Insights into Host Microbe Interactions

This section details some examples ofhow the microbial gene expression pattern may be used to explore the way in which changing microbe or host genetic backgrounds may affect the host-microbe relationship. A comparison of the transcriptional responses of intracellular bacteria with known deletions, or with host cells of different lineage for example, may illuminate functionally significant microbial or host immune response pathways. Rohde et al. [24] modified phagosome acidification of murine macrophages, and compared the intracellular RNA profiles of M. tuberculosis and the less virulent M. bovis BCG (bacillus Calmette-Guerin) to identify factors induced by decreased pH or constrained intracellular growth. Similarly, the shift from tachyzoite to bradyzoite stage in T. gondii was explored by contrasting the intracellular RNA derived from wild-type and differentiation-deficient mutants [59].

An alternative strategy is to vary the host microenvironment encountered by the microbe during infection; Belland et al. [20] used interferon gamma (IFNg) treatment of an epithelial cell line to create a model of C. trachomatis persistence and reactivation. Similarly, Schnappinger et al. [16] compared the transcriptional response of M. tuberculosis to naive and IFNg-activated macrophages derived from wild-type and NOS2-/- (nitric oxide synthase 2) knockout mice. The M. tuberculosis transcriptional profile has also been compared in human immune cells permissive and non permissive for mycobacterial growth, identifying factors differentially expressed by M. tuberculosis after invasion of macrophages and dendritic cells respectively [29]. Genes involved in the response to hypoxia (or nitric oxide), regulated by DosR, and genes associated with nutrient starvation and slow growth were induced 18 h after phagocytosis by dendritic cells compared to the intracellular profile of M. tuberculosis after 18 h macrophage infection. Definition of the M. tuberculosis transcriptional responses to both permissive and nonpermissive intracellular environments should enable both host and mycobacterial factors that influence the ability of mycobacteria to replicate successfully intracellularly to be recognized [29]. Tailleux et al. [29] also measured the transcriptional responses of dendritic cells and macrophages to M. tuberculosis infection, enabling a transcriptional snapshot of the dialogue between bacilli and phagocytic cell types to be created. The introduction of microarray platforms containing both host and microbial genomes should expedite these kinds of analysis further [60]. The integration of the transcriptomes from both infecting and infected cells, extracted simultaneously, and the identification of changing patterns of functionally related host and microbial genes should generate new hypotheses regarding the roles of both host and microbe throughout infection.

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