Live attenuated B. pertussis BPZE1 rescues the immune functions of Respiratory Syncytial virus infected human dendritic cells by promoting Th1/Th17 responses.

Ilaria Schiavoni,Giorgio Fedele,Camille Locht,Peter J Openshaw,Clara M Ausiello,Corinna Schnoeller,Adriano Quattrini,Manuela Bianco,Steven M Varga

doi:10.1371/journal.pone.0100166

Abstract

Respiratory Syncytial virus (RSV) is the leading cause of acute lower respiratory tract viral infection in young children and a major cause of winter hospitalization. Bordetella pertussis is a common cause of bacterial lung disease, affecting a similar age group. Although vaccines are available for B. pertussis infection, disease rates have recently increased in many countries. We have therefore developed a novel live attenuated B. pertussis strain (BPZE1), which has recently undergone a successful clinical phase I trial. In mice, BPZE1 provides protection against disease caused by respiratory viral challenge. Here, we analyze the effect of BPZE1 on antiviral T cell responses induced by human monocyte-derived dendritic cells (MDDC). We found that BPZE1 influences antiviral immune responses at several levels, enhancing MDDC maturation, IL-12p70 production, and shifting T cell cytokine profile towards a Th1/Th17 pattern. These data were supported by the intracellular signaling analysis. RSV infection of MDDC caused MyD88-independent STAT1 phosphorylation, whereas BPZE1 activated MyD88-dependent signaling pathways; co-infection caused both pathways to be activated. These findings suggest that BPZE1 given during infancy might improve the course and outcome of viral lung disease in addition to providing specific protection against B. pertussis infection.

Highlights

Respiratory Syncytial virus (RSV), a single-stranded RNA virus in the Paramyxoviridae family, is the leading cause of acute lower respiratory tract infections in infants and the single major cause of childhood hospitalization in the developed world [1]
We found BPZE1 co-infected with RSV enhances maturation of monocyte-derived dendritic cells (MDDC) and drives the T cells polarization to a putative protective Th1/Th17 response
To determine the conditions of RSV infection, MDDC were infected for 2 h with RSV at two multiplicity of infection (MOI): 0.5 and 1 plaque forming units/cell

Summary

Introduction

Respiratory Syncytial virus (RSV), a single-stranded RNA virus in the Paramyxoviridae family, is the leading cause of acute lower respiratory tract infections in infants and the single major cause of childhood hospitalization in the developed world [1]. 60% of all children are infected with RSV in the first year of life, increasing to 90% by their second year of life [2]. RSV is thought to cause almost 34 million cases per year of acute lower respiratory tract infection in children under 5 years of age, 10% of them being severe. It is thought that RSV bronchiolitis represents an overactive host immune response to infection [6], and there is still no safe and effective RSV vaccine for human use. The human trials of formaldehyde-inactivated RSV vaccine in 1966–1967 caused disastrous worsening of disease and death in infants during subsequent natural RSV infection [7,8]

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Conclusion