Dataset Information

The BCG?BCG1419c Vaccine Candidate Reduces Lung Pathology, IL-6, TNF-?, and IL-10 During Chronic TB Infection.

ABSTRACT: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of human tuberculosis (TB), is estimated to be harbored by up to 2 billion people in a latent TB infection (LTBI) state. The only TB vaccine approved for use in humans, BCG, does not confer protection against establishment of or reactivation from LTBI, so new vaccine candidates are needed to specifically address this need. Following the hypothesis that mycobacterial biofilms resemble aspects of LTBI, we modified BCG by deleting the BCG1419c gene to create the BCG?BCG1419c vaccine strain. In this study, we compared cytokine profiles, bacterial burden, and lung lesions after immunization with BCG or BCG?BCG1419c before and after 6 months of aerosol infection with M. tuberculosis H37Rv in the resistant C57BL/6 mouse model. Our results show that in infected mice, BCG?BCG1419c significantly reduced lung lesions and IL-6 in comparison to the unmodified BCG strain, and was the only vaccine that decreased production of TNF-? and IL-10 compared to non-vaccinated mice, while vaccination with BCG or BCG?BCG1419c significantly reduced IFN-? production. Moreover, transcriptome profiling of BCG?BCG1419c suggests that compared to BCG, it has decreased expression of genes involved in mycolic acids (MAs) metabolism, and antigenic chaperones, which might be involved in reduced pathology compared to BCG-vaccinated mice.

SUBMITTER: Flores-Valdez MA

PROVIDER: S-EPMC6005825 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The BCGΔBCG1419c Vaccine Candidate Reduces Lung Pathology, IL-6, TNF-α, and IL-10 During Chronic TB Infection.

Flores-Valdez Mario A MA Pedroza-Roldán César C Aceves-Sánchez Michel de Jesús MJ Peterson Eliza J R EJR Baliga Nitin S NS Hernández-Pando Rogelio R Troudt JoLynn J Creissen Elizabeth E Izzo Linda L Bielefeldt-Ohmann Helle H Bickett Thomas T Izzo Angelo A AA

Frontiers in microbiology 20180612

<i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), the causative agent of human tuberculosis (TB), is estimated to be harbored by up to 2 billion people in a latent TB infection (LTBI) state. The only TB vaccine approved for use in humans, BCG, does not confer protection against establishment of or reactivation from LTBI, so new vaccine candidates are needed to specifically address this need. Following the hypothesis that mycobacterial biofilms resemble aspects of LTBI, we modified BCG ...[more]

PMID: 29946316

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Project description:BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short-term experiments (30 days), substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF-? and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1+IL-6+TNF-? (IM-1.6.?) and IL-7+IL-15 (IM-7.15). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.? but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.? was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB.

Project description:Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5-15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5-15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.

Dataset Information

The BCG?BCG1419c Vaccine Candidate Reduces Lung Pathology, IL-6, TNF-?, and IL-10 During Chronic TB Infection.

Publications

The BCGΔBCG1419c Vaccine Candidate Reduces Lung Pathology, IL-6, TNF-α, and IL-10 During Chronic TB Infection.

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