Characterization of immune responses of human PBMCs infected with Mycobacterium tuberculosis H37Ra: Impact of donor declared BCG vaccination history on immune responses and M. tuberculosis growth

Introduction: The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK.Materials and Methods: Blood samples were obtained from BCG-immunized infants of mothers with (n = 110) and without (n = 121) latent Mycobacterium tuberculosis infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (n = 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6/CFP10 to assess exposure to or infection with M. tuberculosis or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants.Results: The IFN-γ response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6/CFP10 produced significantly higher IFN-γ, TNF, IL-12p40, IL-1α, IL-1β, IL-1Ra, IP-10, MIP-1α, MIP-1β, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6/CFP10 produced significantly higher amounts of IL-8 (p = 0.0001), IL-10 (p = 0.0022), and IL-13 (p = 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52.Conclusions: Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.

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BCG vaccination of infants confers Mycobacterium tuberculosis strain-specific immune responses to leucocytes

10.22541/au.160196958.83895007/v1 ◽

2020 ◽

Author(s):

Selvakumar Subbian ◽

Pooja Singh ◽

Afsal Kolloli ◽

Elisa Nemes ◽

Thomas Scriba ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Tuberculosis Strain ◽

Bcg Vaccination ◽

Mycobacterium Tuberculosis Strain

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Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz430 ◽

2019 ◽

Vol 221 (1) ◽

pp. 146-155 ◽

Cited By ~ 4

Author(s):

Anthea L Katelaris ◽

Charlotte Jackson ◽

Jo Southern ◽

Rishi K Gupta ◽

Francis Drobniewski ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Vaccine Development ◽

Latent Tuberculosis ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection ◽

Cross Sectional ◽

Bcg Vaccination ◽

Cross Sectional Analysis ◽

Vaccination History ◽

Sectional Analysis

Abstract Background BCG appears to reduce acquisition of Mycobacterium tuberculosis infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of M. tuberculosis infection in adults. Methods We conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored. Results Of 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (adjusted odds ratio = 0.70; 95% confidence interval, .56–.87; P = .0017) yielding a VE of 30%. VE declined with time since vaccination but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with nonvaccinated participants. Conclusions BCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against M. tuberculosis infection as well as disease. This has implications for immunization programs, vaccine development, and tuberculosis control efforts worldwide. Clinical trials registration NCT01162265.

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Lack of Immune Responses to Mycobacterium tuberculosis DosR Regulon Proteins following Mycobacterium bovis BCG Vaccination

Infection and Immunity ◽

10.1128/iai.01999-06 ◽

2007 ◽

Vol 75 (7) ◽

pp. 3523-3530 ◽

Cited By ~ 74

Author(s):

May Young Lin ◽

Annemieke Geluk ◽

Steven G. Smith ◽

Amanda L. Stewart ◽

Annemieke H. Friggen ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Mycobacterium Bovis ◽

Protective Efficacy ◽

Transcriptional Profiling ◽

In Silico Analysis ◽

Dna Encoding ◽

Bcg Vaccination ◽

Dosr Regulon

ABSTRACT Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.

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Characterization of the Secreted MPT53 Antigen ofMycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.69.9.5936-5939.2001 ◽

2001 ◽

Vol 69 (9) ◽

pp. 5936-5939 ◽

Cited By ~ 8

Author(s):

Sadie Johnson ◽

PierNatale Brusasca ◽

Konstantin Lyashchenko ◽

John S. Spencer ◽

Harald G. Wiker ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Mycobacterium Avium ◽

Specific Antibody ◽

Nontuberculous Mycobacteria ◽

Polyclonal Antibodies ◽

Antibody Responses ◽

Delayed Type Hypersensitivity ◽

Secreted Protein

ABSTRACT MPT53 is a secreted protein of Mycobacterium tuberculosis. Southern transfer and hybridization showed mpt53 to be conserved in the M. tuberculosis complex and to have homology with DNA fromMycobacterium avium and other nontuberculous mycobacteria. However, anti-MPT53 polyclonal antibodies detected no antigen in the culture filtrates of M. avium and other nontuberculous mycobacteria. MPT53 of M. tuberculosisinduced strong, tuberculosis-specific antibody responses in guinea pigs but induced no delayed-type hypersensitivity. Involvement in immune responses during human tuberculosis was very modest.

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