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. 2000 Nov;122(2):186–191. doi: 10.1046/j.1365-2249.2000.01382.x

Role of IL-10 in invasive aspergillosis: increased resistance of IL-10 gene knockout mice to lethal systemic aspergillosis

K V Clemons *, G Grunig *,†, R A Sobel ‡, L F Mirels *, D M Rennick *, D A Stevens *
PMCID: PMC1905763  PMID: 11091273

Abstract

IL-10 is associated with a Th2 response, down-regulation of a Th1 response and macrophage activation. We assessed the role of IL-10 during systemic infection with Aspergillus fumigatus. Systemic aspergillosis was established in female C56Bl/6 IL-10−/– (KO) and wild-type (WT) C57Bl/6 mice by i.v. administration of 1 × 105−6 × 105 conidia of A. fumigatus. In two experiments, KO survived longer than did WT (P < 0·001). Determination of fungal burdens in the kidneys and brain showed that KO carried significantly lower burdens in both organs than did WT on day 3 (P < 0·001). Semiquantitative histological analyses showed fewer inflammatory foci/mm2 in brain and kidneys of KO than WT (P < 0·03 and < 0·001, respectively) and that extent of infection and associated tissue injury were greater in WT. Although beneficial in some bacterial infections, exogenous IL-10 has been shown deleterious in models of fungal infection. Our data indicate IL-10 is deleterious during systemic aspergillosis infection, increasing the host susceptibility to lethal infection. We speculate this might be related to greater Th2 or lesser Th1 responses, or down-regulation of macrophage responses, in WT compared with KO.

Keywords: aspergillosis, IL-10, cytokines, host resistance

Introduction

IL-10 is a pleiotropic cytokine that regulates some functions of lymphoid and myeloid cells. IL-10 is produced by Th2 lymphocytes, macrophages, mast cells, and B cells [1–4]. IL-10 has a variety of functions that include down-regulation of T cell activation and of the production of interferon-gamma (IFN-γ), proinflammatory cytokines (e.g. IL-1, tumour necrosis factor-alpha (TNF-α), IL-5) and chemokines; suppression of macrophage function, proliferation and activation; inhibition of nitric oxide production, enhancement of B cell proliferation and antibody production and promotion of a Th2 cellular response by inhibiting differentiation of a Th1 response [1–5]. The influence of IL-10 on infection appears to differ for different microorganisms. In some instances IL-10 plays a beneficial role in resistance to some microbial infections, whereas in other instances IL-10 is deleterious to infection with a variety of microorganisms.

In studies with fungal infections, IL-10 has been demonstrated to be deleterious in experimental models of several pathogenic fungi [6–10]. Innate immunity, in the form of pulmonary macrophages and polymorphonuclear neutrophils (PMN), plays a primary role in resistance against aspergillosis. However, the role played by cytokines in resistance to infection with Aspergillus fumigatus is not well understood, with Th1 mechanisms of cellular resistance (i.e. activation of macrophages) rather than Th2 mechanisms (e.g. antibody-mediated) thought to be more important.

In vitro, IL-10 pretreatment of mononuclear cells reduced the cells' capacity to damage Aspergillus hyphae, whereas phagocytic activity for conidia and inhibition of germination was increased, thus possibly providing a sanctuary for progressive infection [11]. IL-10 had no direct effect on the morphologic forms of A. fumigatus [11]. Furthermore, these authors suggest that host response to Aspergillus infection may be improved by reversal of the immunosuppressive effects of IL-10 [11]. This suggestion may be corroborated in part by the demonstration of an increase in the resistance of susceptible mice to experimental invasive pulmonary aspergillosis after neutralization of IL-4 or IL-10 using MoAbs [12]. In contrast, in a model of experimental allergic bronchopulmonary aspergillosis, the lack of IL-10 in mice resulted in increased mortality and more severe pulmonary inflammation, indicating a beneficial role played by IL-10 in modulating the allergic inflammatory response to Aspergillus antigens and inhibiting inflammatory responses driven by IFN-γ or IL-5 [13]. Aspergillus antigen appears to elicit a dominant Th2-like response in the lungs [13], whereas conidia may influence the lung immune response in a different manner [14].

The importance of IL-10 during systemic infection with A. fumigatus has not previously been examined. In the current study we sought to establish a role for IL-10 during systemic infection to see whether the lack of functional IL-10 in gene-knockout (KO) mice altered the course of systemic aspergillosis. Our results indicate that IL-10 plays a deleterious role in innate resistance to systemic aspergillosis.

Materials and methods

Fungi

The strain of A. fumigatus and the conditions used for growth and preparation of the conidial inoculum in these studies has been described previously [15].

Mice

C57Bl/6 IL-10−/– knockout mice (IL-10 KO) [16,17] were bred in the DNAX animal facility. C57Bl/6 IL-10-sufficient mice (wild-type controls (WT)) were obtained from either Jackson Laboratories (Bar Harbor, ME) or Taconic (Germantown, NY). Female IL-10 KO mice and WT mice were 6–12 weeks of age at the time of infection. All mice were maintained under clean conditions on sterilized bedding at the California Institute for Medical Research. Mice were provided sterilized food and acidified water ad libitum.

Experiment 1

The model of invasive aspergillosis studied was similar to that previously described [15]. In this model, the organs with residual infection are the kidneys and the brain. Thirteen C57Bl/6 IL-10−/– knockout mice (IL-10 KO) and 10 C57Bl/6 IL-10+/+ WT control mice (all approximately 12 weeks of age) were infected intravenously with 6·2 × 105 viable conidia of A. fumigatus, strain 10AF. The severity of infection was determined by tallying deaths through 21 days.

Experiment 2

Female C57Bl/6N IL-10 KO mice (21 mice, 6–9 weeks old) and WT C57Bl/6N (20 mice, 8 weeks old) were infected intravenously with 3·8 × 105 conidia of A. fumigatus 10AF. Ten mice from each group were predesignated for survival study, which was tallied through 14 days of infection. The remaining animals were designated for determination of colony-forming units (CFU) of A. fumigatus in the organs or for tissue samples for histopathology. On day 3 of infection, five mice from each group were killed and the number of colonies of A. fumigatus in the brain and kidneys determined by quantitative plating of organ homogenates [15]. In addition, mice from each group were killed and tissue samples from various organs placed in 10% buffered formalin for histology studies.

Experiment 3

Fifteen IL-10 KO mice and 15 WT control mice were infected intravenously with 1·5 × 105 viable conidia of A. fumigatus strain 10AF. The severity of infection was determined by determining the number of viable CFU of A. fumigatus remaining in the brain and kidneys of 10 mice of each genetic type at day 3 of infection. In addition, mice of each type were killed and organs removed to 10% buffered formalin for semiquantitative histological study.

Semiquantitative histological analyses

Tissue samples were embedded in paraffin and sections stained with haematoxylin and eosin stain for routine evaluation and periodic acid–Schiff (PAS) stain for demonstration of fungi. Microscopic examination revealed that in the brains there were both broad infarct-like necrotic areas with scant inflammation and focal inflammatory cell clusters. In brain sections from each mouse, inflammatory foci (> 10 clustered inflammatory cells) and infarcts (well-defined areas of tissue necrosis and pallor) were counted and the total brain tissue area in each section determined by ruler measurements of two maximal dimensions. In contrast, lesions in the kidneys were primarily inflammatory, with only small foci of associated necrosis. Therefore, only the numbers of inflammatory lesions per mm2 of kidney tissue were determined for each sample. The areas of brain and kidney tissue sections analysed in each group were similar.

Statistical analysis

Statistical analyses of comparative survival were done using a Wilcoxon rank sums test and comparative burdens of CFU in the organs were analysed using a Mann–Whitney U-test as previously described [15]. All analyses were done using GBSTAT ver. 6.0 (Dynamic Microsystems, Inc., Silver Spring, MD).

Results

Experiment 1

The results of the comparative survival observed in this study are presented in Fig. 1. IL-10-sufficient animals (WT controls) died between days 3 and 5 with 50% of the animals dead by day 4. In contrast, IL-10 KO began to die on day 4 and 50% were dead on day 6. Statistical comparison of the day of death by a Wilcoxon rank sums test showed that the WT control mice died significantly sooner than did the IL-10 KO mice (P < 0·001).

Fig. 1.

Fig. 1

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Cumulative mortality of 12-week-old IL-10 knockout (KO) and wild-type (WT) mice infected systemically with 6·2 × 105 conidia of Aspergillus fumigatus. Experiment 1. ○, C57Bl/6 WT; ▪, IL-10 KO.

Experiment 2

The results of the comparative survival observed in the second experiment are similar to those of the initial experiment. The WT mice succumbed to infection significantly earlier than did the IL-10 KO mice (P < 0·001) (Fig. 2), with the first deaths in the WT mice occurring on day 3 versus day 4 for the IL-10 KO mice. Of the mice in the WT group 90% had died by day 3 versus 90% mortality by day 5 in the IL-10 KO group.

Fig. 2.

Fig. 2

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Cumulative mortality of 6–9-week-old IL-10 knockout (KO) and 8-week-old wild-type (WT) mice infected systemically with 3·8 × 105 conidia of Aspergillus fumigatus. Experiment 2. ○, C57Bl/6 WT; ▪, IL-10 KO.

The determination of CFU of A. fumigatus in the organs (brain and kidney) on day 3 showed that WT mice carried higher mean burdens of A. fumigatus in both the brain and kidneys than did the IL-10 KO mice. WT mice carried a mean 10-fold higher burden in the brain than did IL-10 KO mice; log10 geometric mean number of CFU of 4·71 (95% confidence interval (CI) 4·6–4·9) in WT versus 3·71 (95% CI 2·9–4·5). Similarly, WT mice carried about a four-fold higher burden of A. fumigatus in the kidneys than did the IL-10 KO mice; WT mean 4·42 (95% CI 4·2–4·7) versus IL-10 KO mice with a mean of 3·86 (95% CI 3·2–4·5). Statistical comparison showed that although these differences showed a trend, the mean burdens were not significantly different (P = 0·075). This is probably due to the small n of five mice in each group. Regardless, these data suggest that IL-10 KO mice show less severe disease than do their WT counterparts.

Experiment 3

This study was done primarily to assess the comparative numbers of viable organisms in the kidneys and brain just prior to expected death due to infection. In this experiment, the inoculum of A. fumigatus was lowered to study reduction in the severity of infection and a larger number of mice (n = 10 in each group) was used than in experiment 2. The results showed that IL-10 KO carried significantly lower burdens of A. fumigatus in both organs (brain P = 0·0015; kidneys P = 0·0012) (Table 1) than WT controls.

Table 1.

Recovery of Aspergillus fumigatus from the brain and kidneys of IL-10 knockout (KO) and wild-type (WT) mice; experiment 3

Log10 geometric mean CFU per organ (95% CI)
Group
n = 10 Kidney Brain
WT 3·18 (3·1–3·2) 2·78 (2·6–3·0)
IL-10 KO 2·88 (2·7–3·0) 2·39 (2·2–2·5)
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Mice were infected intravenously with 1·5 × 105 conidia of A. fumigatus and the number of colony-forming units (CFU) determined on day 3 post-infection. Statistical analyses of comparative burdens of A. fumigatus showed significant differences between the WT and IL-10 KO mice in both organs: brain, P = 0·0015; kidneys, P = 0·0012. 95% CI, 95% confidence interval.

Histologically there were also differences in the extent of infection and tissue injury between the IL-10 KO and WT mice (Fig. 3). Both types of animals had inflammatory foci in the brain with PMN and intermixed lymphocytes, i.e. microabscesses and necrotic lesions. However, there were fewer fungi detected by PAS stain, significantly fewer inflammatory foci, and smaller and significantly fewer areas of necrosis in the brains of IL-10 KO mice compared with the controls (Table 2). The IL-10 KO mice seemed better able to control the fungi present in the kidneys, as they had fewer fungi detected and significantly fewer inflammatory foci in the kidneys (Table 2). Overall, the comparative semiquantitative histological analyses demonstrate that the extent of infection and the severity of associated tissue injury were significantly reduced in the IL-10 KO mice compared with their WT counterparts.

Fig. 3.

Fig. 3

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Histological features of kidney or brain tissues from IL-10 knockout (KO) and wild-type (WT) mice. (A–D) WT control mice. (E,F) IL-10 KO mice. Overall the extent of infection and the associated tissue injury are greater in the WT than in the IL-10 KO mice. (A) Necrotizing inflammatory focus in the renal cortex of a WT mouse. Haematoxylin and eosin (H–E) (mag. × 137). (B) Same kidney as shown in (A). Numerous fungi (arrowheads) are present. Periodic acid–Schiff (PAS) stain (mag. × 183). (C) Large infarct (central pale area) in the cerebrum of a WT mouse. Several foci of inflammation are present on the edge of the infarct (left side of the field). (H–E, mag. × 46.) (D) Edge of the lesion shown in (C). Numerous hyphae at the edge of and within the infarct are evident. The infarct is on the right side of the field. PAS stain (mag. × 183). (E) Two small inflammatory foci (arrowhead) and focal ischaemic lesion (arrow) in the cerebrum of an IL-10 KO mouse. Most of the parenchyma is intact. (H–E, mag. × 46.) (F) Higher power of inflammatory foci shown in (E). There are no Aspergillus organisms present in this section and the surrounding brain parenchyma is intact. (H–E, mag. × 1275.)

Table 2.

Histological analyses of brain and kidney lesions in IL-10 KO and WT mice systemically infected with 1·5 × 105 conidia of A. fumigatus

Kidney Brain
Mouse n Tissue sample area, mm2 ± s.e.m. No. of inflammatory foci/mm2 ± s.e.m. Tissue sample area mm2 ± s.e.m. No. of necrotic foci/mm2 ± s.e.m. No. of inflammatory foci/mm2 ± s.e.m.
WT 7 62 ± 6 0·68 ± 0·07 91 ± 12 0·06 ± 0·03 0·46 ± 0·16
IL-10 KO 7 52 ± 11 0·14 ± 0·03 88 ± 12 0·02 ± 0·01 0·15 ± 0·04
P NS < 0·0001* NS NS < 0·03*
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*

Mann–Whitney U-test.

Discussion

The study of host response to various fungal pathogens has grown significantly over the last several years, especially in conjunction with the increasing number of systemic and opportunistic infections diagnosed in severely compromised patients. Among the opportunistic fungal infections aspergillosis is extremely important in some patient populations, such as bone marrow transplants, but is relatively uncommon in the normal host. Both innate and acquired mechanisms of resistance are important against aspergillosis. Innate mechanisms of phagocytosis and killing by macrophages and granulocytes are of primary importance [18]. Cytokine regulation of the killing of A. fumigatus by phagocytic cells has been demonstrated by several investigators [11,14,18–21]. However, the role played by IL-10 in innate resistance to Aspergillus infection has only recently been addressed. Cenci et al. [12] reported that resistance to invasive pulmonary aspergillosis in immunocompromised DBA/2 mice was dependent on high levels of TNF-α, IL-12 and IFN-γ. Furthermore, they found that susceptible mice had high levels of IL-4 or IL-10 produced by lung lymphocytes [12].

One difficulty encountered in the study of invasive aspergillosis is the requirement for immunosuppression in murine models to establish reproducible infections [22]. Although the immunosuppression can be accomplished by one of several ways (e.g. glucocorticoids, cyclophosphamide, etc.), these treatments may introduce possible confounding factors and alter both host cell responses and subsequent cytokine synthesis and regulation. Because of these factors, we chose to establish systemic infection via an i.v. route in order to examine the role played by IL-10 in resistance in a not conventionally immunocompromised host (i.e. IL-10 KO mice), whose lymphocytes are skewed to a Th1 response [16,17].

The results of our studies using mice genetically deficient in IL-10 indicate it plays a deleterious role in innate resistance against systemic aspergillosis infection, increasing the susceptibility of the host to lethal infection. This is evidenced by the results showing IL-10-sufficient WT mice were more susceptible to lethal infection with A. fumigatus than were IL-10 KO mice. We also noted differences in susceptibility with different inocula during our studies. However, the mice used in experiment 1 were 12 weeks of age and the ones in experiment 2 were 8 weeks of age. Thus, age-related changes in susceptibility might reasonably explain the apparent differences between the two experiments. These differences could be similar to those reported with experimental murine blastomycosis [23] and paracoccidioidomycosis [24], where even small differences in age can dramatically affect the susceptibility of the mouse. In addition, WT mice carried greater burdens of A. fumigatus in the kidneys and brain, the target organs in this model of infection, and showed greater degrees of tissue damage than did IL-10 KO mice. Similarly, IL-10 has been shown to play a deleterious role in other systemic fungal infections [6–9,25–27].

IL-10 has a variety of functional effects on the cells of the immune system, including effects on T cells and phagocytic cells [1–4]. We speculate that the decreased resistance of the WT mice might be a result of the down-regulation of protective macrophage phagocytic killing activity and of the acquisition of a protective Th1 response by IL-10. Thus, despite the anti-inflammatory properties of IL-10, the improved resistance to infectious foci would explain the interesting and superficially paradoxical reduction of inflammation in the IL-10 KO mice.

Invasive aspergillosis is a devastating disease. Although invasive pulmonary aspergillosis is associated with neutropenic patients, other patient populations acquire the disease as well [28–33]. Because dissemination to the brain is not uncommon [34–37], it is also important to study the host resistance to aspergillosis in compartments other than the lungs. Current therapeutic modalities are inadequate and even though successful in some instances the overall results of treatment are poor, with mortality approaching 80% in some patient populations [30,38]. Studies of histoplasmosis in TNF-α-depleted mice indicated that administering both anti-IL-4 and anti-IL-10 antibody increases resistance to infection [25]. Similarly, administration of an antibody directed against IL-10 was reported to increase the resistance of leukopenic mice to invasive pulmonary aspergillosis [12]. Our results are suggestive that a potential approach to therapy of systemic aspergillosis infection might involve a blockage of IL-10 functions, which might result in a beneficial increase in host resistance via Th1 pathways. Preliminary studies are currently underway in our laboratory to address this possibility.

In conclusion, we have demonstrated that mice deficient in IL-10 show an increased innate resistance to systemic aspergillosis. Thus, IL-10 has been shown to play a pivotal role in regulating the resistance of the normal host to this fungal pathogen. Additional studies are needed to determine whether down-regulation of effector cell activity or of a developing Th1 response are responsible in this regulation of resistance.

Acknowledgments

Presented in part at the 36th Annual Meeting of the Infectious Diseases Society of America, November 12–15 1998, Denver, Colorado, Abst. 336. All animal experimentation was done under the approval of the Institutional Animal Care and Use Committee of the California Institute for Medical Research.

References

  • 1.Ho AS-Y, Moore KW. Interleukin-10 and its receptor. Ther Immunol. 1994;1:173–85. [PubMed] [Google Scholar]
  • 2.Moore KW, O'garra A, de Waal Maleyt R, Viera P, Mosmann TR. Interleukin-10. Ann Rev Immunol. 1993;11:165–90. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  • 3.de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin-10. Ann Med. 1995;27:537–41. doi: 10.3109/07853899509002465. [DOI] [PubMed] [Google Scholar]
  • 4.Goldman M, Velu T, Pretolani M. Interleukin-10. Actions and therapeutic potential. Biodrugs. 1997;7:6–14. doi: 10.2165/00063030-199707010-00002. [DOI] [PubMed] [Google Scholar]
  • 5.Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol. 1998;161:3299–306. [PubMed] [Google Scholar]
  • 6.Fierer J, Walls L, Eckmann L, Yamamoto T, Kirkland TN. Importance of interleukin-10 in genetic susceptibility of mice to Coccidioides immitis. Infect Immun. 1998;66:4397–402. doi: 10.1128/iai.66.9.4397-4402.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Monari C, Retini C, Palazzetti B, Bistoni F, Vecchiarelli A. Regulatory role of exogenous IL-10 in the development of immune response versus Cryptococcus neoformans. Clin Exp Immunol. 1997;109:242–7. doi: 10.1046/j.1365-2249.1997.4021303.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Tonnetti L, Spaccapelo R, Cenci E, Mencacci A, Puccetti P, Coffman RL, Bistoni F, Romani L. Interleukin-4 and -10 exacerbate candidiasis in mice. Eur J Immunol. 1995;25:1559–65. doi: 10.1002/eji.1830250614. [DOI] [PubMed] [Google Scholar]
  • 9.Romani L, Puccetti P, Mencacci A, Cenci E, Spaccapelo R, Tonnetti L, Grohmann U, Bistoni F. Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans. J Immunol. 1994;152:3514–21. [PubMed] [Google Scholar]
  • 10.Vecchiarelli A, Retini C, Monari C, Tascini C, Bistoni F, Kozel TR. Purified capsular polysaccharide of Cryptococcus neoformans induces interleukin-10 secretion by human monocytes. Infect Immun. 1996;64:2846–9. doi: 10.1128/iai.64.7.2846-2849.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Roilides E, Dimitriadou A, Kadiltsoglou I, Sein T, Karpouzas J, Pizzo PA, Walsh TJ. IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J Immunol. 1997;158:322–9. [PubMed] [Google Scholar]
  • 12.Cenci E, Mencacci A, d'ostiani CF, Del Sero G, Mosci P, Montagnoli C, Bacci A, Romani L. Cytokine- and T helper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis. J Infect Dis. 1998;178:1750–60. doi: 10.1086/314493. [DOI] [PubMed] [Google Scholar]
  • 13.Grunig G, Corry DB, Leach MW, Seymour BW, Kurup VP, Rennick DM. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med. 1997;185:1089–99. doi: 10.1084/jem.185.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Grazziutti ML, Rex JH, Cowart RE, Anaissie EJ, Ford A, Savary CA. Aspergillus fumigatus conidia induce a Th1-type cytokine response. J Infect Dis. 1997;176:1579–83. doi: 10.1086/514157. [DOI] [PubMed] [Google Scholar]
  • 15.Hanson LH, Clemons KV, Denning DW, Stevens DA. Efficacy of oral saperconazole in systemic murine aspergillosis. J Med Vet Mycol. 1995;33:311–7. doi: 10.1080/02681219580000631. [DOI] [PubMed] [Google Scholar]
  • 16.Rennick DM, Fort MM, Davidson NJ. Studies with IL-10−/– mice: an overview. J Leuk Biol. 1997;61:389–96. doi: 10.1002/jlb.61.4.389. [DOI] [PubMed] [Google Scholar]
  • 17.Rennick D, Davidson N, Berg D. Interleukin-10 gene knock-out mice: a model of chronic inflammation. Clin Immunol Immunopathol. 1995;76:S174–S8. doi: 10.1016/s0090-1229(95)90144-2. [DOI] [PubMed] [Google Scholar]
  • 18.de Repentigny L, Petitbois S, Boushira M, Michaliszyn E, Senechal S, Gendron N, Montplaisir S. Acquired immunity in experimental murine aspergillosis is mediated by macrophages. Infect Immun. 1993;61:3791–802. doi: 10.1128/iai.61.9.3791-3802.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Meier-Osusky I, Schoedon G, Blauer F, Schneemann M, Schaffner A. Comparison of the antimicrobial activity of deactivated human macrophages challenged with Aspergillus fumigatus and Listeria monocytogenes. J Infect Dis. 1996;174:651–4. doi: 10.1093/infdis/174.3.651. [DOI] [PubMed] [Google Scholar]
  • 20.Nagai H, Guo J, Choi H, Kurup V. Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis. 1995;172:1554–60. doi: 10.1093/infdis/172.6.1554. [DOI] [PubMed] [Google Scholar]
  • 21.Cenci E, Perito S, Enssle KH, Mosci P, Latge JP, Romani L, Bistoni F. Th1 and Th2 cytokines in mice with invasive aspergillosis. Infect Immun. 1997;65:564–70. doi: 10.1128/iai.65.2.564-570.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Polak A. Experimental models in antifungal chemotherapy. Mycoses. 1998;41:1–30. doi: 10.1111/j.1439-0507.1998.tb00371.x. [DOI] [PubMed] [Google Scholar]
  • 23.Brass C, Stevens D. Maturity as a critical determinant of resistance to fungal infections: studies in murine blastomycosis. Infect Immun. 1982;36:387–95. doi: 10.1128/iai.36.1.387-395.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Brummer E, Castaneda E, Restrepo A. Paracoccidioidomycosis: an update. Clin Microbiol Rev. 1993;6:89–117. doi: 10.1128/cmr.6.2.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Allendoerfer R, Deepe Gs., Jr Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol. 1998;160:6072–82. [PubMed] [Google Scholar]
  • 26.Cenci E, Romani L, Mencacci A, Spaccapelo R, Schiaffella E, Puccetti P, Bistoni F. Interleukin-4 and interleukin-10 inhibit nitric oxide-dependent macrophage killing of Candida albicans. Eur J Immunol. 1993;23:1034–8. doi: 10.1002/eji.1830230508. [DOI] [PubMed] [Google Scholar]
  • 27.Levitz SM, Tabuni A, Nong SH, Golenbock DT. Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans, Candida albicans, and lipopolysaccharide. Infect Immun. 1996;64:945–51. doi: 10.1128/iai.64.3.945-951.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Cohen J, Denning DW, Viviani MA. Epidemiology of invasive asper‐gillosis in European cancer centres. EORTC Invasive Fungal Infections Cooperative Group. Eur J Clin Microbiol Infect Dis. 1993;12:392–3. doi: 10.1007/BF01964440. [DOI] [PubMed] [Google Scholar]
  • 29.Carlson GL, Mughal MM, Birch M, Denning DW. Aspergillus wound infection following laparostomy. J Infect. 1996;33:119–21. doi: 10.1016/s0163-4453(96)93062-5. [DOI] [PubMed] [Google Scholar]
  • 30.Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147–201. doi: 10.1093/clinids/12.6.1147. [DOI] [PubMed] [Google Scholar]
  • 31.Khoo SH, Denning DW. Invasive aspergillosis in patients with AIDS. Clin Infect Dis. 1994;19(Suppl. 1):S41–48. doi: 10.1093/clinids/19.supplement_1.s41. [DOI] [PubMed] [Google Scholar]
  • 32.Khoo SH, Denning DW. Cure of chronic invasive sinus aspergillosis with oral saperconazole. J Med Vet Mycol. 1995;33:63–66. doi: 10.1080/02681219580000131. [DOI] [PubMed] [Google Scholar]
  • 33.Kramer MR, Marshall SE, Denning DW, et al. Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Ann Intern Med. 1990;113:327–9. doi: 10.7326/0003-4819-113-4-327. [DOI] [PubMed] [Google Scholar]
  • 34.Hagensee ME, Bauwens JE, Kjos B, Bowden RA. Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, 1984–92. Clin Infect Dis. 1994;19:402–8. doi: 10.1093/clinids/19.3.402. [DOI] [PubMed] [Google Scholar]
  • 35.Boon AP, O'brien D, Adams DH. 10 year review of invasive aspergillosis detected at necropsy. J Clin Pathol. 1991;44:452–4. doi: 10.1136/jcp.44.6.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Manfredi R, Salfi N, Alampi G, Mazzoni A, Nanetti A, de Cillia C, Chiodo F. AIDS-related visceral aspergillosis: an under diagnosed disease during life? Mycoses. 1998;41:453–60. doi: 10.1111/j.1439-0507.1998.tb00705.x. [DOI] [PubMed] [Google Scholar]
  • 37.Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract. 1998;194:473–86. doi: 10.1016/s0344-0338(98)80116-7. [DOI] [PubMed] [Google Scholar]
  • 38.Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis. 1996;23:608–15. doi: 10.1093/clinids/23.3.608. [DOI] [PubMed] [Google Scholar]

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