Tissue metabolic changes drive cytokine responses to Mycobacterium tuberculosis

Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis (Mtb). Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms (SNPs) that were trans-acting for in vitro cytokine responses to Mtb stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis

Salmonella Typhimurium Induces Immune Paralysis in Human Peripheral Monocytes

LPS tolerance, a well-described phenomenon, is characterized by immune paralysis. Recent studies suggest that this paralysis occurs due to metabolic reprogramming and epigenetic changes in immune cells after an initial stimulus, leading to anergy and an inability to respond to subsequent stimuli. This process is a form of innate immune memory. This study aimed to investigate whether Salmonella Typhimurium can induce changes in innate immune cells, specifically exploring its capacity to elicit either trained immunity or tolerance. Using an in vivo protocol for trained immunity, human adherent monocytes were isolated from multiple donors and stimulated with live and heat-killed strains of Salmonella Typhimurium. Following a wash and a six-day resting period, the monocytes were re-stimulated with LPS and Pam3Cys. Pro-inflammatory cytokines were measured from supernatants at various time points. Additionally, lactate production, a key metabolite in these processes, was assessed. The findings indicate that Salmonella Typhimurium induces tolerance in human adherent monocytes, as evidenced by a lack of response to the second stimuli. This non-responsiveness is physiologically significant, as it may prevent tissue damage during sepsis by curbing excessive inflammatory signals. These findings may have significant implications for the management of sepsis and other conditions characterized by dysregulated immune responses.Agencia Nacional de Investigación e Innovació

Salmonella LVR01 induces dual innate immune memory responses in tumor models

Innate immune memory operates in two modes: trained immunity, which amplifies cellular responsiveness, and tolerance, which reduces the immune response to later challenges. Agents such as beta-glucan, Leishmania, BCG, and LPS are known to trigger one of these effects. BCG, an established immunotherapy for bladder cancer, uses trained immunity to enhance anti-tumor adaptive responses. Salmonella has also shown potential in cancer treatment, generating strong but short-lived anti-tumor immune responses. This study investigates whether Salmonella LVR01 can induce trained immunity and how this influences anti-tumor activity. In vivo stimulation of bone marrow cells with Salmonella LVR01 was performed, followed by a secondary stimulus to evaluate trained immunity through cytokine production. The impact of Salmonella LVR01 on tumor growth and survival was examined in mouse models, with tumors implanted after bacterial administration. In vitro assays were conducted to measure cytokine production in mouse monocytes following stimulation with Salmonella. Salmonella LVR01 led to an increased cytokine response in bone marrow cells, consistent with trained immunity. This enhanced response was associated with slower tumor growth and improved survival in treated mice. However, in vitro studies showed that stimulation of monocytes with Salmonella resulted in reduced cytokine production, indicating immune tolerance. These dual effects may explain the temporary benefits of Salmonella-based cancer therapies, underscoring the need for further research to refine these treatments.Agencia Nacional de Investigación e Innovació

Prophylactic treatment with attenuated Salmonella LVR01 helps to control tumour growth: role of trained immunity

Attenuated Salmonella immunotherapy has been successfully evaluated as a therapeutic option for cancer. Its potential is attributed to a direct effect, by invading and killing tumour cells, and an indirect one, by stimulating the immune system, particularly at the tumour microenvironment. In this work, we explore the potential of an attenuated Salmonella Typhymurium (LVR01, aroC-) as a prophylactic approach for the treatment of cancer in two preclinical models (B16F10 melanoma and A20 non-Hodgkin lymphoma). Intraperitoneal pre-treatment with 1x106 CFU of LVR01, applied one week before tumour implantation, resulted in a retarded tumour growth and hence a prolonged animal survival, in both tumour models. This effect was not directly ascribed to Salmonella, as pretreatment with LVR01 30 days before tumour implantation also revealed anti-cancer activity, in the absence of circulating bacteria. Thus, the anti-tumour effect ought to be immune-mediated. However, no differences in percentage of CD8+ T lymphocytes, NK cells nor myeloid CD11b+ cells were found between LVR01-pre-treated and control mice, in both models. These results suggest that the antitumour activity is independent of tumour-infiltrating immune cell numbers, but still dependent on cell functionality. In this regard, splenocytes from LVR01-pre-treated melanoma-bearing mice produced higher amounts of IL-6 and TNF-α upon stimulation with an unrelated stimulus (Candida albicans), a mechanism associated to trained immunity. Actually, LVR01 reached bone marrow after intraperitoneal administration and boosted proinflammatory cytokines levels in serum after a challenge with a second stimulus. In addition, pre-treatment with heat-killed LVR01 resulted in loss of anti-tumour effect in B16F10 melanoma model. Altogether, these results suggest that Salmonella induces central trained immunity, which could help to control tumour growth and extend animal survival. Further studies are currently undergoing to confirm this hypothesis.Agencia Nacional de Investigación e Innovació