehyde-mock control (FI-Mock) (p = 0.0058) and PBS (p = 0.0123) immunized cotton rats. These results revealed that decreased levels of pulmonary PD-1 at the mRNA and protein level was associated with ERD in animals vaccinated with inactivated RSV vaccine upon subsequent viral infection
Summary
Programmed cell death-1 (PD-1) is a receptor that belongs to the CD28 superfamily[1]. In the 1960s, a clinical trial involving formaldehyde-inactivated RSV (FI-RSV) resulted in hospitalization of 80% of the participants and 2 deaths following a RSV infection[31,32,33,34] This severe adverse reaction, commonly known as vaccine-induced enhanced respiratory disease (ERD), is yet to be fully understood but might be linked to the induction of a Th2-biased immune response leading to pulmonary inflammation, airway obstruction and mucus hypersecretion as observed in the trial participants and some animal models[35,36,37,38]. With increasing number of vaccines and therapeutics being evaluated in cotton rats prior to clinical trials, it would be important to better understand the immune system of this animal model[45,46,47]
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