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Comparing the effects of two different strains of mycobacteria, Mycobacterium vaccae NCTC 11659 and M. vaccae ATCC 15483, on stress-resilient behaviors and lipid-immune signaling in rats.

ABSTRACT: Stress-related disorders, such as posttraumatic stress disorder (PTSD), are highly prevalent and often difficult to treat. In rodents, stress-related, anxiety-like defensive behavioral responses may be characterized by social avoidance, exacerbated inflammation, and altered metabolic states. We have previously shown that, in rodents, subcutaneous injections of a heat-killed preparation of the soil-derived bacterium Mycobacterium vaccae NCTC 11659 promotes stress resilience effects that are associated with immunoregulatory signaling in the periphery and the brain. In the current study, we sought to determine whether treatment with a heat-killed preparation of the closely related M. vaccae type strain, M. vaccae ATCC 15483, would also promote stress-resilience in adult male rats, likely due to biologically similar characteristics of the two strains. Here we show that immunization with either M. vaccae NCTC 11659 or M. vaccae ATCC 15483 prevents stress-induced increases in hippocampal interleukin 6 mRNA expression, consistent with previous studies showing that M. vaccae NCTC 11659 prevents stress-induced increases in peripheral IL-6 secretion, and prevents exaggeration of anxiety-like defensive behavioral responses assessed 24 h after exposure to inescapable tail shock stress (IS) in adult male rats. Analysis of mRNA expression, protein abundance, and flow cytometry data demonstrate overlapping but also unique effects of treatment with the two M. vaccae strains on immunological and metabolic signaling in the host. These data support the hypothesis that treatment with different M. vaccae strains may immunize the host against stress-induced dysregulation of physiology and behavior.

SUBMITTER: Loupy KM

PROVIDER: S-EPMC7749860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tuberculosis (TB) is one of the leading causes of death worldwide, especially in developing countries. Neonatal BCG vaccination occurs in various regions, but the level of protection varies in different populations. Recently, Mycobacterium vaccae is found to be an immunomodulating therapeutic agent that could confer a significant level of protection against TB. It is the only vaccine in a phase III trial from WHO to assess its efficacy and safety in preventing TB disease in people with latent TB infection. However, the mechanism of immunotherapy of M. vaccae remains poorly understood. In this study, the full genome of M. vaccae was obtained by next-generation sequencing technology, and a proteogenomic approach was successfully applied to further perform genome annotation using high resolution and high accuracy MS data. A total of 3,387 proteins (22,508 unique peptides) were identified, and 581 proteins annotated as hypothetical proteins in the genome database were confirmed. Furthermore, 38 novel protein products not annotated at the genome level were detected and validated. Additionally, the translational start sites of 445 proteins were confirmed, and 98 proteins were validated through extension of their translational start sites based on N terminus-derived peptides. The physicochemical characteristics of the identified proteins were determined. Thirty-five immunogenic proteins of M. vaccae were identified by immunoproteomic analysis, and 20 of them were selected to be expressed and validated by Western blot for immunoreactivity to serum from patients infected with M. tuberculosis The results revealed that eight of them showed strong specific reactive signals on the immunoblots. Furthermore, cellular immune response was further examined and one protein displayed a higher cellular immune level in pulmonary TB patients. Twelve identified immunogenic proteins have orthologous in H37Rv and BCG. This is the first study to obtain the full genome and annotation of M. vaccae using a proteogenomic approach, and some immunogenic proteins that were validated by immunoproteomic analysis could contribute to the understanding of the mechanism of M. vaccae immunotherapy.

Project description:Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.

Dataset Information

Comparing the effects of two different strains of mycobacteria, Mycobacterium vaccae NCTC 11659 and M. vaccae ATCC 15483, on stress-resilient behaviors and lipid-immune signaling in rats.

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