Corticosteroids modulate Seoul virus infection, regulatory T-cell responses and matrix metalloprotease 9 expression in male, but not female, Norway rats
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.
AraiS.,
BennettS. N.,
SumibcayL.,
CookJ. A.,
SongJ. W.,
HopeA.,
ParmenterC.,
NerurkarV. R.,
YatesT. L.,
YanagiharaR.2008; Phylogenetically distinct hantaviruses in the masked shrew ( Sorex cinereus ) and dusky shrew ( Sorex monticolus ) in the United States. Am J Trop Med Hyg 78:348–351
BishayiB.,
GhoshS.2003; Metabolic and immunological responses associated with in vivo glucocorticoid depletion by adrenalectomy in mature Swiss albino rats. Life Sci 73:3159–3174[CrossRef]
DunstR.,
MettangT.,
KuhlmannU.1998; Severe thrombocytopenia and response to corticosteroids in a case of nephropathia epidemica. Am J Kidney Dis 31:116–120[CrossRef]
EasterbrookJ. D.,
KleinS. L.2008; Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats. J Med Virol 80:1308–1318[CrossRef]
EasterbrookJ. D.,
ZinkM. C.,
KleinS. L.2007; Regulatory T cells enhance persistence of the zoonotic pathogen Seoul virus in its reservoir host. Proc Natl Acad Sci U S A 104:15502–15507[CrossRef]
EberhardtW.,
SchulzeM.,
EngelsC.,
KlasmeierE.,
PfeilschifterJ.2002; Glucocorticoid-mediated suppression of cytokine-induced matrix metalloproteinase-9 expression in rat mesangial cells: involvement of nuclear factor- κ B and Ets transcription factors. Mol Endocrinol 16:1752–1766[CrossRef]
HannahM. F.,
BajicV. B.,
KleinS. L.2008; Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats. Brain Behav Immun 22:503–516[CrossRef]
HinsonE. R.,
ShoneS. M.,
ZinkM. C.,
GlassG. E.,
KleinS. L.2004; Wounding: the primary mode of Seoul virus transmission among male Norway rats. Am J Trop Med Hyg 70:310–317
HutchinsonK. L.,
RollinP. E.,
PetersC. J.1998; Pathogenesis of a North American hantavirus, Black Creek Canal virus, in experimentally infected Sigmodon hispidus . Am J Trop Med Hyg 59:58–65
KasselO.,
HerrlichP.2007; Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. Mol Cell Endocrinol 275:13–29[CrossRef]
KilpatrickE. D.,
TerajimaM.,
KosterF. T.,
CatalinaM. D.,
CruzJ.,
EnnisF. A.2004; Role of specific CD8+ T cells in the severity of a fulminant zoonotic viral hemorrhagic fever, hantavirus pulmonary syndrome. J Immunol 172:3297–3304[CrossRef]
KleinS. L.,
BirdB. H.,
GlassG. E.2000; Sex differences in Seoul virus infection are not related to adult sex steroid concentrations in Norway rats. J Virol 74:8213–8217[CrossRef]
KleinS. L.,
BirdB. H.,
GlassG. E.2001; Sex differences in immune responses and viral shedding following Seoul virus infection in Norway rats. Am J Trop Med Hyg 65:57–63
KleinS. L.,
MarsonA. L.,
ScottA. L.,
KetnerG.,
GlassG. E.2002; Neonatal sex steroids affect responses to Seoul virus infection in male but not female Norway rats. Brain Behav Immun 16:736–746[CrossRef]
KleinS. L.,
CernetichA.,
HilmerS.,
HoffmanE. P.,
ScottA. L.,
GlassG. E.2004; Differential expression of immunoregulatory genes in male and female Norway rats following infection with Seoul virus. J Med Virol 74:180–190[CrossRef]
LafrenieR. M.,
WahlL. M.,
EpsteinJ. S.,
HewlettI. K.,
YamadaK. M.,
DhawanS.1996; HIV-1-Tat modulates the function of monocytes and alters their interactions with microvessel endothelial cells. A mechanism of HIV pathogenesis. J Immunol 156:1638–1645
LeeH. W.,
LeeP. W.,
BaekL. J.,
SongC. K.,
SeongI. W.1981; Intraspecific transmission of Hantaan virus, etiologic agent of Korean Hemorrhagic fever, in the rodent. Am J Trop Med Hyg 30:1106–1112
MillerA. H.,
SpencerR. L.,
PearceB. D.,
PisellT. L.,
AzrieliY.,
TanapatP.,
ModayH.,
RheeR.,
McEwenB. S.1998; Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system. Cell Immunol 186:45–54[CrossRef]
MoriM.,
RothmanA. L.,
KuraneI.,
MontoyaJ. M.,
NolteK. B.,
NormanJ. E.,
WaiteD. C.,
KosterF. T.,
EnnisF. A.1999; High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome. J Infect Dis 179:295–302[CrossRef]
NilssonU. W.,
GarvinS.,
DabrosinC.2007; MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat 102:253–261[CrossRef]
ParrelliJ. M.,
MeislerN.,
CutroneoK. R.1998; Identification of a glucocorticoid response element in the human transforming growth factor beta 1 gene promoter. Int J Biochem Cell Biol 30:623–627[CrossRef]
PlaceN. J.,
KenagyG. J.2000; Seasonal changes in plasma testosterone and glucocorticosteroids in free-living male yellow-pine chipmunks and the response to capture and handling. J Comp Physiol [B] 170:245–251[CrossRef]
PlyusninA.,
MorzunovS. P.2001; Virus evolution and genetic diversity of hantaviruses and their rodent hosts. In Hantaviruses pp 47–75Edited bySchmaljohnC.,
NicholS. T.
New York: Springer;
PuyraimondA.,
WeitzmanJ. B.,
BabioleE.,
MenashiS.1999; Examining the relationship between the gelatinolytic balance and the invasive capacity of endothelial cells. J Cell Sci 112:1283–1290
SchountzT.,
PrescottJ.,
CogswellA. C.,
OkoL.,
Mirowsky-GarciaK.,
GalvezA. P.,
HjelleB.2007; Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus. Proc Natl Acad Sci U S A 104:15496–15501[CrossRef]
SilvermanM. N.,
PearceB. D.,
BironC. A.,
MillerA. H.2005; Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18:41–78[CrossRef]
XieB.,
DongZ.,
FidlerI. J.1994; Regulatory mechanisms for the expression of type IV collagenases/gelatinases in murine macrophages. J Immunol 152:3637–3644
You-TenK. E.,
LappW. S.1996; The role of endogenous glucocorticoids on host T cell populations in the peripheral lymphoid organs of mice with graft-versus-host disease. Transplantation 61:76–83[CrossRef]
Corticosteroids modulate Seoul virus infection, regulatory T-cell responses and matrix metalloprotease 9 expression in male, but not female, Norway rats