Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques

Dijkman, Karin; Sombroek, Claudia C.; Vervenne, Richard A. W.; Hofman, Sam; Boot, Charelle; Remarque, Edmond J.; Kocken, Clemens H. M.; Ottenhoff, Tom H. M.; Kondova, Ivanela; Khayum, M. A.; Haanstra, Krista G.; Vierboom, Michel; Verreck, Frank A. W.

doi:10.1038/s41591-018-0319-9

Cited by 245 publications

(293 citation statements)

References 41 publications

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“…At week 7 post-Mtb infection, in addition to CW- and ESAT-6/CFP-10-stimulated CD4 T cells that singly-expressed either IFN-γ and IL-17 (Figure 6A-C) , we found Mtb-specific T cells that co-expressed IFN-γ and IL-17 (Figure 6D) . While these IFN-γ/IL-17 double positive cells were present at relatively low frequencies, our results are consistent with recently published data showing that rhesus macaques who were protected from developing TB following mucosal vaccination with BCG, harbored mycobacteria-specific IFN-γ/IL-17 double-positive CD4 T cells(28). Together, the data represented in Figures 5 and 6 show that in addition to Mtb antigen-specific IFN-γ+ T cells, Mtb-specific IL-17+ and IFN-γ/IL-17 double-positive T cells are present in the airways of asymptomatic rhesus macaques, suggesting an association between balanced Th 1 /Th 17 responses at mucosal sites of infection and immune control of Mtb infection.…”

Section: Resultssupporting

confidence: 93%

“…Our results indicate that both IFN-γ single-positive and IFN-γ+IL-17+ double-positive cells emerge soon after Mtb infection and persist for several weeks, thus likely contributing to controlling Mtb infection during LTBI. These data support and extend previous studies in mice (50, 55, 56) and in macaques (28, 53) suggesting that balanced Th 1 and Th 17 responses are associated with enhanced immunity to TB. Future studies that selectively deplete IL-17 or IFN-γ + CD4 T cells in the context of LTBI or vaccination in macaques will provide more direct evidence for the role of these cells in LTBI.…”

Section: Discussionsupporting

confidence: 91%

“…Although IL-17 is a hallmark of Th 17 cells, IL-17/IFN-γ double-positive T cells are also known to be present at mucosal sites of inflammation(28). We sought to investigate whether Mtb-specific CD4 T cells that express both IFN-γ and IL-17 are present in BAL (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…Higher levels of poly-functional T-cell subsets has been directly related with an improved efficacy in other vaccine models against intracellular pathogens (51,52). In agreement with this observation, an improved outcome was detected in the St/CDA group, which showed an increase in the frequency of polyfunctional CD4 and CD8 T-cell subsets.…”

Section: Discussionsupporting

confidence: 70%

Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

et al. 2020

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There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections lead. Trypanosoma cruzi, the causative agent of Chagas disease, is an excellent example of a silent parasitic invasion that affects millions of people worldwide due to its progression into the symptomatic chronic phase of infection. In search for novel vaccine candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanisms of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist, like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.

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Strategy to Enhance Dendritic Cell‐Mediated DNA Vaccination in the Lung

Kim

Hsueh

Kim

et al. 2020

Advanced Therapeutics

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Here, a new paradigm is introduced to promote pulmonary DNA vaccination. Specifically, it is demonstrated that nanoparticles designed to rapidly penetrate airway mucus (mucus-penetrating particle or MPP) enhance the delivery of an inhaled model DNA vaccine (i.e., ovalbumin-expressing plasmids) to pulmonary dendritic cells (DC), leading to robust and durable local and trans-mucosal immunity. In contrast, mucus-impermeable particles are poorly taken up by pulmonary DC following inhalation, despite their superior ability to mediate DC uptake in vitro compared to MPP. In addition to the enhanced immunity achieved in mucosal surfaces, inhaled MPP unexpectedly provides significantly greater systemic immune responses compared to gold-standard approaches applied in the clinic for systemic vaccination, including intradermal injection and intramuscular electroporation. It is also shown here that inhaled MPP significantly enhances the survival of an orthotopic mouse model of aggressive lung cancer compared to the gold-standard approaches. Importantly, it is discovered that MPP-mediated pulmonary DNA vaccination induces memory T-cell immunity, particularly the ready-to-act effector memory-biased phenotype, both locally and systemically. The findings here underscore the importance of breaching the airway mucus barrier to facilitate DNA vaccine uptake by pulmonary DC and thus to initiate full-blown immune responses.

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Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques

Cited by 245 publications

References 41 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

Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

Strategy to Enhance Dendritic Cell‐Mediated DNA Vaccination in the Lung

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