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Nutritional Sciences Graduate Program and * Departments of Animal Sciences, Nutritional Sciences and Microbiology and Molecular Immunology, University of Missouri, Columbia, MO 65211
3To whom correspondence should be addressed. E-mail: FritscheK{at}missouri.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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2 log10; P < 0.001) compared with their naïve counterparts. However, when the immunization dose was reduced to 103 bacteria, a modest diet treatment effect was observed, such that compared with immune lard-fed mice, immune fish oil–fed mice had significantly greater bacterial loads in their liver and spleen (i.e., 0.5 log10; P < 0.01). These data demonstrate for the first time that although dietary (n-3) PUFA can significantly impair host resistance to a primary as well as a secondary L. monocytogenes infection, the impairment of the immunological memory response is much less severe.
KEY WORDS: • (n-3) polyunsaturated fatty acids • fish oil • immunological memory • bacterial infection • mice
The long-chain (n-3) PUFA have immunomodulatory and anti-inflammatory properties that are well documented [see (1 –3 ) for recent reviews]. Their consumption has been reported to benefit patients suffering from a number of inflammatory and autoimmune diseases including rheumatoid arthritis (4 ), immunoglobulin A nephropathy (5 ), systemic lupus erythematosus (6 ,7 ), inflammatory bowel disease (8 ,9 ) and asthma (10 ,11 ). However, a growing body of evidence suggests that high (n-3) PUFA intake can impair infectious disease resistance to certain pathogens [see review (12 )]. This impairment is usually characterized by decreased pathogen clearance and reduced host survival. Although studies to date have examined the effect of (n-3) PUFA on primary immune responses, few studies have investigated their effect on the generation of immunological memory against an infectious agent.
Over the past decade, our laboratory has carefully defined the effect of (n-3) PUFA on infectious disease resistance using the murine listeriosis model. Listeriosis is an infectious disease that is caused by the intracellular, gram-positive bacteria, Listeria monocytogenes. This pathogen has been used by many investigators to better define the various factors and cells that are involved in the host response to intracellular pathogens (13
,14
). Protective immunity against intracellular pathogens, such as L. monocytogenes, requires a coordinated response from the host’s innate and cell-mediated immune system (15
). These responses are efficiently coordinated by the cytokine, interleukin-12 (IL-12), which promotes T-cell differentiation toward a cell-mediated (i.e., T-helper 1-type) immune response (16
). After resolution of a primary infection, the host develops a state of long-lived immunological "memory" against reinfection (17
). Upon subsequent encounter with the bacteria, antigen-specific memory cells respond with greater speed and efficiency (18
), controlling bacterial growth and promoting a more rapid clearance of bacteria from the organs. The exact mechanisms that are involved in memory cell differentiation are poorly understood, but memory cells are believed to derive from antigen-specific, effector CD4+ and CD8+ T lymphocytes that survive growth factor–induced clonal contraction (19
,20
). The frequency of memory T cells generated is closely correlated with the extent of effector cell proliferation during the primary response (21
). We reported recently that antigen-specific proliferation of naïve CD4+ T cells was significantly diminished in mice fed a diet enriched in (n-3) PUFA (22
). Further, we reported that during primary murine listeriosis, mice that were fed diets high in (n-3) PUFA exhibited impaired bacterial clearance and survival (23
), diminished early IL-12 and interferon-gamma (IFN
) production (24
). Thus, we hypothesized that (n-3) PUFA would reduce the formation of antigen-specific memory cells, thereby impairing immunological memory and leaving mice more susceptible to a secondary challenge.
To test this hypothesis, we fed mice one of two experimental diets that were nutritionally complete and differed only in the source of fat, i.e., lard or menhaden fish oil [the latter source is rich in (n-3) PUFA, whereas the former contains no (n-3) PUFA]. We measured the effect of dietary (n-3) PUFA on immunological memory responses using the following two approaches: 1) host protection experiments in which we compared bacterial load in the liver and spleen of naïve and immune mice, and 2) functional assessment of L. monocytogenes–specific memory cells by measuring ex vivo antigen-specific IFN production from splenocytes isolated from immune mice fed either lard- or fish oil–containing diets.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Specific pathogen–free 3- to 4-wk-old female BALB/c AnNHsd mice were used for all experiments (Harlan, Indianapolis, IN). Mice were housed at the Animal Sciences Research Center four per cage in polycarbonate cages containing aspen wood shavings. The room was maintained on a 12-h light:dark cycle at 23°C and 40–50% relative humidity. Initially, mice had free access to a commercial rodent diet (Purina Mills, St. Louis, MO) and autoclaved water. After a 1-wk acclimation period, mice were randomly assigned to one of two experimental diet treatment groups, i.e., lard or fish oil. The experimental diets were nutritionally complete and were based on the semipurified AIN-93G diet (25 ). The diets were modified to contain 180 g fat/kg diet, while maintaining the same nutrient-to-energy ratio of the original lower fat diet (Table 1 ). For these experiments, we chose this level of fat for two reasons. First, the experimental diets that we use in our studies were designed to mimic the average level of fat in current diets of the U.S. population. Second, the higher than usual fat content of these experimental diets allows a greater level of (n-3) PUFA enrichment with a widely used fish oil source of these fatty acids, i.e., menhaden fish oil.
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Bacterial infection.
Listeria monocytogenes, EGD strain (a generous gift from Dr. Charles Czuprynski, University of Wisconsin-Madison) was grown in tryptic soy broth (Difco, Sparks, MD) overnight at 37°C to obtain a bacteria culture in log-growth phase. After three washes with sterile PBS (Life Technologies, Grand Island, NY), the concentration of the bacteria was estimated via optical density, then diluted with saline to the desired infectious dose. For each experiment, the actual administered dose was confirmed by plating bacteria dilutions on blood agar plates. Bacterial challenges were given intravenously (i.v.) in a final volume of 0.2 mL via the lateral tail vein.
The murine listeriosis infectious disease model has been characterized extensively for host response to primary infections using either intraperitoneal (i.p.) or i.v. routes of infection. All of our previous experiments with this pathogen used the i.p. route. However, most of the recent publications characterizing the development of L. monocytogenes–specific memory cells have described investigations using the i.v. route of infection. Therefore, we chose to adopt the i.v. route for our present application of this infectious disease model.
Host survival experiments.
For all infectious disease investigations, the route and dose for any given pathogen must be chosen carefully, because both of these parameters can have a significant effect on the host response and final outcome. To characterize immune memory response in a high (n-3) PUFA environment, we had to define an effective immunizing dose for our system. Defining what constituted a sublethal, yet immunizing dose of L. monocytogenes in all dietary treatment groups was an important objective for our early experiments. Pilot experiments with mice fed a commercial rodent diet suggested that an i.v. injection of 105 or 106 colony forming units (cfu) of L. monocytogenes per mouse would help us define immunizing and challenge doses. The former is usually set at 0.1 or 0.01 of the 50% lethal dose (LD50).
Thus, mice were fed either of the two experimental diets for 28 d, then injected intravenously with 105 or 106 cfu of bacteria per mouse. After bacterial challenge, mice were monitored twice daily for signs of morbidity and mortality. Mice found to be moribund (e.g., diarrhea, lethargy, weight loss, unresponsiveness) were killed humanely by inhalation of CO2 followed by cervical dislocation. The deaths of these mice were recorded for the next 12 h because previous experience indicated that such mice would have most likely died during this time period had they not been humanely killed. Survival was monitored for 14 d postchallenge.
Host protection experiments: bacterial clearance in naïve vs. immune mice.
Mice were fed either of the two experimental diets for 28 d; mice randomly assigned to the "immune" group then received an immunization of 103 or 104 cfu L. monocytogenes per mouse. Thirty-five days postimmunization, both naïve and immune mice received a challenge dose of 105 cfu bacteria per mouse. The timing of the secondary challenge was based on studies that have characterized immunological memory responses against L. monocytogenes (26
,27
). Three days postchallenge, mice were anesthetized with an intramuscular injection of ketamine (200 mg/kg) and xylazine (16 mg/kg), then humanely killed by exsanguination. Bacterial loads in the liver and spleen were enumerated by plating serial 10-fold dilutions of organ homogenates in PBS on L. monocytogenes–supportive agar plates (McBride agar, Difco). Plates were incubated at 37°C for at least 48 h, then bacteria colonies were counted. Our limit of detection was 102 cfu bacteria/organ. Results were expressed as the mean cfu of L. monocytogenes per organ. Host protection was calculated by subtracting the mean bacterial load of immune mice from naïve mice within the same diet treatment group (28
).
Functional assessment of antigen-specific memory cells.
Mice were fed either of the two experimental diets for 28 d as described previously. Thirty-five days after immunization with 2 x 103 cfu L. monocytogenes, mice were anesthetized, then humanely killed. Spleens were aseptically removed and splenocytes isolated by density gradient centrifugation using Histopaque-1077 (Sigma Chemical, St. Louis, MO) as described previously (29
). Nucleated cells were enumerated electronically with a Coulter Counter, model ZM (Beckman Coulter, Fullerton, CA), then resuspended in HEPES-buffered RPMI 1640 media (Gibco BRL Products, Invitrogen, Carlsbad, CA) containing 50,000 U/L penicillin, 50 mg/L streptomycin, 50 mg/L gentamycin (Vedco, St. Joseph, MO), 2 mmol/L L-glutamine, and 100 mL/L fetal bovine serum (herein referred to as complete medium). Aliquots of cells were put into 96-well, tissue culture–treated, flat-bottomed plates at a density of 106 cells/well in 0.2 mL of complete medium. Cells were stimulated in duplicate with 0.2 or 1.0 mg/L of a polyclonal stimulus, concanavalin A (Con A, Sigma), and 0.1, 1.0, or 10 mg protein/L of an antigen-specific stimulus. The latter stimulus consisted of an overnight culture of L. monocytogenes that was heat-killed, sonicated and adjusted to a given total protein concentration as indicated. After 24 h, the culture supernatants were collected and stored at -70°C until analyzed for IFN.
IFN analysis.
Culture supernatants were analyzed for IFN in duplicate by a sandwich ELISA using an R&D Duoset (Minneapolis, MN) according to the manufacturer’s instructions. The optical density of the wells was measured at 450 nm, with a 540 nm reference, using a plate reader (Tecan Rainbow, Research Triangle Park, NC). All samples were analyzed during the same ELISA procedure. The limit of detection was 0.626 µg/L, and the intra-assay CV was 7.0%.
Statistical analysis.
The effects of dietary fat and immunization and their interactions were analyzed by two-way ANOVA using SAS (version 6.12 for Windows, Cary, NC). Values in the tables and figures are presented as least-squares (LS) means and SEM. Significant differences (P < 0.05) between treatments were identified by the Least Significant Difference test. All organ weights were expressed relative to body weight. The organ bacterial load data were log10 transformed before analyses. For samples that had undetectable bacteria, values equal to the limit of detection (i.e., 102 cfu/organ) rather than "zeros" were used in the analyses. The effects of dietary fat and stimuli concentration on ex vivo IFN production were evaluated by ANOVA using the general linear model for each stimulus (i.e., Con A and bacterial antigen) independently. Survival curves were compared using the Mantel-Haenszel log rank test using GraphPad Prism version 3.0a (GraphPad Software, San Diego, CA).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After an i.v. challenge with either 105 (Fig. 1A ) or 106 (Fig. 1 B) cfu L. monocytogenes, most deaths occurred between 3 and 5 d postchallenge. At the lower challenge dose (Fig. 1 A), no deaths occurred in the lard-fed mice, whereas 60% of the fish oil–fed mice died. At the higher challenge dose (Fig. 1 B), 70% of the lard-fed mice died, and 100% of the fish oil–fed mice died. At both challenge doses, the survival curve of mice fed fish oil differed from that of those fed lard (P < 0.01).
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Based on the data from the survival experiments, we decided to use two different doses of L. monocytogenes to immunize mice, i.e., 103 and 104 cfu/mouse. Much to our surprise, at the higher immunizing dose (i.e., 104 cfu/mouse), 6 of 12 mice consuming the (n-3) PUFA diet died, whereas all lard-fed mice survived (P < 0.001 for diet treatment effect). At the lower immunizing dose, there were no deaths in either diet treatment group. Thirty-five days after immunization, before these immune mice were to be rechallenged with 105 bacteria, we were unable to detect viable L. monocytogenes in the spleen or liver of immune mice (data not shown).
Diet treatments did not affect body weight before immunization (data not shown). Three days postchallenge with 105 cfu bacteria, mice that received the higher immunization dose had body weights that did not differ between lard- and fish oil–treated groups (Table 2 ). The relative liver weight was greater only in the naïve, fish oil–treated group (P < 0.05). Relative spleen weight was greater in both naïve and immune fish oil–fed mice (P < 0.001). At the lower immunizing dose, naïve and immune mice in the fish oil group had reduced body weight compared with their lard-fed counterparts (P < 0.001). Relative liver and spleen weights were greater in the mice consuming the fish oil diet (P < 0.001).
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5-fold) in their liver (P < 0.01) and spleen (P < 0.001) than lard-fed mice.
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We were unable to detect bacteria in either the spleen or liver 35 d postimmunization (data not shown). Spleen-derived antigen-experienced lymphocytes dose dependently (P < 0.001) secreted IFN in response to Con A and a crude bacterial antigen preparation (Table 3
). Compared with splenocytes from immune mice, splenocytes from unchallenged (naïve) mice secreted less IFN in response to Con A and did not make any detectable IFN in response to the bacterial antigen preparation (data not shown). IFN production by antigen-experienced lymphocytes did not differ significantly between diet treatment groups in response to either polyclonal (Con A) or antigen-specific (bacterial antigen) stimulation.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Our data are not entirely consistent with the earlier work of Chandra et al. (32 ). They reported that compared with mice fed the control diet devoid of (n-3) PUFA, mice fed a (n-3) PUFA-enriched diet exhibited a similar recall response to L. monocytogenes. However, that study had some important limitations. First, the experimental diet used contained only a modest amount of (n-3) PUFA (i.e., 0.2% eicosapentaenoic acid and docosahexaenoic acid); it also contained other immunomodulatory nutrients (i.e., nucleotides and arginine). Thus, it is unclear whether the lack of effect by (n-3) PUFA in that study was a consequence of low intake or interference by the other immunomodulatory nutrients. Second, the authors measured immunological memory via a delayed-type hypersensitivity (DTH) test. This test is an indirect measure of memory cell activity and cannot separate alterations in inflammation from antigen-specific, cell-mediated immune responses. The inability to separate these two elements is important because both may be influenced by (n-3) PUFA. Finally, the DTH response is driven primarily by CD4+ T lymphocytes, whereas host defense against L. monocytogenes is mediated predominately by CD8+ T lymphocytes (33 ).
Our host protection experiments were not without their limitations. First, the BALB/c mouse strain used in this study has a genetic predisposition toward humoral immune responses (i.e., T-helper 2–like) due in part to differential expression of the toll-like receptors and production of IL-12 (34
). This phenotype makes the strain more susceptible to a T-helper 1 (Th1)-type disease, and dictates that care must be taken when extrapolating these results to other species and mouse strains. Second, it was not our intention for mice to die from immunization. The fact that we observed a significantly greater number of deaths (i.e., 50%) in the (n-3) PUFA treatment group immunized with only 104 cfu L. monocytogenes underscores the conclusion that (n-3) PUFA profoundly impair host resistance during primary listeriosis. In this experiment, survivor bias made it difficult to discern diet-induced differences in bacterial clearance upon secondary challenge. In other words, the fish oil–fed mice that survived, by default, had the least impaired immune response. Thus, we might predict that upon rechallenge, the response of surviving fish oil–fed mice would be less likely to differ significantly from that of lard-fed mice. This shortcoming was addressed with the lower immunization dose. Reducing the dose 10-fold ensured that all mice survived the initial infection. Under these conditions, we did note that fish oil–fed immune mice exhibited a modest impairment in bacterial clearance compared with lard-fed mice. It is possible that the lighter body weight of fish oil–fed mice in this second experiment contributed to these differences in bacterial load. It is unclear whether such a difference (i.e., 0.5 log10) in bacteria numbers would be of biological significance. It is clear that compared with the primary response, the difference in bacterial load between diet treatments was much less during the secondary immune response. When the data from these two studies are analyzed as the reduction in bacterial load afforded by the immunization (i.e., host protection), it suggests that dietary (n-3) PUFA not only do not impair the recall response, but because of the greater bacterial load during primary listeriosis, the (n-3) PUFA diet actually provided 10-fold greater protection to the immune mice than the lard diet. Such an interpretation would be misleading and we do not support this approach for our data analysis. Overall, our data support the conclusion that if a mouse survives a primary L. monocytogenes infection, it is able to mount a relatively effective immunological memory response, regardless of high (n-3) PUFA intake.
To provide more direct evidence for this conclusion, we examined the effect of dietary (n-3) PUFA on the development of immunological memory at the cellular level, using ex vivo IFN production as a marker for antigen-experienced memory cell activity. This Th1-type cytokine is produced by CD4+ and CD8+ T lymphocytes, and is critical for host protection during primary (35
) and secondary (36
) listeriosis. Other researchers have demonstrated that CD8+ T memory cells secrete IFN within 6 h of antigen contact (37
). We found that (n-3) PUFA consumption did not affect IFN production by antigen-experienced splenocytes. The response we measured was indeed antigen-specific because under identical conditions, naïve cells did not respond with measurable IFN production. Furthermore, the response to the polyclonal stimulus was greater in immune cells than in naïve cells, confirming that the immune cell preparations contained memory cells able to respond with greater and more rapid cytokine production. These data suggest that (n-3) PUFA do not markedly affect in vivo generation or differentiation of L. monocytogenes–specific memory cells.
We recognize that measuring IFN in the supernatant of crude splenocyte cultures is not a very precise method of enumerating immune memory cells. However, enumeration was not our primary objective with this approach; rather, we simply wanted to show that memory cells had been generated in vivo and were present. Such an approach has been used by a number of prominent immunologists to assess the presence of antigen-specific, "memory" cell activity [e.g., (36
,38
)]. However, we are in the process of establishing more sophisticated methods with which to evaluate the phenotypic and functional activity of memory cells generated in a high (n-3) PUFA environment. For example, we have begun to use intracellular cytokine staining in conjunction with flow cytometry for the analysis of antigen-stimulated IFN production by CD4+ and CD8+ T cells. Also, we intend to measure the appearance of the dominant antigen-specific CD8+ T-cell populations using a recently acquired major histocompatibility complex-tetramer reagent loaded with a listeriolysin O peptide from the NIH Tetramer Core facility (Rockville, MD). The results from these types of analyses will be available in forthcoming publications.
Our current findings suggest that in terms of infectious disease resistance, the action of (n-3) PUFA on the innate arm of the immune system may be more important than their effect on T-lymphocyte function. During listeriosis, cells of the innate immune system (i.e., macrophages, natural killer cells, neutrophils, dendritic cells) play a critical role in controlling bacterial growth in the initial stages of infection. It is this stage of host defense that seems most seriously impaired by (n-3) PUFA. Previously, we reported that mice fed (n-3) PUFA produce significantly less IL-12 and IFN during the early stages of a primary L. monocytogenes infection (24
,39
). Therefore, the (n-3) PUFA-fed mice fall behind in the race to control early bacterial growth, resulting in L. monocytogenes spreading throughout host tissues. By the time adaptive immunity has generated sufficient numbers of effector cells against the infectious agent, many host cells have become infected. In the face of an effective CD8+ cytotoxic lymphocyte response, the host may die from tissue damage caused by its own immune system. However, because recall responses are less dependent upon innate immunity, the effect of (n-3) PUFA on secondary immunity appears to be more limited. In this case, the adaptive immune system has already established antigen-specific memory cells directed against the infectious agent. Our data suggest that the (n-3) PUFA-induced impairment in innate immunity (i.e., IL-12 and IFN production) does not play an important role in the host’s response to a secondary infection. This is consistent with the evidence that IFN is not essential for an effective recall response against L. monocytogenes (40
).
In summary, we report the novel finding that dietary (n-3) PUFA intake impairs host resistance of mice against L. monocytogenes during a primary infection, yet (n-3) PUFA have a much more modest effect on the generation of immunological memory and the ability to mount a secondary immune response. When considering the implications of our findings on human health, two population groups come to mind, i.e., infants and the elderly. The undeveloped/compromised immune systems in both groups may make them more susceptible to (n-3) PUFA–mediated impairment of infectious disease resistance. Furthermore, to some extent, these two groups have been targeted for increased (n-3) PUFA intake (41 –44 ). However, we would be remiss to not point out that the amount of (n-3) PUFA fed to the mice in our studies is far in excess of what is likely to be consumed by humans. We have yet to determine how much (n-3) PUFA is required before murine host resistance is compromised, or whether (n-3) PUFA alter mouse and human immune cell responses to L. monocytogenes in the same manner and to the same extent. Our long-term goal is to gain a better understanding of the effect of (n-3) PUFA on the phenotypic differentiation of the memory cell, so that we can predict how dietary (n-3) PUFA may affect susceptibility to infectious disease over a lifetime.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by a U.S. Department of Agriculture grant (#00–35200–9115) and the University of Missouri’s Food-for-the-21st-Century Program.
4 Abbreviations used: cfu, colony forming units; Con A, concanavalin A; DTH, delayed-type hypersensitivity; IFN, interferon-gamma; IL-12, interleukin-12; i.p., intraperitoneal; i.v., intravenous; LD50, 50% lethal dose; Th1, T-helper 1.
Manuscript received 1 October 2002. Initial review completed 1 November 2002. Revision accepted 15 January 2003.
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LITERATURE CITED |
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