Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection

• Published in: PloS one Vol. 12; no. 4; p. e0175844
• Main Authors: Seshadri, Chetan, Sedaghat, Nafiseh, Campo, Monica, Peterson, Glenna, Wells, Richard D., Olson, Gregory S., Sherman, David R., Stein, Catherine M., Mayanja-Kizza, Harriet, Shojaie, Ali, Boom, W. Henry, Hawn, Thomas R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.04.2017; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Adults; Age; Antibiotics; Antigens; Antiinfectives and antibacterials; Arthritis; Assaying; Bacillus Calmette-Guerin vaccine; BCG; Bioinformatics; Biology and Life Sciences; Blood; Body mass; Case-Control Studies; CCR5 protein; Cell activation; Cell culture; Children; Chromosome 11; Computation; Computer and Information Sciences; Computer programs; Cryopreservation; Cytokines - genetics; Diabetes mellitus; Diagnosis; Disease resistance; Drug Resistance, Bacterial - genetics; Drugs; Engineering; Enrichment; Enrollments; Epidemiology; Exposure; Female; Gene expression; Gene Regulatory Networks - genetics; Gene set enrichment analysis; Genetic aspects; Genomes; Health risks; Historical account; HIV; Hospitals; Households; Human immunodeficiency virus; Humans; Immune response; Immune system; Immunological memory; Infections; Infectious diseases; Inflammation; Inflammation - genetics; Inhibition; Inhibitors; Interferon; Latent Tuberculosis - genetics; Lymphoma; Male; Mathematical analysis; Medicine; Medicine and Health Sciences; Microbial drug resistance; Monocytes - drug effects; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - pathogenicity; Nucleic acids; Oxidative phosphorylation; Pharmacology; Proteins; Rheumatoid arthritis; Risk; Risk factors; Skin; Small Molecule Libraries - therapeutic use; Statistical analysis; Statistics; Studies; Topology; Transcription; Transcription (Genetics); Transcription, Genetic - genetics; Tuberculosis; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - genetics; Young Adult; Cleveland Ohio; Uganda; Ohio; United States > US; Kampala Uganda
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0175844

Understanding 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. To 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. Cases (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. We 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. 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. These data identify a potential cellular mechanism underlying the clinical phenomenon of resistance to M.tb infection despite known exposure to an infectious contact.