Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion

Abstract

Francisella tularensis is a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Two subspecies (type A and B strains) of the pathogen exist, the former being much more virulent than the latter for humans and other higher mammals. In this study, we examined the effect of virulent strains of F. tularensis infection on the thymus and thymocytes and the potential mechanisms involved. Low-dose aerosol exposure of C57BL/6 mice with type A, but not type B, F. tularensis caused severe reduction in thymus weight and destruction of thymocytes, particularly CD4 + CD8 + thymocytes, by day 4 after infection. The depletion of thymocytes was accompanied by a significant increase in circulating cortisone levels and could be partially prevented by adrenalectomy. Moreover, thymus atrophy and thymocyte depletion following infection were abolished in mice deficient in tumor necrosis factor receptors 1 and 2, but not in FasL-deficient mice. The severe destruction of the thymus and selective depletion of immature thymocytes during type A F. tularensis infection may represent a key pathogenic mechanism in tularemia and could hinder the development of an effective primary immune response against this highly virulent pathogen.

Acute Thymic Involution and Mechanisms for Recovery

“…More recently, infection with F. tularensis Yama strain, a virulent Japanese strain, caused a drastic increase in IFN-γ and the DP thymocytes and a decrease in the DN thymocytes in the blood (Hotta et al 2016). Thus, it seems that DP thymocyte loss in the thymus that was reported by Chen et al (2005) may be associated with an increase in DP thymocytes in the blood of F. tularensis-infected hosts.…”

“…However, reversal of the ATI and T cell depletion was observed in mice deficient for TNF receptors 1 and 2, but not in Fas ligand-deficient mice (Chen et al 2005). More recently, infection with F. tularensis Yama strain, a virulent Japanese strain, caused a drastic increase in IFN-γ and the DP thymocytes and a decrease in the DN thymocytes in the blood (Hotta et al 2016).…”

Francisella tularensis Suppresses the Proinflammatory Response of Endothelial Cells via the Endothelial Protein C Receptor

“…Furthermore, this bacterium often proves lethal before an adaptive immune response can be mounted (12,13). This rapid lethality makes deciphering the innate immune response to F. tularensis imperative for understanding the pathogenesis of tularemia.…”

“…tularensis is capable of disseminating to various host tissues (6), where it is thought to replicate primarily within macrophages (10,11). The ability of F. tularensis to survive within macrophages and its lethality before an acquired immune response can be mounted (12,13) make it imperative to elucidate the role of innate immunity and how this organism may modulate it during the course of infection. The LVS impairs agonist-induced secretion of proinflammatory cytokines by monocytes/macrophages of both murine and human origin (14,15).…”

Current and emerging assays for Francisella tularensis detection: a review

“…This type of analysis was performed in some clinical studies (Sumida et al, 1992;Porsch-Ozcurumez et al, 2004) and it was used for microbiological and immunological research purposes (Abd et al, 2003;Chen et al, 2005). However, the detection of F. tularensis or a valid diagnostic system based on flow cytometry still remain a challenge.…”