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. 2017 Mar;187(3):399-407.
doi: 10.1111/cei.12893. Epub 2016 Nov 29.

In-utero coxsackievirus B4 infection of the mouse thymus

Affiliations

In-utero coxsackievirus B4 infection of the mouse thymus

H Jaïdane et al. Clin Exp Immunol. 2017 Mar.

Abstract

Type B coxsackievirus (CV-B) infections are involved frequently in the triggering of several autoimmune diseases such as myocarditis, dilated cardiomyopathy, pericarditis, pancreatitis, type 1 diabetes, encephalitis, thyroiditis or Sjögren's syndrome. Serological and virological evidence suggests that maternal infections during pregnancy can play a role in the appearance of these diseases in offspring. The current study aims to explore the effect of an in-utero CV-B infection on the fetal thymus, the central site for programming immunological self-tolerance. In this perspective, female Swiss albino mice were inoculated intraperitoneally or orally with the diabetogenic CV-B4 E2 strain at gestational days 10 or 17. Offspring were killed at different post-inoculation times, and their thymuses were analysed for evidence of infection and alterations in thymic T cell subsets. In-utero CV-B infection of the thymus was demonstrated during the course of vertical transmission, as attested by viral RNA and infectious virus detection in most analysed samples. No histopathological changes were evident. Thymic T cells were not depleted, despite being positive for viral RNA. As evidenced by flow cytometry analysis, CV-B infection of the fetal thymus induced significant changes of thymic T cell populations, particularly with maternal inoculation at gestational day 10. Altogether, these findings suggest that CV-B infection of the fetal thymus may play an important role in the genesis of autoimmune diseases.

Keywords: T cell differentiation; fetal thymus; mouse model; type B Coxsackieviruses (CV-B); vertical transmission.

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Figures

Figure 1
Figure 1
Viral progeny titration in CV‐B4‐infected thymuses. The thymuses of six mice (three offspring born to each of two dams) of each experimental condition (oral virus inoculation at days 10G or 17G, and in the absence of inoculation) were subjected to viral progeny titration, by the plaque assay method, at different post‐inoculation (p.i.) times (day 17 gestation and days 0 and 5 from birth). Data are representative of two independent experiments with n = 3 thymuses per group and per time‐point, in each. Results are plotted as mean titres plaque‐forming units (p.f.u.)/mg of tissue) ± standard deviations.
Figure 2
Figure 2
Effects of CV‐B4 on thymus weight. The thymic index [(thymus weight/whole body weight) × 100] was calculated at day 5 from birth for six mice (three offspring born to each of two dams) of each experimental condition [oral virus inoculation at days 10 gestation (G) or 17G, and in the absence of inoculation]. Data are representative of two independent experiments with n =  3 thymuses per group in each. Results are expressed as mean percentages ± standard deviations.
Figure 3
Figure 3
Effects of CV‐B4 on thymus integrity. The thymuses of six mice (three offspring born to each of two dams) of each experimental condition [oral virus inoculation at day 10 gestation (G) or 17G, and in the absence of inoculation] were subjected to histological examination at different post‐inoculation (p.i.) times (day 17G and days 0 and 5 from birth). No histopathological change was observed in all examined sections. Representative sections from a negative control thymus (a) and a thymus stemming from an intraperitoneal inoculation of CV‐B4 E2 at day 10G. (b) Both sampled at day 5 from birth, and examined after haematoxylin and eosin staining. Gr × 400. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
CV‐B4 E2 infects thymic T cells. Representative agarose gel electrophoresis of amplicons specific to CV‐B4 E2 RNA in thymic T cells of offspring, sampled the day of birth (day 0), from negative control dams (lane NC) and dams inoculated intraperitoneally at day 10G (lanes 1 and 2) or orally (lanes 3 and 4). L = 100 base pairs (bp) DNA ladder; PC = positive control.
Figure 5
Figure 5
Effects of CV‐B4 E2 in‐utero infection on T cell differentiation. Thymic T cell suspensions were prepared from thymuses, collected at different post‐inoculation (p.i.) times, on offspring from negative control and CV‐B4 E2‐inoculated [either at day 10 gestation (G) or 17G, by the intraperitoneal or the oral route] dams, stained with anti‐CD90, anti‐CD4 and anti‐CD8 antibodies and analysed by fluorescence activated cell sorter (FACS). Histograms represent the DN, DP, SP4 and SP8 populations among total thymocytes (CD90+ cells). Data are representative of four independent experiments with n  =  3 thymuses per group and per time‐point in each. Results are expressed as mean percentages ± standard deviations; *P < 0·05 versus mock. DN = double‐negative CD4CD8; DP = double‐positive CD4+CD8+; SP4 = single‐positive CD4+CD8; SP8: single‐positive CD4CD8+.

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