* Department of Microbiology and Molecular Genetics, Department of Food Science and Human Nutrition,
Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824; and
Department of Microbiology and Immunology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia 26506
1 To whom correspondence should be addressed at 234 G.M. Trout Building, Michigan State University, East Lansing, MI 488241224. Fax: (517) 353-8963. E-mail: pestka{at}msu.edu.
Received March 24, 2005; accepted June 9, 2005
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ABSTRACT |
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Key Words: trichothecenes; deoxynivalenol; reovirus.
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INTRODUCTION |
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The potential for trichothecene mycotoxins to alter human immune responses remains unknown. However, trichothecenes enhance or suppress systemic responses to experimental infections with Salmonella (Bottex et al., 1990; Kubena et al., 2001
; Tai and Pestka, 1990
; Ziprin and Elissalde, 1990
), Listeria (Ziprin et al., 1987
; Ziprin and McMurray, 1988
), Staphylococcus (Cooray and Jonsson, 1990
), and herpes simplex (Friend et al., 1983
). Prolonged consumption of DON by mice induces elevated serum IgA and IgA immune complexes, kidney mesangial IgA deposition, and hematuria which are clinical signs of human IgA nephropathy (IgAN) (Pestka, 2003
). DON-induced upregulation of IL-6 appears to be critical to DON-induced IgAN, based its robust induction in vivo (Zhou et al., 1997
, 1998
, 2003b
), as well as studies employing IL-6 deficient mice (Pestka and Zhou, 2000
), antibody neutralization (Yan et al., 1997
), and ex vivo cultures (Yan et al., 1998
). In addition, exposure to lipopolysaccharide potentiates DON-induced inflammation and cytotoxicity in the mucosal and systemic compartments (Islam et al., 2002
; 2003
; Islam and Pestka, 2003
; Zhou et al., 1999
, 2000
). Although, DON's reported effects on the GI tract and IgA production suggest that this toxin might interfere with the immune response to enteric viruses, this possibility has not been systematically addressed.
Reovirus (respiratory enteric orphan virus) is a double-stranded RNA virus that has been isolated from the GI and respiratory tracts of both humans and animals (Nibert et al., 1996). Enteric reovirus infection produces a self-limited infection in which the virus is cleared from gastrointestinal tract within 7 to 14 days after onset (Barkon et al., 1996
; Rubin et al., 1985
). Mucosal immune responses to enteric reovirus infection have been well characterized with regards to induction of virus-specific intestinal IgA (London et al., 1987
; Major and Cuff, 1996
; Silvey et al., 2001
) and serum IgG (Major and Cuff, 1996
; Virgin et al., 1988
), as well as cell-mediated immune responses (Cuff et al., 1993
; London et al., 1987
) and cytokine production (Fan et al., 1998
; Mathers and Cuff, 2004
) in gastrointestinal-associated lymphoid tissues (GALT) of mice. Notably, Cuff et al. (1998)
successfully used enteric reovirus infection as a tool to assess the immunotoxic effects of cyclophosphamide on GI immune system, suggesting that this virus is an excellent laboratory model for investigating intestinal immune responses.
The objective of this research was to test the hypothesis that DON exposure modulates the immune response to enteric reovirus. The results indicated that DON impaired reovirus clearance but enhanced reovirus-specific immunoglobulin responses, which correlated with suppressed Th1 and enhanced Th2 cytokine responses, respectively.
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MATERIALS AND METHODS |
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Virus.
Reovirus serotype 1, strain Lang (T1/L) was used for all experiments. The virus was grown in L929 fibroblast cells at 34°C in DMEM medium (Sigma) with 5% (v/v) fetal calf serum (Sigma), 100 U/ml of penicillin, 100 µg/ml of streptomycin (Sigma), and 0.25 µg/ml of amphotericin B (GIBCO). The third-passage plaque-purified virion (Fulong et al., 1988) was used for mouse infection and prepared by extraction with 1,1,2-trichloro-1,2,2-trifluoroethane (Sigma), followed by discontinuous CsCl gradient centrifugation as previously described (Silvey et al., 2001
). Titers of the purified virus were determined by plaque assay (Cuff et al., 1990
).
Experimental design and sample collection.
DON, purified as described previously by Clifford et al. (2003), was dissolved in endotoxin-free water. Mice were treated once with 2 to 25 mg/kg bw DON po. The highest dose represents approximately one third the LD50 and was selected based on its demonstrated capacity to modulate gene expression in mice (Zhou et al., 1997
). After 2 or 12 h, animals were infected by oral gavage with 3 x 107 plaque forming units (PFU) of reovirus in a total volume of 100 µl borate-buffered saline (pH 7.4) containing 2% (w/v) of gelatin (London et al., 1987
). At specified time intervals, fecal pellets were collected and/or mice were bled from lateral saphenous vein (Hem et al., 1998
). At experiment termination, mice were anesthetized with metaflurane, bled from retroorbital plexus, and immediately euthanized by cervical dislocation. Serum was separated from clotted blood samples and stored at 4°C for later analysis. Fecal pellets were collected at intervals after infection and weighed. The material was suspended at 0.1 g/ml in phosphate-buffered saline, held on ice for 2 h, and then sonicated for 15 s. Solutions were cleared by high speed centrifugation for 10 min at 4°C. Supernatants were used directly for specific antibody detection by ELISA and for total RNA purification. Intestines and spleens were procured from euthanized mice and processed as described below.
Lymphoid fragment cultures.
The lymphoid fragment culture system of Logan et al. (1991), as modified by Cuff et al. (1998)
, was used to study immunoglobulin secretion. Briefly, seven Peyer's patches (PP) per mouse were removed from intestine, pooled, and washed three times in HBSS with 5 µg/ml of gentamicin and twice with tissue culture medium (TCM) consisting of RPMI 1640 medium supplemented with 10% (v/v) FBS, 2 mM L-glutamine, 0.5 µM 2-mercaptoethanol, 5 µg/ml of gentamicin, 100 unit/ml penicillin, and 100 µg/ml streptomycin. Individual patches were cut in half and incubated collectively in 2 ml of TCM for 5 days at 37°C under 5% CO2 without additional stimulation. Lamina propria (LP) cultures were established, after removing PP, by splitting intestine longitudinally and cutting it into pieces 23 cm long. The fragments were washed at least three times with HBSS with 0.2% NaHCO3, 0.1M HEPES, and 5 µg/ml gentamicin. One half of the fragments were used for viral titer detection, and the other half were incubated twice for 30 min in 5 mM EDTA in HBSS to remove epithelial cells. Fragments were washed twice more and then incubated in 3 ml of TCM for 5 days at 37°C under 5% CO2. Culture supernatants were harvested and stored at 4°C for antibody detection by ELISA.
Virus titration.
For viral plaque counts of GI tract, intestinal segments were placed in 2 ml of sterile phosphate-buffered saline, freeze-thawed three times, and sonicated. Virus titers were measured by standard viral plaque assay (Major and Cuff, 1997). Briefly, tissues were homogenized in 3 ml saline containing 0.5% gelatin. Serial dilutions (100 µl) in TCM were incubated on monolayers of L-929 fibroblasts in 12-well tissue culture plates for 45 min at 34°C and thereafter overlaid with 3 ml of 1% agar in Medium 199 (Sigma) and cultured at 34°C. Plaques were counted after 7 days incubation.
Real-time PCR for reovirus.
For fecal pellet analyses, total RNA was extracted from 200 µl of supernatant of 10% (w/v) fecal suspension using TRIZOL (Invitrogen). PCR primers were selected from published sequence of 2 core spike (L2 gene) of reovirus T1/L (Breun et al., 2001
) as follows: forward, 5' ctg acg tcg atc agg tcg ttg 3' and reverse, 5' gat gtg gca tgc atg cat gag 3'. The size of the expected amplicon was 97 bp. To denature dsRNA, 1 µg of the template was incubated for 5 min at 95°C with 250 pM of random primers (Promega) or L2 forward primer in total volume of 12 µl and then snap cooled on ice. Reverse transcriptase reaction was performed by adding 4 µl of 5x RT reaction buffer, 2 µl of 0.1M DTT, 1 µl of 10mM dNTP, and 1 µl of Superscript II reverse transcriptase (Invitrogen) at 42°C for 60 min. Purified reoviruses were added into 10% (w/w) of fecal pellet suspension from vehicle mice at concentrations of 0, 101, 102, 103, 104,105 106, 107 PFU/ml as standard sample for standard curve and sensitivity determination.
ELISA.
Serum, culture fluid, and supernatant of fecal suspension were assayed for virus-specific antibody by ELISA by a modification of the procedure of Major and Cuff (1997). Briefly, 96-well plates were coated overnight at 4°C with 50 µl /well of purified reovirus T1/L, diluted to 1 x 108 particles/ml in 0.1 M NaHCO3 (pH 9.6). Plates were washed four times with PBS with 0.1% Tween 20 (PBS-T) and blocked with 100 µl of blocking buffer (3% [w/v] bovine serum albumin [BSA] in PBS-T) for 2 h at room temperature. Serial dilutions (100 µl) of serum, culture fluids, or fecal supernatants were added to each well in duplicate and incubated at 4°C for 16 h. The plates were washed seven times with PBS-T, and 100 µl of goat anti-mouse IgG2A-, IgG1-, or IgA-HRP conjugates (1:3000) in blocking buffer was added to each well. Plates then were incubated at room temperature for 2 h. Following seven washes with PBS-T, 100 µl of K-Blue Max TMB substrate (Neogen) was added to each well, and plates were incubated at room temperature for 5 min. Reaction was terminated by adding 50 µl of 2 N H2SO4, and absorbance was read at 450 nm on ELISA reader. Absorbance 450 was used as endpoint for fecal and fragment cultures. For sera, titers were designated as the highest serum dilution that yielded absorbances of 0.2 or higher; the geometric mean antibody titer was then calculated.
Real-time PCR for cytokines.
For cytokine PCR, PPs were collected and immediately put into RNAlater reagent (Ambion) at 4°C. Total RNAs were isolated with TRIZOL (Invitrogen). Primer sequences for amplification of cytokines (Table 1) were designed according to the sequences of cytokine mRNA from Genebank and published data (Overbergh et al., 2003; Samuel and Knutson, 1983
). RNA (1 µg) for amplification of cytokines was denatured by incubation at 70°C for 10 min with 250 pM Oligo (dT)1215 primer (Invitrogen). Real-time PCR was performed as previously described (Kinser et al., 2004
) on an ABI Prism 7700 Sequence Detector with ABI SYBR Green PCR core kit (Applied Biosystem). Reactions contained a total volume of 12.5 µl: 1 µM primer pair, 3 mM Mg+2, 0.8 mM dNTP mixture, 6 ng cDNA template, 0.075 µl Taq Gold DNA polymerase (ABI). Reactions were started by incubation at 95°C for 5 min and followed by 40 two-step thermal cycles of 15 s denaturation at 95°C, 60 s primer annealing and extension at 60°C. Real-time measurements were taken, and a threshold cycle (Ct) value for each sample was calculated. Three negative controls and known positive standard curve samples ranging from 101 to 108 copies/ml of target gene were used for each run. All samples were analyzed in duplicate.
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Statistics.
Data were analyzed using Sigma Stat software (Jandel Scientific, San Rafael, CA). For comparisons of two groups of data, Student's t-test was performed. For comparison of multiple groups of data, a Kruskal-Wallis one-way ANOVA on ranks was used. Data sets were considered significantly different when p < 0.05.
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RESULTS |
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DON Suppresses TGF-ß mRNA Expression
TGF-ß is known to be a switch factor in the IgA response. DON exposure significantly elevated TGF-ß mRNA in PP within 2 h (Fig. 11). However, at 3, 5, and 7 days, TGF-ß mRNA expression was less in mice treated with reovirus and DON than with reovirus alone. These data suggest that elevated IgA switching resulting from increased TGF-ß might not explain aforementioned increases in IgA production.
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DISCUSSION |
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The critical immunologic determinants for resistance to reovirus and other enteric viruses remain unclear. Resistance is multifactorial and includes elements of innate and adaptive immunity. It is likely that decreased IFN- responses in DON-exposed mice contributed to impaired cellular or innate immune responses in early resistance to infection. The observation that DON inhibited IFN-
expression early during the infection is consistent with diminished clearance of reovirus infection and a suppressed Th1 response. Suppression of IFN-
production has been previously shown to be mediated by IL-4 (Szabo et al., 2003
), IL-6 (Diehl and Rincon, 2002
), and IL-10 (Conti et al., 2003
). Thus, upregulation of these Th2 cytokines by DON might have mediated IFN-
suppression. IFN-
plays a key role in antiviral immunity by multiple mechanisms including suppression of viral replication, macrophage activation, inducible nitric oxide synthase expression, and stimulation of specific cytotoxic immunity via cell-surface-bound antigen associated MHC proteins (Boehm et al., 1997
; Shtrichman and Samuel, 2001
). Suppression of IFN-
expression might have impaired one or more of these mechanisms, thus prolonging reovirus replication and survival. Future efforts should focus on clarifying how DON suppression of IFN-
modulates reovirus-induced changes of macrophage, NK, dendritic, or T-cell function as well as epithelial cell physiology, pIgR levels, or immune tolerance.
Ultimately, the IFN- response recovered (day 8) and likely facilitated removal of the virus in conjunction with elevated reovirus-specific IgA. It should be noted that IgG2A response is a major isotype of IgG induced by reovirus (Major and Cuff, 1996
), and this is considered to be Th1 dependent, with IFN-
acting as a switch factor. The capacity to mount a robust IgG2A response by day 10 is consistent with recovery of IFN-
production and a Th1 immune response.
Although class-switching to IgA-committed B cells is thought to involve TGF-ß (Nakamura et al., 1996; van Ginkel et al., 1999
), our results suggest that the increased reovirus-specific IgA response could not be explained by elevated TGF-ß. It is, further, not clear whether Th1 or Th2 cells are beneficial for optimal secretory IgA production. However, Th2 cytokines play a role in terminal differentiation of B cells that are already committed to IgA, whereas Th1-type cytokine IFN-
is implicated in the induction of the polymeric Ig receptor (pIgR) needed for transport of secretory IgA (van Ginkel et al., 2000
). The Th2 cell produces more IL-4, thereby expanding Th2 cells, which support the associated immune response involving secretion of IL-4, IL-5, IL-6, IL-9, IL-10, IL-13. IL-4 supports IgG1 subclass and IgE production, but IgA is also produced during a Th2-dominated response (Boyaka et al., 2001
; Yamamoto et al., 1996
). Thus, increased IL-4 might act at the level of class switching or by driving differentiation of IgA-committed B cells, along with IL-6, to plasma cells.
Enhanced mucosal and systemic IgA responses to reovirus are congruent with previous findings that chronic DON exposure potentiates total serum and fecal IgA (Dong et al., 1991; Forsell et al., 1986
; Greene et al., 1994
) as well as ex vivo PP and splenic IgA production (Bondy and Pestka, 1991
; Dong et al., 1991
; Forsell et al., 1986
; Greene et al., 1994
). Chronic DON exposure also enhances IgA responses to intestinal and self antigens (Pestka et al., 1990b
; Rasooly and Pestka, 1992
, 1994
; Rasooly et al., 1994
). These earlier findings, consistent with DON-induced potentiation of reovirus-specific IgA, occurred in feces, serum, and fragment cultures during late-stage infection observed here. Previously, we have observed that DON is an effective inducer of IL-6 (Zhou et al., 1998
, 1999
) and that elevated IL-6 is crucial to increased IgA responses observed in mice chronically exposed to DON (Pestka and Zhou, 2000
). Thus, it was not surprising to observe that acute DON-exposed mice had markedly increased IL-6 mRNA expression in PP. Further evidence of a skewed Th2 response were DON potentiation of serum IgG1 as well as the marked elevations of IL-4 and IL-10 mRNA in PPs of DON-exposed mice. All three of these cytokines can promote proliferation and terminal differentiation of Ig-secreting cells and downregulate Th1 responses (Conti et al., 2003
; Diehl and Rincon, 2002
; Mathers and Cuff, 2004
; Yamamoto et al., 1996
). Taken together, these data are consistent in DON enhancement of the Th2 response to reovirus.
The mechanism by which DON rapidly enhances the cytokine responses has been characterized previously. In T cells and macrophages, DON can increase cytokine gene expression by enhancing both activation of key transcription factors (Chung et al., 2003; Li et al., 2000
; Ouyang et al., 1996
; Wong et al., 2002
; Zhou et al., 2003a
) and cytokine mRNA stability (Chung et al., 2003
; Li et al., 1997
; Wong et al., 2002
). Both enhanced transactivition and mRNA stabilization of immune and inflammatory genes by DON have been linked to activation of p38 and ERK 1/2 MAPKs via the ribotoxic stress response (Chung et al., 2003
; Moon and Pestka, 2002
; Moon et al., 2003
). Two signaling transducers upstream of the MAPKs that appeared to mediate DON's action are double-stranded RNA-activated protein kinase R (Zhou et al., 2003b
) and the Src-family tyrosine kinases (Zhou and Pestka, in press). The potential for interactive effects of reovirus with these transduction pathways is a potential target for further study.
Assessment of potential xenobiotic modulation of mucosal immune function has lagged behind well-established methods for measuring systemic immunotoxicity (Bondy and Pestka, 2005; Kawabata et al., 1995
). The results presented herein and previously (Cuff et al., 1998
) suggest reovirus model to be a robust approach for monitoring dysregulation of host resistance as well as Th1 and Th2 responses by immunotoxic chemicals. Real-time PCR is a rapid, sensitive method for detection of viral genomic RNA and DNA and can be used to monitor viral infections (Idesawa et al., 2004
; Pang et al., 2004
; Van Rijn et al., 2004
). The demonstration that virus contamination in feces could be monitored using reovirus L2 gene real-time PCR and that it correlated with PFU assays in the intestine indicates that this is a facile approach for noninvasive monitoring of the course of reovirus infection in experimental mice.
These results have relevance to human safety assessment. The dose-response experiment suggested that as little as 2 mg/kg bw of DON potentiated reovirus L2 RNA levels in PP, whereas 10 mg/kg bw was required for significant potentiation of this RNA in fecal contents. Differences between the two endpoints might relate to RT PCR sensitivity within these two matrices. In addition, the mRNA might exist as two species in these matrices. In feces, it is likely the PCR is detecting viral RNA, whereas RNA in PP might include viral RNA as well as mRNA undergoing translation. Nevertheless, the data suggest that a relatively low dose of DON was sufficient to increase the viral burden in this model. The 2 mg/kg bw dose is equivalent to 13 ppm of DON in mouse diet, and such concentrations have been found in contaminated human food samples (Abouzied et al., 1991). These findings are particularly important in view of the 100-fold safety factor that is used establishing tolerable daily intake of natural toxins (Pestka and Smolinski, 2005
). Future studies to relate to how chronic exposure to DON at low concentrations might affect response to reovirus challenge.
Taken together, the results presented herein suggest DON transiently suppresses the host response to enteric reovirus by interfering with the Th1-driven IFN- response, thereby increasing severity of the infection and virus shedding in feces. Corresponding increases in DON-mediated Th2 cytokines, notably IL-4 and IL-6, might concurrently drive elevated reovirus-specific IgA and IgG responses that were observed at experiment termination. From the perspective of host resistance, these observations are important for two reasons. First, elevated viral load in intestinal tissue is likely to increase inflammation and discomfort to the host during the infection process. Second, elevated fecal shedding will enhance the spread of this virus among individuals. From the perspective of immunotoxicity, these data are important because they suggest that, in addition to induction of apoptosis, trichothecenes might also suppress host response by selectively modulating cytokine responses to an infecting pathogen. In the future, it will be desirable to further explore mechanisms for Th1/Th2 modulation in this and other viral models following acute and chronic DON exposure.
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ACKNOWLEDGMENTS |
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