Comparison of Gene Expression Profiles of Macrophages and Dendritic Cells In Vitro Upon Infection with Different Pathogens

Several studies [1-3] compared the responses of macrophages or dendritic cells upon infection with different pathogens. Huang et al. [1] determined the gene expression profiles of human monocyte-derived dendritic cells in response to Escherichia coli SD54, Candida albicans, and influenzavirus as well as to their molecular components by using oligonucleotide arrays representing 6800 genes. While 166 genes were found to be regulated in common by all these pathogens, 118 genes were specifically regulated by E.coli, 58 specifically by influenzavirus whereas C. albicans only modulated the expression of a subset of E. coli-regulated genes. The 166 common regulated genes may represent a core response of dendritic cells against microbes, while other genes specifically reflect the interaction with a certain type of pathogen. Interestingly, rapidly after cell contact with any of the pathogens, a decline in the transcripts of genes associated with phagocytosis and pathogen recognition was observed, whereas genes encoding cytokines were simultaneously upregulated. Strikingly, these authors also found that the molecular components of the pathogens (lipopolysaccharide, mannan, dsRNA), particularly lipopolysaccharide (LPS), may mimic a large part of the bacterial response. Surprisingly, the fungal component mannan reflected the response to a bacterial pathogen rather than that of the fungal agent. Unfortunately, the nature of the E. coli strains (e.g., expression of pathogenicity factors that might affect gene expression) was not addressed in this study.

Nau et al. [2] infected monocyte-derived macrophages with Listeria monocytogenes EGD, Staphylococcus aureus ISP794, Mycobacterium bovis BCG, Salmonella typhimurium (ATCC 14028), or E. coli O157:H7. In addition, they used several bacterial components such as E. coli or Salmonella LPS, lipoteichoic acid (LTA) and muramyl dipeptide, fMLP protein, protein A, mannose, or heat shock proteins. Microarray analyses were performed using a microarray comprising 6800 genes. A total of 977 genes were significantly changed upon stimulation by one or more bacteria. Despite the diversity of the bacteria studied, a shared transcriptional response was elicited consisting of 132 genes induced and 59 repressed. The authors defined this response as a common activation program of macrophages against gram-positive bacteria, gram-negative bacteria, and mycobacteria. This activation program included cytokines such as IL-6, TNF-a, IL-12, chemokines such as IL-8, IP-10, MCP-1, adhesion molecules such as CD44, ICAM-1, cytokine receptors, genes involved in tissue remodeling (e.g., MMP1, MMP10), stress response (GADD45A) and several transcription factors.

The activation program induced by several bacteria in macrophages was also elicited by bacterial components which function as ligands for Toll-like receptor (TLR)-2 (e.g., LTA) or TLR-4 (e.g., LPS) but not by other bacterial components such as fMLP, protein A, or mannose, indicating that the activation program is due to signaling mediated by macrophage TLRs. In addition to the common response, distinct alterations of the response due to specific bacteria were noticed. For example, Mycobacteriumbovis induced IL-12 p40 and IL-15 only poorly compared to E. coli and S. aureus.

A further study carried out by Boldrick et al. [3] compared infection of peripheral blood mononuclear cells with viable or killed E. coli, S. aureus clinical strains, and various Bordetella pertussis strains. In this study eight time points in a range of 24 h after infection were analyzed. A group of 515 unique genes was found whose expression level changed most dramatically. Most of these genes responded in a strikingly stereotypic manner to all bacterial treatments and also to pharmacological stimulants such as phorbol myristate acetate (PMA) ionomycin. More than 200 genes were regulated in common by all bacterial stimuli.

Chaussabel et al. [4] infected monocyte-derived dendritic cells and macrophages from a total of seven healthy donors with five different pathogens which all produce chronic infections: the bacterium Mycobacterium tuberculosis, the intracellu-larly located protozoons Leishmania major, Leishmania donovani, and Toxoplasma gondii, and the extracellular helminth Brugia malayi for 16 h after infection. One interesting finding of this study was that the constitutive gene expression in dendritic cells and macrophages was very similar, comprising about 3692 shared genes, while only 130 genes were uniquely expressed in macrophages and 286 genes specifically expressed in dendritic cells. However, after exposure to the pathogens, macrophages and dendritic cells exhibited different gene expression profiles. In general, the response to each pathogen was much more diverse and specific in dendritic cells than in macrophages. Interestingly, the extracellular parasite B. malayi induced only up to 14 genes in dendritic cells, depending on the number ofparasites, indicating that the transcriptional response to this pathogen is almost silent.

Since dendritic cells responded more diversely upon exposure to these pathogens, the authors focused on four gene clusters found in dendritic cells. Leishma-

nia spp., Mtuberculosis, and T. gondii induced genes belonging to the NF-jB signaling pathway (NFKB1, NFKB2), apoptosis regulators (TRAF1, TRADD), and TNF-related molecules as well as genes involved in cell growth and cytokine production (STAT1, PTPN2, WNT5a, DUSP1) (cluster I). Cluster II comprises inflammatory mediators (e.g., RANTES, MIP-1b, GRO-1-3, IL-8, IL-6, IL-1b, TNF-a), and adhesion molecules (e.g., CD44, ICAM1), which were induced by Leishma-nia spp. and M. tuberculosis, but not by T. gondii. A third cluster of genes was highly induced by T. gondii and M. tuberculosis, moderately by L. major, and slightly by L. donovani. Most of these genes were interferon-regulated genes involved in signaling (STAT1 and 4, IRF-4 and 7), antiviral activities (MX1, MX2, ISG15, ISG20), or proliferation (IFITM). This subgroup was found to be also transcrip-tionally regulated in macrophages, but the pattern of regulation induced by the different pathogens was different from that in dendritic cells. A second subgroup included interferon-induced chemokines (IP10, MIG). This subgroup showed a similar expression pattern in dendritic cells and macrophages. In addition, genes involved in antigen processing and presentation were highly upregulated only in T. gondii and M. tuberculosis, but exclusively in dendritic cells and not in macrophages.

While genes of cluster I (e.g., NFKB1) were induced in dendritic cells by M. tuberculosis, T. gondii, L. major, and L. donovani, in macrophages only M. tuberculosis and L. major induced these genes. Genes of cluster II which in dendritic cells were induced by M. tuberculosis, L. major, and L. donovani, but not by T. gondii, were induced by all these pathogens in macrophages. The most diverse pattern was found in cluster III for the subgroups of interferon-induced genes upon infection with different pathogens in dendritic cells and macrophages.

Taken together, the most striking finding of this study is that, besides the general differences of the response of dendritic cells and macrophages to these pathogens, unique and pathogen-specific expression profiles can be identified for both dendritic cells and macrophages. This might reflect the idea that antigen-presenting cells respond with specific signaling pathways to various pathogens, which explains the specific features of host-pathogen interaction resulting in a distinct course of infection. Clearly, such studies need to be extended, and the pattern recognition receptors engaged or modulated by various pathogens have to be defined in detail in order to explain both the specificity and the convergence of gene expression patterns.

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