Interplay between IDO1 and iNOS in human retinal pigment epithelial cells.

Human retinal pigment epithelial (hRPE) cells form a selectively permeable monolayer between the neural retina and the highly permeable choroidal vessels. Thus, hRPE cells bear important regulatory functions and are potential targets of pathogens in vivo. Endogenous bacterial endophthalmitis (EBE) is frequently caused by infections with the Gram-positive bacterium Staphylococcus aureus (S. aureus). Upon microbial infection, interferon gamma (IFN-γ), a major cytokine of the adaptive immune response, induces a broad spectrum of effector molecules, such as the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase-1 (IDO1). We stimulated human RPE (hRPE) cells in vitro with proinflammatory cytokines and analyzed the expression levels and enzymatic activities of IDO1 and inducible nitric oxide synthase (iNOS), another antimicrobial effector molecule. The antimicrobial capacity was analyzed in infection experiments using S. aureus and Toxoplasma gondii (T. gondii). Our aim was to characterize the particular importance of IDO1 and iNOS during EBE. We found that an IFN-γ stimulation of hPRE cells induced the expression of IDO1, which inhibited the growth of T. gondii and S. aureus. A co-stimulation with IFN-γ, interleukin-1 beta, and tumor necrosis factor alpha induced a strong expression of iNOS. The iNOS-derived nitric oxide production was dependent on cell-culture conditions; however, it could not cause antimicrobial effects. iNOS did not act synergistically with IDO1. Instead, iNOS activity inhibited IDO1-mediated tryptophan degradation and bacteriostasis. This effect was reversible by the addition of the iNOS inhibitor NG-monomethyl-L-arginine. In conclusion, iNOS mediates anti-inflammatory effects in hRPE cells stimulated with high amounts of IFN-γ together with tumor necrosis factor alpha and Interleukin-1 beta and prevents potential IDO1-dependent tissue damage.

hCMV-Mediated Immune Escape Mechanisms Favor Pathogen Growth and Disturb the Immune Privilege of the Eye.

Human retinal pigment epithelial (hRPE) cells are important for the establishment and maintenance of the immune privilege of the eye. They function as target cells for human cytomegalovirus (hCMV), but are able to restrict viral replication. hCMV causes opportunistic posterior uveitis such as retinitis and chorioretinitis. Both mainly occur in severely immunocompromised patients and rarely manifest in immunocompetent individuals. In this study, hRPE cells were infected with hCMV in vitro and activated with proinflammatory cytokines. The enzymatic activities of indoleamine 2,3-dioxygenase-1 (IDO1) and inducible nitric oxide synthase (iNOS) were determined. The antimicrobial capacity of both molecules was analyzed in co-infection experiments using Staphylococcus aureus (S. aureus) and Toxoplasma gondii (T. gondii), causing uveitis in patients. We show that an hCMV infection of hRPE cells blocks IDO1 and iNOS mediated antimicrobial defense mechanisms necessary for the control of S. aureus and T. gondii. hCMV also inhibits immune suppressive effector mechanisms in hRPE. The interferon gamma-induced IDO1 dependent immune regulation was severely blocked, as detected by the loss of T cell inhibition. We conclude that an active hCMV infection in the eye might favor the replication of pathogens causing co-infections in immunosuppressed individuals. An hCMV caused blockade of IDO1 might weaken the eye's immune privilege and favor the development of post-infectious autoimmune uveitis.

Experimental Porcine Toxoplasma gondii Infection as a Representative Model for Human Toxoplasmosis.

Porcine infections are currently not the state-of-the-art model to study human diseases. Nevertheless, the course of human and porcine toxoplasmosis is much more comparable than that of human and murine toxoplasmosis. For example, severity of infection, transplacental transmission, and interferon-gamma-induced antiparasitic effector mechanisms are similar in pigs and humans. In addition, the severe immunosuppression during acute infection described in mice does not occur in the experimentally infected ones. Thus, we hypothesise that porcine Toxoplasma gondii infection data are more representative for human toxoplasmosis. We therefore suggest that the animal model chosen must be critically evaluated for its assignability to human diseases.

Negative Impact of Hypoxia on Tryptophan 2,3-Dioxygenase Function.

Tryptophan is an essential amino acid for hosts and pathogens. The liver enzyme tryptophan 2,3-dioxygenase (TDO) provokes, by its ability to degrade tryptophan to N-formylkynurenine, the precursor of the immune-relevant kynurenines, direct and indirect antimicrobial and immunoregulatory states. Up to now these TDO-mediated broad-spectrum effector functions have never been observed under hypoxia in vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO and ex vivo murine TDO functions under different oxygen conditions and show that TDO-induced restrictions of clinically relevant pathogens (bacteria, parasites) and of T cell proliferation are abrogated under hypoxic conditions. We pinpointed the loss of TDO efficiency to the reduction of TDO activity, since cell survival and TDO protein levels were unaffected. In conclusion, the potent antimicrobial as well as immunoregulatory effects of TDO were substantially impaired under hypoxic conditions that pathophysiologically occur in vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens.

Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase.

Despite a rigorous blockade of interferon-γ (IFN-γ) signalling in infected fibroblasts as a mechanism of immune evasion by human cytomegalovirus (HCMV), IFN-γ induced indoleamine-2,3-dioxygenase (IDO) has been proposed to represent the major antiviral restriction factor limiting HCMV replication in epithelial cells. Here we show that HCMV efficiently blocks transcription of IFN-γ-induced IDO mRNA both in infected fibroblasts and epithelial cells even in the presence of a preexisting IFN-induced antiviral state. This interference results in severe suppression of IDO bioactivity in HCMV-infected cells and restoration of vigorous HCMV replication. Depletion of IDO expression nonetheless substantially alleviated the antiviral impact of IFN-γ treatment in both cell types. These findings highlight the effectiveness of this IFN-γ induced effector gene in restricting HCMV productivity, but also the impact of viral counter-measures.

Animals are key to human toxoplasmosis.

Toxoplasma gondii is an extremely sucessfull protozoal parasite which infects almost all mamalian species including humans. Approximately 30% of the human population worldwide is chronically infected with T. gondii. In general, human infection is asymptomatic but the parasite may induce severe disease in fetuses and immunocompromised patients. In addition, T. gondii may cause sight-threatening posterior uveitis in immunocompetent patients. Apart from few exceptions, humans acquire T. gondii from animals. Both, the oral uptake of T. gondii oocysts released by specific hosts, i.e. felidae, and of cysts persisting in muscle cells of animals result in human toxoplasmosis. In the present review, we discuss recent new data on the cell biology of T. gondii and parasite diversity in animals. In addition, we focus on the impact of these various parasite strains and their different virulence on the clinical outcome of human congenital toxoplasmosis and T. gondii uveitis.

Genotyping of samples from German patients with ocular, cerebral and systemic toxoplasmosis reveals a predominance of Toxoplasma gondii type II.

Toxoplasmosis is an important zoonosis transmitted from animals to humans world-wide. In order to determine Toxoplasma gondii genotypes in individuals living in Germany and to compare findings with those in animals, we analysed nine independent and unlinked genetic markers (nSAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico) by PCR-RFLP in 83 archived T. gondii-positive DNA samples from patients with ocular toxoplasmosis (n=35), toxoplasmic encephalitis (n=32), systemic toxoplasmosis after bone-marrow transplantation (n=15) and congenital toxoplasmosis (n=1). In 46 of these 83 samples the presence of T. gondii DNA was confirmed by conventional end-point PCR. Among these, 17 T. gondii-positive samples were typed at all nine loci. The majority (15/17, 88.2%) of these samples were of T. gondii type II (i.e., including both, the Apico type II and Apico type I variants). In addition, in one sample a T. gondii type II/type III allele combination and in another sample a T. gondii genotype displaying type III alleles at all markers was observed. In the remaining 11 samples, in which T. gondii could only be partially typed, exclusively type II (n=10) or type III (n=1) alleles were observed. Results of the present study suggest that the majority of patients in Germany are infected with type II T. gondii regardless of the clinical manifestation of toxoplasmosis. This finding is in accord with the predominance of type II T. gondii in oocysts isolated from cats and in tissues of other intermediate hosts in Germany.

Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells.

Human mesenchymal stromal cells (MSC) possess immunosuppressive and antimicrobial effects that are partly mediated by the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). Therefore MSC represent a promising novel cellular immunosuppressant which has the potential to control steroid-refractory acute graft versus host disease (GvHD). In addition, MSC are capable of reducing the risk of infection in patients after haematopoietic stem cell transplantation (HST). Recent data indicate that signals from the microenvironment including those from microbes may modulate MSC effector functions. As Cytomegalovirus (CMV) represents a prominent pathogen in immunocompromised hosts, especially in patients following HST, we investigated the impact of CMV infection on MSC-mediated effects on the immune system. We demonstrate that CMV-infected MSC lose their cytokine-induced immunosuppressive capacity and are no longer able to restrict microbial growth. IDO expression is substantially impaired following CMV infection of MSC and this interaction critically depends on intact virus and the number of MSC as well as the viral load. Since overt CMV infection may undermine the clinical efficacy of MSC in the treatment of GvHD in transplant patients, we recommend that patients scheduled for MSC therapy should undergo thorough evaluation for an active CMV infection and receive CMV-directed antiviral therapy prior to the administration of MSC.

Humoral immune responses in chickens and turkeys after infection with Toxoplasma gondii by using recombinant antigens.

Toxoplasma gondii is a parasite which can be transmitted to humans via the consumption of contaminated meat products derived from different animal species, e.g., poultry. In Europe, the consumption rate of poultry meat is high and may pose a risk for humans. However, little is known about the prevalence and immune response against T. gondii in these animals. Based on these circumstances, we experimentally infected 18 turkeys and 16 chickens with the parasite. Turkeys were infected either with tachyzoites on different routes or with various amounts of oocysts. In contrast, chickens were only infected with different doses of oocysts. The immunoglobulin (Ig) Y humoral immune responses of these animals were investigated in a lineblot assay against the recombinant T. gondii antigens rGRA1, rGRA6, rGRA9, rSAG1, and rSUB1. By using the recombinant antigens rGRA6, rGRA9, and rSUB1 in the lineblot assay, we found a correlation between the humoral immune response and the parasite stage in turkeys. Thereby, an infection with oocysts induced a stronger, permanent long-lasting antibody response compared to tachyzoite-infected animals. Only a minor relation between the oocyst infection dose and the manifestation of the immune response in chickens was found 7 days post infection (dpi) by using rGRA1 and rGRA9. However, an inconstant detection of antigen-specific IgY antibodies in the lineblot assay seems not to be a sufficient method for the identification of a Toxoplasma infection in chickens. In contrast, the detection of anti-rGRA6, anti-rGRA9, and anti-rSUB1 IgY antibodies showed potential for the identification of an infection in turkeys.

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo.

IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O(2) < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-γ are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-γ concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-γ under hypoxia was restricted to the urogenital serovars D and L(2), but was not observed with the ocular serovar A. Impaired effectiveness of IFN-γ on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-γ effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women.

Effect of Safety Measures on Bacterial Contamination Rates of Blood Components in Germany.

SUMMARY: Requirements for bacterial testing of blood components on a defined quantity as part of routine quality control were introduced in Germany by the National Advisory Committee Blood of the German Federal Ministry of Health in 1997. The philosophy was to establish standardized methods for bacterial testing. Numerous measures to reduce the risk of bacterial contamination were implemented into the blood donation and manufacturing processes between 1999 and 2002. German Blood establishments performed culture-based bacterial testing on random samples of platelet concentrates (PCs), red blood cells (RBCs) and fresh frozen plasma (FFP) and reported data out of the production periods 1998, 2001 and 2005/2006. While the bacterial contamination rate of apheresis PCs remained nearly unchanged, it decreased by 70% for pooled PCs to a rate of 0.158% in the last observation period. Leukocyte-depleted RBCs with diversion of the initial blood volume showed a contamination rate of 0.029% which is significantly lower than that of RBCs without leukocyte depletion and diversion (0.157%). The contamination rate of plasma decreased by 80%. Preventive measures resulted in a significant reduction of bacterial contamination of blood components. Long-term monitoring with standardized methods for bacteria testing supports evaluation of the cumulative effect of contamination reducing measures.

Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase.

In mammals, the regulation of local tryptophan concentrations by the IFN-gamma-i inducible enzyme IDO is a prominent antimicrobial and immunoregulatory effector mechanism. Here, we show for the first time that another tryptophan-degrading enzyme, the liver-specific tryptophan 2,3-dioxygenase (TDO), is also capable of mediating antimicrobial and immunoregulatory effects. Using a tetracycline inducible eukaryotic system, we were able to express recombinant TDO protein, which exhibits functional properties of native TDO. We found that HeLa cells expressing recombinant TDO were capable of inhibiting the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) and viruses (herpes simplex virus). These TDO-mediated antimicrobial effects could be blocked by the addition of tryptophan. In addition, we observed that, similar to IDO-positive cells, TDO-positive cells were capable of inhibiting anti CD3-driven T-cell proliferation and IFN-gamma production. Furthermore, TDO-positive cells also restricted alloantigen-induced T-cell activation. Here, we describe for the first time that TDO mediates antimicrobial and immunoregulatory effects and suggest that TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation.

The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients.

Individuals serologically positive for the chronic infection with the parasite Toxoplasma gondii (TG) display certain personality traits differently from uninfected individuals. Experimental data in mice demonstrate that TG infection modulates behaviour. However, psychiatric patients with a personality disorder have not yet been investigated systematically. In our sample containing 896 psychiatric inpatients with the primary diagnoses of schizophrenia, major depression, schizoaffective or bipolar disorder and 214 psychiatrically unaffected controls (same geographic region, sampled during same time period) we analysed for effects of the additional diagnosis of a personality disorder in the patients. Psychiatrically, a patient can meet the criteria of a personality disorder additionally to any of the mentioned primary diagnoses. We applied logistic regression and cross-table statistics, separated groups by the presence/absence of a personality disorder (ICD-10) and adjusted for age between groups. We found that among all patients the additional diagnosis of a personality disorder was significantly associated with TG infection. Furthermore, only in the patients with an additional personality disorder medium titre responses (1:16-1:64) were associated with chronic course and high C-reactive protein (CRP) levels whereas high titre response (>1:64) was associated with a more acute recurrent clinical course. In the older individuals only there was a preponderance of medium titre responses (1:16-1:64) among the patients with personality disorder compared to those without and controls. We conclude that TG infection and the host's response to it make a difference for the diagnosis of a personality disorder. Our data support that TG infection can modulate human behaviour and personality traits.

The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects.

The interferon (IFN)-gamma-inducible tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties. In this study, we provide evidence that both tryptophan starvation and production of toxic tryptophan metabolites are involved in the immunoregulation mediated by IDO, whereas tryptophan starvation seems to be the only antibacterial effector mechanism. A long-studied controversy in the IDO research field is the seemingly contradictory effect of IDO in the defence against infectious diseases. On the one hand, IFN-gamma-induced IDO activity mediates an antimicrobial effect, while at the same time IDO inhibits T-cell proliferation and IFN-gamma production. Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence. We found that the minimum concentration of tryptophan required for bacterial growth is 10-40-fold higher than the minimum concentration necessary for T-cell activation. Therefore, we suggest that during the first phase of infection the IDO-mediated tryptophan depletion has a predominantly antimicrobial effect whereas in the next stage, and with ongoing tryptophan degradation, the minimum threshold concentration of tryptophan for T-cell activation is undercut, resulting in an inhibition of T-cell growth and subsequent IDO activation.

Suppression of cellular immunity by cord blood-derived unrestricted somatic stem cells is cytokine-dependent.

Unrestricted somatic stem cells (USSC) have the potential to differentiate into tissues derived from all three germinal layers and therefore hold promise for use in regenerative therapies. Furthermore, they have haematopoietic stromal activity, a characteristic that may be exploited to enhance haematopoietic engraftment. Both applications may require USSC to be used in an allogeneic, HLA-mismatched setting. We have therefore studied their in vitro interaction with cellular immunity. USSC showed no allostimulatory activity and caused only minimal inhibition of allogeneic T-cell responses. However, following pre-stimulation with IFNgamma and TNFalpha, they inhibited T-cell proliferation in an indoleamine 2, 3-dioxygenase-dependent manner and suppressed graft-versus-host type reactions. In addition, USSC inhibited DC maturation and function. This inhibition was overridden by stronger DC maturation signals provided by IL-1beta, IL-6, PGE(2) and TNFalpha compared to TNFalpha alone. Pre-stimulation of USSC with IFNgamma and TNFalpha had a similar effect: Inhibition of DC maturation was no longer observed. Thus, USSC are conditionally immunosuppressive, and IFNgamma and TNFalpha constitute a switch, which regulates their immunological properties. They either suppress T-cell responses in the presence of both cytokines or in their absence block DC differentiation and function. These activities may contribute to fine-tuning the immune system especially at sites of tissue damage in order to ensure appropriate differentiation of USSC and subsequent tissue repair. Therapeutically, they may help to protect USSC and possibly their progeny from immune rejection.

Indoleamine 2,3-dioxygenase is involved in defense against Neospora caninum in human and bovine cells.

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii. In nature this parasite is found especially in dogs and cattle, but it may also infect other livestock. The growth of N. caninum, which is an obligate intracellular parasite, is controlled mainly by the cell-mediated immune response. During infection the cytokine gamma interferon (IFN-gamma) plays a prominent role in regulating the growth of N. caninum in natural and experimental disease. The present study showed that induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the inhibition of parasite growth that is mediated by IFN-gamma-activated bovine fibroblasts and endothelial cells. This antiparasite effect could be abrogated by addition of tryptophan, as well as by the IDO-specific inhibitor 1-L-methyltryptophan. In conclusion, our data show that human and bovine cells use the same effector mechanism to control the growth of N. caninum.

Sputum colour for diagnosis of a bacterial infection in patients with acute cough.

OBJECTIVE: Sputum colour plays an important role in the disease concepts for acute cough, both in the patients' and the doctors' view. However, it is unclear whether the sputum colour can be used for diagnosis of a bacterial infection. DESIGN: Cross-sectional study. SETTING: A total of 42 GP practices in Dusseldorf, Germany. SUBJECTS: Sputum samples obtained from 241 patients suffering from an episode of acute cough seeing their doctor within a routine consultation. MAIN OUTCOME MEASURES: Relation of sputum colour and microbiological proof of bacterial infection defined as positive culture and at least a moderate number of leucocytes per low magnification field. RESULTS: In 28 samples (12%) a bacterial infection was proven. Yellowish or greenish colour of the sputum sample and bacterial infection showed a significant correlation (p = 0.014, Fisher's exact test). The sensitivity of yellowish or greenish sputum used as a test for a bacterial infection was 0.79 (95% CI 0.63-0.94); the specificity was 0.46 (95% CI 0.038-0.53). The positive likelihood-ratio (+LR) was 1.46 (95% CI 1.17-1.85). CONCLUSIONS: The sputum colour of patients with acute cough and no underlying chronic lung disease does not imply therapeutic consequences such as prescription of antibiotics.

Indoleamine 2,3-Dioxygenase Activity During Acute Toxoplasmosis and the Suppressed T Cell Proliferation in Mice.

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite and belongs to the phylum Apicomplexa. T. gondii is of medical and veterinary importance, because T. gondii causes the parasitic disease toxoplasmosis. In human cells, the interferon-gamma inducible indoleamine 2,3-dioxygenase 1 (IDO1) is an antimicrobial effector mechanism that degrades tryptophan to kynurenine and thus limits pathogen proliferation in vitro. Furthermore, IDO is described to have immunosuppressive properties, e.g., regulatory T cell differentiation and T cell suppression in humans and mice. However, there is only little known about the role of IDO1 in mice during acute toxoplasmosis. To shed further light on the role of mIDO1 in vivo, we have used a specifically adjusted experimental model. Therein, we infected mIDO1-deficient (IDO-/-) C57BL/6 mice and appropriate wild-type (WT) control mice with a high dose of T. gondii ME49 tachyozoites (type II strain) via the intraperitoneal route and compared the phenotype of IDO-/- and WT mice during acute toxoplasmosis. During murine T. gondii infection, we found mIDO1 mRNA and mIDO1 protein, as well as mIDO1-mediated tryptophan degradation in lungs of WT mice. IDO-/- mice show no tryptophan degradation in the lung during infection. Even though T. gondii is tryptophan auxotroph and rapidly replicates during acute infection, the parasite load was similar in IDO-/- mice compared to WT mice 7 days post-infection. IDO1 is described to have immunosuppressive properties, and since T cell suppression is observed during acute toxoplasmosis, we analyzed the possible involvement of mIDO1. Here, we did not find differences in the intensity of ex vivo mitogen stimulated T cell proliferation between WT and IDO-/- mice. Concomitant nitric oxide synthase inhibition and interleukin-2 supplementation increased the T cell proliferation from both genotypes drastically, but not completely. In sum, we analyzed the involvement of mIDO1 during acute murine toxoplasmosis in our specifically adjusted experimental model and found a definite mIDO1 induction. Nevertheless, mIDO1 seems to be functional redundant as an antiparasitic defense mechanism during acute toxoplasmosis in mice. Furthermore, we suggest that the systemic T cell suppression observed during acute toxoplasmosis is influenced by nitric oxide activity and IL-2 deprivation.

Microbe-host interplay in atopic dermatitis and psoriasis.

Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe (Staphylococcus aureus), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis.

Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-gamma-induced tryptophan degradation.

Pneumonia caused by bacterial, viral and parasitic pathogens is one of the most common clinical problems facing primary and secondary care physicians. Staphylococcus aureus is a common cause of lung abscesses in humans and, in immunocompromised patients, herpes simplex virus type I and Toxoplasma gondii can cause severe life-threatening pneumonia. The authors focused their interest in the antimicrobial effects mediated by human lung cells against these pathogens. It was found that IFN-gamma-stimulated lung cells are capable of inhibiting T cell proliferation and restrict the replication of microorganisms such as T. gondii, S. aureus and herpes simplex virus. This immunoregulatory and antimicrobial effect was enhanced in the presence of IL-1 or tumor necrosis factor-alpha (TNF-alpha). Furthermore, the IFN-gamma-dependent antimicrobial effects of HBE4-E6/E7 (human lung bronchus epithelial cells) and A549 (human type II alveolar cells) correlated with the activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). It was found that both the abrogation of IDO activity by the specific IDO-inhibitor 1-L-methyltryptophan and the supplementation of cultures with tryptophan result in an inhibition of IFN-gamma-induced antimicrobial effects mediated by lung cells. Therefore it is suggested that tryptophan depletion via IFN-gamma-mediated IDO induction is a major antibacterial, antiparasitic, antiviral and immunoregulatory mechanism in human lung cells.