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>>> The Placental Protein Syncytin-1 Impairs Antiviral Responses and Exaggerates Inflammatory Responses to Influenza

Jorge M. Tolosa, 1 Kristy S. Parsons, 2 Philip M. Hansbro, 2 Roger Smith, 1 and Peter A. B. Wark 2 , 3 ,*


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382184/


Background

Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1. We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza.

Conclusions

Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza.

Introduction

The advantage of genetic diversity has ensured the success of sexual reproduction in evolution, but in placental mammals it comes with the inherent dilemma that the maternal immune system must tolerate the existence of the semi-allogenic foetus/placenta that expresses both self (maternal) and non-self (paternal) antigens[1]. It is also clear that to prevent maternal rejection of the foetus and to sustain a successful pregnancy, potent mechanisms of immune regulation must be activated, such as suppression of T cell activation and function[2,3] and the generation of suppressor T regulatory (TReg) cells that function in an antigen specific manner[4]. Recent advances have demonstrated the importance of co-ordinating immune responses between pathogen detection (non-self antigens) by the innate immune system and activation or suppression of adaptive immune responses. In this regard dendritic cells (DCs) are an essential link in coordinating these immune responses in health and in pregnancy[5,6]. The placenta also appears to play an important though poorly understood role in promoting the immunotolerant state[2].

The human placenta is unique amongst tissues in having the highest expression of human endogenous retroviruses. These are evolutionary fossils, which at some ancient time point have infected germ line cells. Their ongoing high level expression in the placenta implies that they have imparted an evolutionary advantage for the host[7]. Syncytin-1 is a naturally occurring placental protein that is encoded by one of these retroviruses and has been shown to fuse human cytotrophoblast cells and promote syncytialisation that is crucial for placental formation[8]. Recently we also determined that human syncytin-1 released from the placenta suppresses maternal immune responses demonstrating it’s potential to play a role in maternal/foetal tolerance[9].

Maternal immune tolerance may come at the cost of increased susceptibility to infection, with pregnant women at greater risk of infection from intracellular bacteria and viruses[10]. The emergence of a new pandemic strain of swine influenza in 2009 (herein referred to as H1N1pdm09) recently refocussed attention on this issue. In this pandemic 50% of the women who died were pregnant. This is a startling statistic that emphasises that pregnant women are at increased risk of developing infection with influenza and are also more likely to develop severe disease[11]. This increase in mortality and morbidity is also observed during seasonal influenza; with numerous studies reporting increased rates of influenza-induced respiratory hospitalisations in pregnant compared to non-pregnant women[12–15]. While several comorbidities have been identified that predisposed to susceptibility to H1N1pdm09 infection, pregnancy is the most intriguing as it imparts a temporary susceptibility of the maternal immune system to infection. To further understand this phenomenon, it is of particular note that those pregnant women with severe H1N1pdm09 infection presented with an acute syndrome of severe respiratory compromise and systemic inflammation, associated with aberrant immune responses. This is characterised by intense acute inflammation (increased levels of the cytokine IL-6), but also reduced antiviral T-helper (TH)-1 responses (reduced IFN-?) and heightened suppressor T cell signals (IL-10)[16]. The implications of these observations are that the development of a maternal state of immune tolerance may particularly impair their immune response to novel pathogens such as H1N1pdm09.

To further explain the susceptibility of pregnant women to influenza we hypothesised that the human endogenous retroviral envelope protein syncytin-1 suppresses maternal cell mediated immune responses to influenza viruses, impairing antiviral DCs, promoting the development of suppressor TReg cells and inhibiting the development of robust anti-viral TH-1 immune responses...

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