Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection

Abstract

RationaleUnderstanding mechanisms of resistance to M. tuberculosis (M.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases, such as HIV.ObjectivesTo compare the early transcriptional response of M.tb-infected monocytes between Ugandan household contacts of tuberculosis patients who demonstrate clinical resistance to M.tb infection (cases) and matched controls with latent tuberculosis infection.MethodsCases (n = 10) and controls (n = 18) were selected from a long-term household contact study in which cases did not convert their tuberculin skin test (TST) or develop tuberculosis over two years of follow up. We obtained genome-wide transcriptional profiles of M.tb-infected peripheral blood monocytes and used Gene Set Enrichment Analysis and interaction networks to identify cellular processes associated with resistance to clinical M.tb infection.Measurements and main resultsWe discovered gene sets associated with histone deacetylases that were differentially expressed when comparing resistant and susceptible subjects. We used small molecule inhibitors to demonstrate that histone deacetylase function is important for the pro-inflammatory response to in-vitro M.tb infection in human monocytes.ConclusionsMonocytes from individuals who appear to resist clinical M.tb infection differentially activate pathways controlled by histone deacetylase in response to in-vitro M.tb infection when compared to those who are susceptible and develop latent tuberculosis. These data identify a potential cellular mechanism underlying the clinical phenomenon of resistance to M.tb infection despite known exposure to an infectious contact.

Illuminating host-mycobacterial interactions with functional genomic screening to inhibit mycobacterial pathogenesis

“…Deletion of IFNAR1 (interferon alpha and beta receptor subunit 1) in the type I interferon signaling pathway can increase resistance to Mtb in mice (Mayer-Barber et al, 2014), and a proline deletion in IFNAR1 increases resistance to TB in some human populations (Zhang et al, 2018). HDAC (histone deacetylase) regulates the pro-inflammatory response of host cells, and HDAC inhibition restricts intracellular Mtb growth (Seshadri et al, 2017). PDE (phosphodiesterase) inhibitors improve the clearance of Mtb in rabbit lungs, restrict Mtb growth, and increase mouse survival (Maiga et al, 2012; Subbian et al, 2011).…”

Genomics of Human Pulmonary Tuberculosis: from Genes to Pathways

“…We identified a locus near IL12B , a previously described candidate gene that has been shown to affect response to TB in mice as well as define highly susceptible families that have an IL12B knockout as well as among persons with MSMD. We have also studied persistently tuberculin skin test negativity despite close and prolonged exposure to active TB cases [64, 65] – while the focus here is on infection and not disease, this resistance phenotype may help identify novel targets for vaccine development and host directed therapies [66]. …”

“…Gene expression studies indicated that the sodium butyrate pathway was associated with persistent TST negativity. Follow-up studies demonstrated that sodium butyrate and histone deacetylase inhibitors were associated with immunological response to MTB in vitro [66]. While these studies had smaller sample sizes, they often included independent case-control replication sets with functional validation relevant to TB biology.…”

“…As mentioned above, examination of pathways instead of single gene effects has revealed novel therapeutic insight for TB [66]. Network approaches may be better for discovery and characterization of gene-gene interactions and pathways associated with disease than standard analytical approaches, because variants may have unremarkable individual effects but instead affect the phenotype through gene-gene interactions [71, 72].…”

Human Genomics of Mycobacterium tuberculosis Infection and Disease

“…Transcriptomics has proven less powerful in differentiating healthy controls from LTBI patients although recent transcriptomics studies identified histone deacetylation as a key event in Mtb infection resistance in monocytes (24). Unfortunately, there is no gold-standard for identifying LTBI patients who are truly infected with Mtb since we cannot distinguish a possible anamnestic response to Mtb antigens from persistent infection.…”