Prevention of tuberculosis in macaques after intravenous BCG immunization

Darrah, Patricia A.; Zeppa, Joseph J.; Maiello, Pauline; Hackney, Joshua A.; Wadsworth, Marc H.; Hughes, Travis; Pokkali, Supriya; Swanson, Phillip A.; Grant, Nicole L.; Rodgers, Mark; Kamath, Megha; Causgrove, Chelsea M; Laddy, Dominick J.; Bonavia, Aurelio; Casimiro, Danilo R.; Lin, Philana Ling; Klein, Edwin; White, Alexander G.; Scanga, Charles A.; Shalek, Alex K.; Roederer, Mario; Flynn, JoAnne L.; Seder, Robert A.

doi:10.1038/s41586-019-1817-8

Cited by 463 publications

(617 citation statements)

References 58 publications

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“…Previous studies in NHPs assessed antigen-specific immune responses in BAL at early time points macaques in infected macaques (35, 40-42), or during vaccination (43-45) (28). However, in-depth analysis of the phenotypes, functionality and kinetics of Mtb antigen-specific immune responses in blood and BAL during establishment and maintenance of asymptomatic latent infection have been lacking.…”

Section: Discussionmentioning

confidence: 99%

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Shanmugasundaram

Bucşan

Ganatra

et al. 2020

Preprint

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27Mycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control 28 during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-29 human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb 30 antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic 31 rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 32 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and 33 memory CD4 and CD8 T cells producing IFN-γ in the airways compared to peripheral blood, 34 which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-35 17/IFN-γ double-positive T cells were present in the airways but were largely absent in the 36 periphery, suggesting that balanced mucosal Th 1 /Th 17 responses are associated with LTBI. The 37 majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine 38 receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in 39 granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb 40 burden. Our findings provide novel insights into antigen-specific T cell responses associated 41 with asymptomatic Mtb infection that are relevant for developing better strategies to control TB. 42 43 46 51 (LTBI)(1). Individuals with LTBI are defined as having a positive tuberculin skin test (TST) 52 and/or Interferon-gamma Release Assay (IGRA), a normal chest radiograph and the absence of 53 clinical signs and symptoms of disease(2). Latently-infected individuals are generally thought to 54 contain Mtb within granulomatous lesions in the lung without completely eradicating bacteria, 55 although direct evidence for the persistence of Mtb in human LTBI is lacking. Moreover, it is 56 increasingly recognized that clinically asymptomatic individuals likely reflect a spectrum of 57 infection outcomes, ranging from individuals who may have eliminated infection, to those with 58 low levels of replicating or non-replicating persistent bacteria, to individuals who may harbor 59 actively replicating bacteria without exhibiting overt clinical symptoms(3-5). Identifying immune 60 responses associated with asymptomatic Mtb infection states will provide key insights into 61 mechanisms of immune control that protect against progressing to active TB disease. 62 63 Antigen-specific T cell responses are critical for immune control of Mtb infection. In response to 64 Mtb infection, the majority of infected people mount robust CD4 T cell responses involving T 65 helper 1 (Th 1 ) cytokines such as IFN-γ and TNF-α, which are important for activating 66 macrophages and curtailing Mtb replication in the lung(6, 7). In addition, IL-17 and Th 17 67 responses have emerged as important for protective immunity against TB, but mucosal Mtb-68 specific Th 17 responses during immune control of LTBI in humans remain poorly studied. In 69 general, the na...

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Section: Discussionmentioning

confidence: 99%

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Shanmugasundaram

Bucşan

Ganatra

et al. 2020

Preprint

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“…In the present study, mice were immunized with BCG by intravenous injection, which has been shown to elicit stronger immune responses than other routine immunization routes (Darrah et al, 2020). DTH responses in vivo along with various immune factors were assessed.…”

Section: Discussionmentioning

confidence: 99%

Identification of Secreted O-Mannosylated Proteins From BCG and Characterization of Immunodominant Antigens BCG_0470 and BCG_0980

Deng

Zhang

et al. 2020

Front. Microbiol.

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Bacterial glycoproteins have been investigated as vaccine candidates as well as diagnostic biomarkers. However, they are poorly understood in Mycobacterium bovis strain bacille Calmette-Guérin (BCG), a non-pathogenic model of Mycobacterium tuberculosis. To understand the roles of secreted O-mannosylated glycoproteins in BCG, we conducted a ConA lectin-affinity chromatography and mass spectra analysis to identify O-mannosylated proteins in BCG culture filtrate. Subsequent screening of antigens was performed using polyclonal antibodies obtained from a BCG-immunized mouse, with 15 endogenous O-mannosylated proteins eventually identified. Of these, BCG_0470 and BCG_0980 (PstS3) were revealed as the immunodominant antigens. To examine the protective effects of the antigens, recombinant antigens proteins were first expressed in Mycobacterium smegmatis and Escherichia coli, with the purified proteins then used to boost BCG primed-mice. Overall, the treated mice showed a greater delayed-type hypersensitivity response in vivo, as well as stronger Th1 responses, including higher level of IFN-7, TNF-α, and specific-IgG. Therefore, mannosylated proteins BCG_0470 and BCG_0980 effectively amplified the immune responses induced by BCG in mice. Together, our results suggest that the oligosaccharide chains containing mannose are the antigenic determinants of glycoproteins, providing key insight for future vaccine optimization and design.

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“…Nine out of 10 macaques were highly protected against tuberculosis after intravenous administration of the BCG vaccine. 7 Animals immunized intradermally or by aerosols showed significantly higher rates of infection when challenged with Mycobacterium tuberculosis delivered intrapulmonary six months post-vaccination. Furthermore, intravenous delivery increased the count and persistence of antigen-responsive CD4 + and CD8 + T cells in the lungs.…”

Section: Intravenous Administration Of the Bcg Vaccine Improves Protementioning

confidence: 95%

Human Vaccines & Immunotherapeutics: news

2020

Human Vaccines & Immunotherapeutics

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Prevention of tuberculosis in macaques after intravenous BCG immunization

Cited by 463 publications

References 58 publications

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Identification of Secreted O-Mannosylated Proteins From BCG and Characterization of Immunodominant Antigens BCG_0470 and BCG_0980

Human Vaccines & Immunotherapeutics: news

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