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.
Highlights
Despite the availability of cost-effective drugs and a safe vaccine, Mycobacterium tuberculosis (M.tb) was responsible for over 1.5 million deaths worldwide in 2014[1]
Monocytes 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
Principal components analysis revealed that infection was the greatest source of variability in the data, accounting for 40% in PC1, and this was much greater than any technical variable, such as batch, RNA quality, or RNA yield (Fig 1b and data not shown)
Summary
Despite the availability of cost-effective drugs and a safe vaccine, Mycobacterium tuberculosis (M.tb) was responsible for over 1.5 million deaths worldwide in 2014[1]. Animal studies have revealed the importance of IFN-γ and TNF- α for controlling mycobacterial replication[2,3,4]. Co-infection with HIV has emerged as a major reason for the resurgence in tuberculosis, and this effect is not purely due to T-cell depletion [6,7,8,9,10]. These studies have only uncovered a partial understanding of the mechanisms underlying susceptibility to mycobacterial infection and disease
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