Potential Role of HPA Axis and Sympathetic Nervous Responses in Depletion of B Cells Induced by H9N2 Avian Influenza Virus Infection

Wenbao Qi,Jin Tian,Ming Liao,Peirong Jiao,Zhangyong Ning,Jun He,Changhui Zhang,Stephen V Gordon

doi:10.1371/journal.pone.0051029

Wenbao Qi, Jin Tian + Show 6 more

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https://doi.org/10.1371/journal.pone.0051029

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Abstract

Except severe pulmonary disease caused by influenza virus infection, an impaired immune system is also a clinic characteristic. However, the mechanism(s) of influenza virus infection-induced depletion of B cells was unknown. Here, we compared the effect of two variant virulence H9N2 virus infections on mouse B cells. Our study found that the infection with highly pathogenic virus (V) of led to depletion of spleen B cells and bone marrow (BM) early B cells, compared to lowly pathogenic virus (Ts). Moreover, high apoptosis and cell cycle arrest in spleen and BM were detected, suggesting important factors for the reduction of B cells in both organs. Further, this effect was not caused by virus replication in spleen and BM. Compared to Ts virus infection, V virus resulted in higher glucocorticoids (GCs) and lower leptin level in plasma. Intraperitoneal GCs receptor antagonist RU486 injection was sufficient to prevent the loss of spleen B cell and BM pro- and immature B cells, but similar result was not observed in leptin-treated mice. Depletion of spleen B cells and BM pro-B cells was also reversed by chemical sympathectomy mediated by the norepinephrine (NE) analog 6-hydroxydopamine (6-OHDA), but the treatment didn't affect the GCs level. This study demonstrated that depletion of B cells induced by H9N2 AIV was dependent on HPA axis and sympathetic response.

Highlights

Influenza A virus infection causes severe disease in humans and is an important topic in clinical health [1]
We systematically investigated the effect of variant virulence H9N2 AIV on early and mature B cells respectively from central and peripheral immune organs and found the infection with highly pathgenetic H9N2 AIV induced a reduction of spleen B cells and bone marrow (BM) early B cells
The data presented in this report firstly provides evidence that the hypothalamic– pituitary axis (HPA) axis and sympathetic nervous system are involved in the loss of spleen B cells and BM early B cells caused by H9N2 AVI

Summary

Introduction

Influenza A virus infection causes severe disease in humans and is an important topic in clinical health [1]. Severe destruction of lung tissue was observed by pathologists in human patients, which was further confirmed by mouse models of highly pathogenic avian influenza virus infection (HPAIV). One hallmark of influenza virus infection in humans and other animal models was a strong reduction of T, B lymphocytes leading to limit the activation of immune responses [3]. Recent studies using mice models to investigate the mechanism(s) of lymphopenia in severe influenza infection have implicated HPAIV infection was able to transport infectious virus from the lungs into the thymus causing functional damage of the thymus and interfering with T lymphocyte development, which was thought as a potential factor for T cells reduction [4]

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