IFNγ and iNOS-Mediated Alterations in the Bone Marrow and Thymus and Its Impact on Mycobacterium avium-Induced Thymic Atrophy

Abstract

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 leads to progressive thymic atrophy. We previously showed that M. avium-induced thymic atrophy results from increased glucocorticoid levels that synergize with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators act is not understood. We hypothesized that IFNγ and NO promote thymic atrophy through their effects on bone marrow (BM) T cell precursors and T cell differentiation in the thymus. We show that M. avium infection cause a reduction in the percentage and number of common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice show an overall impaired ability to reconstitute thymi of RAGKO mice, in part due to IFNγ. Thymi from infected mice present an IFNγ and NO-driven inflammation. When transplanted under the kidney capsule of uninfected mice, thymi from infected mice are unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS; and a decrease on active caspase-3 positive thymocytes, which is not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of defects mediated by IFNγ and NO, including alterations in the BM T cell precursors, the thymic structure and the thymocyte differentiation.

SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

“…Several mechanisms have been shown to influence thymic atrophy for pathogenic infection such as NK-cell activation, increased levels of glucocorticoids as well as heightened IFN-γ secretion by the thymocytes [9,14,23]. Previously studies have shown that pathogenic infections cause thymic atrophy associated with apoptosis of thymocytes which could be mediated by IFN-γ induced tissue injury [9,11,29]. Our data shows that SARS-CoV-2 infection results in profound elevation (∼five-fold) of IFN-γ by CD45 + cells and to a lesser extent (∼two-fold) by CD45 − cells (Fig.…”

HSC-derived fatty acid oxidation in steady-state and stressed hematopoiesis

“…Recent studies have shown that high mortality (more than 25%) is associated with MAC pulmonary disease [55]. Mouse models of M. avium infection elicit an IFN-g response but not an IFN-a response [56], which is specifically dependent on IFNg-induced activation of macrophages [57]. Studies on mice infected with M. avium have shown expansion of Lin-c-kit + Sca-1 + (LSK) cells and that intravenous injection of M. avium causes expansion of Lin-ckit + Sca-1 + , CD34 + , Flk2 À (ST-HSC) cells 4 weeks after the infection [56,58].…”