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. 2008 Nov;89(Pt 11):2723-2730.
doi: 10.1099/vir.0.2008/03715-0.

Corticosteroids modulate Seoul virus infection, regulatory T-cell responses and matrix metalloprotease 9 expression in male, but not female, Norway rats

Judith D Easterbrook  1 , Sabra L Klein  1
Affiliations

Corticosteroids modulate Seoul virus infection, regulatory T-cell responses and matrix metalloprotease 9 expression in male, but not female, Norway rats

Judith D Easterbrook et al. J Gen Virol. 2008 Nov.

Abstract

Human hantaviral disease is mediated by excessive proinflammatory and CD8+ T-cell responses, which can be alleviated by administration of corticosteroids. In contrast with humans, male rats that are infected with their species-specific hantavirus, Seoul virus (SEOV), have reduced proinflammatory and elevated regulatory T-cell responses in tissues where virus persists. To determine the effects of glucocorticoids on SEOV persistence and immune responses during infection, male and female Norway rats received sham surgeries (sham) or were adrenalectomized (ADX0), in some of which corticosterone was replaced at low (ADX10) or high (ADX80) doses. Rats were inoculated with SEOV and serum corticosterone, SEOV RNA, gene expression and protein production were measured at different time points post-inoculation. We observed that SEOV infection suppressed corticosterone in sham males to concentrations seen in ADX0 males. Furthermore, males with low corticosterone had more SEOV RNA in the lungs than either females or males with high corticosterone concentrations during peak infection. Although high concentrations of corticosterone suppressed the expression of innate antiviral and proinflammatory mediators to a greater extent in females than in males, these immunomodulatory effects did not correlate with SEOV load. Males with low corticosterone concentrations and high viral load had elevated regulatory T-cell responses and expression of matrix metalloprotease (MMP)-9. MMP-9 is a glycogenase that disrupts cellular matrices and may facilitate extravasation of SEOV-infected cells from circulation into lung tissue. Suppression of glucocorticoids may thus contribute to more efficient dissemination of SEOV in male than in female rats.

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Figures

Figure 1
Figure 1. Circulating corticosterone concentrations were reduced in male rats during SEOV infection
Corticosterone in the serum of male (a) and female (b) rats that were ADX with corticosterone replaced at 0% (ADX0), 10% (ADX10), or 80% (ADX80) and in rats that received sham surgeries (sham) was measured by EIA. The gray boxes represent physiological concentrations of corticosterone in male and female rodents. Sham male rats had reduced concentrations of circulating corticosterone throughout SEOV infection that were comparable to ADX0 males (P<0.05).
Figure 2
Figure 2. Male rats with low circulating corticosterone had the most SEOV RNA in the lungs during peak infection
Genomic SEOV RNA was measured by real-time RT-PCR in lung tissue of male (a) and female (b) rats that were sham operated or ADX with corticosterone replaced and inoculated with SEOV. Sham and ADX0 males had more SEOV RNA in the lungs at Day 15 p.i. than either ADX10 or ADX80 males or all groups of females (*), P<0.05.
Figure 3
Figure 3. The expression of Ifnβ and Tnfα was elevated in the lungs of female, but not male, rats during SEOV infection and was reduced by administration of a high dose of corticosterone
Expression of Ifnβ and Tgfβ in the lungs of sham male and female rats (a and d) and males (b and e) and females (c and f) that had corticosterone manipulated was measured Days 0, 3, 15, 30, and 40 p.i. by real-time RT-PCR. Gene expression is displayed as relative to expression in uninfected rats in the same treatment group (green line) and the expression of each cytokine was normalized to Gapdh. The expression of Ifnβ and Tnfα was higher in the lungs of sham females than sham males during SEOV infection (*), P<0.05. High dose corticosterone (ADX80) eliminated the elevated expression of both Ifnβ and Tnfα in the lungs of female rats during SEOV infection (†), P<0.05.
Figure 4
Figure 4. Elevated regulatory T cell activity and Mmp9 expression was associated with low circulating corticosterone in male, but not female, rats
The expression of Tgfβ and Mmp9 in the lungs of sham male and female rats (a and d), as well as males (b and e) and females (c and f) that that were ADX with corticosterone replaced was measured Days 0, 3, 15, 30, and 40 p.i. by real-time RT-PCR. Gene expression was normalized to Gapdh and is expressed as relative to expression in uninfected rats in the same corticosterone treatment group (green line). Sham males had higher expression of Tgfβ and Mmp9 in the lungs than sham females during SEOV infection (*), P<0.05. Males with low concentrations of circulating corticosterone had higher expression of Tgfβ and Mmp9 than ADX80 males (†), P<0.05.
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