Severe influenza A(H1N1)pdm09 infection induces thymic atrophy through activating innate CD8+CD44hi T cells by upregulating IFN-γ

Abstract

Thymic atrophy has been described as a consequence of infection by several pathogens including highly pathogenic avian influenza virus and is induced through diverse mechanisms. However, whether influenza A(H1N1)pdm09 infection induces thymic atrophy and the mechanisms underlying this process have not been completely elucidated. Our results show that severe infection of influenza A(H1N1)pdm09 led to progressive thymic atrophy and CD4+CD8+ double-positive (DP) T-cells depletion due to apoptosis. The viruses were present in thymus, where they activated thymic innate CD8+CD44hi single-positive (SP) thymocytes to secrete a large amount of IFN-γ. Milder thymic atrophy was observed in innate CD8+ T-cell-deficient mice (C57BL/6J). Neutralization of IFN-γ could significantly rescue the atrophy, but peramivir treatment did not significantly alleviate thymic atrophy. In this study, we demonstrated that thymic innate CD8+CD44hi SP T-cells have critical roles in influenza A(H1N1)pdm09 infection-induced thymic atrophy through secreting IFN-γ. This exceptional mechanism might serve as a target for the prevention and treatment of thymic atrophy induced by influenza A(H1N1)pdm09.

Acute Thymic Involution and Mechanisms for Recovery

“…Because conducting research investigations on the thymuses of HIV-infected humans (Verinaud et al 2004) is difficult, many animal model systems have been developed. The simian immunodeficiency virus (SIV)-infected monkey model is much better than the feline and murine models, on the basis that this species not only acts as a natural host for the infection, but also offers Duan et al 2015;Hu et al 2016;Liu et al 2014 Parasites…”

“…This study demonstrated that use of an antiviral drug was ineffective whereas inhibition of CD8 + cells could reverse the thymic involution. This unique mechanistic insight might therefore lead to better preventive measures as well as a therapeutic tool to reverse the influenza A(H1N1)pdm09-induced ATI (Liu et al 2014). Very recently, in vitro and in vivo studies demonstrated that oral administration of phenylethanoid glycosides extracted from Ligustrum purpurascens has a protective effect that involved increasing the production of IFN-γ in IFN-γ knockout mice during an infection with H1N1 (Hu et al 2016).…”

“…It is considered a primary immune organ in jawed vertebrates, in which it plays important roles in the selection, proliferation, development and differentiation of T cells and provides protection against infections by various pathogens (Bajoghli and Guo 2011;Gameiro et al 2010;Liu et al 2014). Despite its significance in immunity (Miller 2002;Samara et al 2016), the shrinkage of thymus that occurs with aging results in a decrease in tissue mass along with architectural alterations.…”

NK-cells are involved in thymic atrophy induced by influenza A virus infection

“…versus mock-infected). IFN-c is a key cytokine involved in the protective immune response against various pathogen infections (Flynn et al, 1993;Julkunen et al, 2001), but has also been shown to participate in the induction of pathological courses, especially thymic atrophy and T-cell depletion during viral or bacterial infections (Borges et al, 2012;Deobagkar-Lele et al, 2013;Liu et al, 2014).…”

“…Trypanosoma cruzi, Plasmodium chaubi) and fungal infections (exemplified by experimental infections with Paracoccidioides brasiliensis and Histoplasma capsulatum) (Savino, 2006). To date, several mechanisms have been implicated in influenza virus infection-induced thymic atrophy, such as interference with T-lymphocyte development, increased levels of glucocorticoids and elevated IFN-c production by innate CD8 + T-cells (Liu et al, 2014;Tian et al, 2012;Vogel et al, 2010).…”