Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells

Abstract

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world's population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.We hypothesized that gene expression profiles in innate immune cells may be used to classify individuals with respect to their susceptibility to develop active TB. To test this hypothesis, we differentiated dendritic cells (DCs) from monocytes isolated from individuals that had recovered from a past episode of active TB, which we refer to as susceptible, and from individuals with confirmed latent TB, which we refer to as putatively resistant (this group is enriched in resistant individuals but we cannot exclude that some still have the potential to develop active TB 22 ). We infected the DCs with MTB because these innate immune cells help shape the adaptive immune response, which is critical for fighting MTB 23,24 . We discovered that the gene expression differences between innate immune cells from resistant and susceptible individuals were present primarily in the non-infected state, that these differentially expressed genes were enriched for nearby SNPs with low p-values in TB susceptibility GWAS, and furthermore, that these gene expression levels could be used to classify individuals based on their susceptibility status. Results Susceptible individuals have an altered transcriptome in the non-infected stateWe obtained whole blood samples from 25 healthy male Caucasian individuals (Supplementary Data S1). Six of the donors had recovered from active TB, and are thus putatively susceptible. The remaining 19 tested positive for latent TB without ever experiencing symptoms of active TB, and are thus putatively resistant. We isolated dendritic cells (DCs) and treated them with Mycobacterium tuberculosis (MTB) or a mock control for 18 hours. To measure genome-wide gen...

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