title: Dissecting host factors that regulate the early stages of tuberculosis infection.
abstract: Incomplete understanding of mechanisms involved in the host-pathogen interactions constrains our efforts to eliminate tuberculosis. In many individuals, resulting from immune response to mycobacterial infection organised structures called granulomas are formed. To identify host responses that may control at least the early stages of infection, we employed an in vitro granuloma model. Here, human PBMCs were infected with live Mycobacterium tuberculosis in culture, and the appearance of granuloma-like structures was monitored over the next several days. Production of cytokines and chemokines in culture supernatants was monitored at various times, and the resulting temporal profiles were examined for possible correlations with either granuloma formation, or bacterial growth. While a positive association of TNF-α and IFN-γ secretion levels with extent of granuloma formation could clearly be identified, we were, however, unable to detect any statistically significant relationship between any cytokine/chemokine and bacterial growth. Examination of specific host cellular biochemical pathways revealed that either modulation of neutral lipid homeostasis through inhibition of the Gi-protein coupled receptor GPR109A, or regulation of host metabolic pathways through addition of vitamin D, provided a more effective means of controlling infection. A subsequent genotypic analysis for a select subset of genes belonging to pathways known to be significant for TB pathology revealed associations of polymorphisms with cytokine secretions and bacterial growth independently. Collectively therefore, the present study supports that key metabolic pathways of the host cell, rather than levels of relevant cytokines/chemokines might be more critical for regulating the intracellular mycobacterial load, in the context of granuloma formation.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, 110067 New Delhi, India. Electronic address: nehaagr25@gmail.com.
authors.forename: Neha
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, 741251 West Bengal, India. Electronic address: cb1@nibmg.ac.in.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Bhattacharyya
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, 741251 West Bengal, India. Electronic address: am2@nibmg.ac.in.
authors.forename: Ankur
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, 110067 New Delhi, India. Electronic address: uullah@btk.fi.
authors.forename: Ubaid
authors.initials: U
authors.lastname: Ullah
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, 741251 West Bengal, India. Electronic address: bp1@nibmg.ac.in.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Pandit
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, 110067 New Delhi, India. Electronic address: kanury@icgeb.res.in.
authors.forename: Kanury V S
authors.initials: KVS
authors.lastname: Rao
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, 741251 West Bengal, India. Electronic address: ppm1@nibmg.ac.in.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Majumder
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: Cytokines; Genotype; Human PBMC; In vitro granuloma model; Tuberculosis