title: Pro- and anti-inflammatory cytokines against Rv2031 are elevated during latent tuberculosis: a study in cohorts of tuberculosis patients, household contacts and community controls in an endemic setting.
abstract: Tuberculosis (TB) is among the leading causes of morbidity and mortality. The causative agent, Mycobacterium tuberculosis (Mtb), has evolved virulent factors for entry, survival, multiplication and immune evasion. Rv2031 (also called alpha crystallin, hspX, 16-kDa antigen), one of the most immunogenic latency antigens, is believed to play a key role in long-term viability of Mtb. Here, we report the dynamics of pro-inflammatory (IFN-γ, TNF-α) and anti-inflammatory (IL-10) cytokines against Rv2031 using whole blood assay in human cohorts in a TB endemic setting. Cytokine responses to ESAT-6-CFP-10 were also measured for comparison. Blood samples were collected from smear positive pulmonary TB patients and their contacts at baseline, 6 and 12 months, and from community controls at entry. At baseline, 54.4% of controls and 73.2% of contacts were QFT-GIT test positive. Baseline IFN-γ, TNF-α and IL-10 responses to Rv2031 were significantly higher in controls compared to contacts and untreated patients (p<0.001). Furthermore, untreated patients had significantly higher TNF-α and IL-10 responses to Rv2031 compared to contacts (p<0.001). In contacts and treated patients, IFN-γ, TNF-α and IL-10 responses to Rv2031 significantly increased over 12 months (p<0.0001) and became comparable with the corresponding levels in controls. There was a positive and significant correlation between Rv2031 and ESAT-6-CFP-10 specific cytokine responses in each study group. The fact that the levels of IFN-γ, TNF-α and IL-10 against Rv2031 were highest during latent TB infection may indicate their potential as markers of protection against TB. Taken together, the findings of this study suggest the potential of IFN-γ, TNF-α and IL-10 against Rv2031 as biomarkers of the host response to Mtb during convalescence from, and the absence of, active tuberculosis.
authors.affiliation: Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia; Department of Community Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway.
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Belay
authors.affiliation: Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Mengistu
authors.initials: M
authors.lastname: Legesse
authors.affiliation: Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
authors.forename: Adane
authors.initials: A
authors.lastname: Mihret
authors.affiliation: Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
authors.forename: Yonas
authors.initials: Y
authors.lastname: Bekele
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.affiliation: Department of Community Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Bjune
authors.affiliation: Department of Community Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway.
authors.forename: Fekadu
authors.initials: F
authors.lastname: Abebe
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D016022:Case-Control Studies; D016358:Contact Tracing; D019353:Endemic Diseases; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D055985:Latent Tuberculosis / Q000097:blood* / Q000453:epidemiology / Q000382:microbiology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000097:blood* / Q000453:epidemiology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C118127:HspX protein, Mycobacterium tuberculosis; C508609:IL10 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma