bims-traimu 2023-08-20 papers

Issue of 2023–08–20
four papers selected by
Yantong Wan, Southern Medical University

Cell Rep. 2023 Aug 16. pii: S2211-1247(23)01018-5. [Epub ahead of print]42(8): 113007

Lower female survival from an opportunistic infection reveals progesterone-driven sex bias in trained immunity.

Alexander P Earhart, Natalia G Karasseva, Kathryn M Storey, Benjamin Olthoff, Md Bodruzzaman Sarker, Kimberly G Laffey, Margaret J Lange, R Scott Rector, Laura C Schulz, Diana Gil, Claudia M Neuhauser, Adam G Schrum.

Immune responses differ between females and males, although such sex-based variance is incompletely understood. Observing that bacteremia of the opportunistic pathogen Burkholderia gladioli caused many more deaths of female than male mice bearing genetic deficiencies in adaptive immunity, we determined that this was associated with sex bias in the innate immune memory response called trained immunity. Female attenuation of trained immunity varies with estrous cycle stage and correlates with serum progesterone, a hormone that decreases glycolytic capacity and recall cytokine secretion induced by antigen non-specific stimuli. Progesterone receptor antagonism rescues female trained immune responses and survival from controlled B. gladioli infection to magnitudes similar to those of males. These data demonstrate progesterone-dependent sex bias in trained immunity where attenuation of female responses is associated with survival outcomes from opportunistic infection.

Keywords: Burkholderia gladioli; CP: Immunology; glycolytic capacity; innate immune memory; oppotunistic infection; progesterone; progesterone receptor; sex as a biological variable; sex bias; trained immunity

DOI: https://doi.org/10.1016/j.celrep.2023.113007

J Immunol. 2023 Aug 14. pii: ji2200848. [Epub ahead of print]

4-Octyl Itaconate and Dimethyl Fumarate Induce Secretion of the Anti-Inflammatory Protein Annexin A1 via NRF2.

Ciana Diskin, Emily A Day, Órlaith C Henry, Juliana E Toller-Kawahisa, Luke A J O'Neill.

Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of the endogenous metabolite itaconate, which is abundantly produced by LPS-activated macrophages, has recently been identified as a potent anti-inflammatory agent. The anti-inflammatory effects of 4-OI share a significant overlap with those of dimethyl fumarate (DMF), a derivate of another Krebs cycle metabolite fumarate, which is already in use clinically for the treatment of inflammatory diseases. In this study we show that both 4-OI and DMF induce secretion of the 33-kDa form of annexin A1 from murine bone marrow-derived macrophages, an effect that is much more pronounced in LPS-stimulated cells. We also show that this 4-OI- and DMF-driven annexin A1 secretion is NRF2-dependent and that other means of activating NRF2 give rise to the same response. Lastly, we demonstrate that the cholesterol transporter ABCA1, which has previously been implicated in annexin A1 secretion, is required for this process in macrophages. Our findings contribute to the growing body of knowledge on the anti-inflammatory effects of the Krebs cycle metabolite derivatives 4-OI and DMF.

DOI: https://doi.org/10.4049/jimmunol.2200848

Emerg Microbes Infect. 2023 Aug 16. 2249130

A TLR9 agonist synergistically enhances protective immunity induced by an Alum-adjuvanted H7N9 inactivated whole-virion vaccine.

Tsai-Teng Tzeng, Kit Man Chai, I-Hua Chen, Ray-Yuan Chang, Jen-Rong Chiang, Shih-Jen Liu.

Antigen sparing is an important strategy for pandemic vaccine development because of the limitation of worldwide vaccine production during disease outbreaks. However, several clinical studies have demonstrated that the current aluminum (Alum)-adjuvanted influenza vaccines fail to sufficiently enhance immune responses to meet licensing criteria. Here, we used pandemic H7N9 as a model virus to demonstrate that a 10-fold lower amount of vaccine antigen combined with Alum and TLR9 agonist can provide stronger protective effects than using Alum as the sole adjuvant. We found that the Alum/CpG 1018 combination adjuvant could induce more robust virus-specific humoral immune responses, including higher total IgG production, hemagglutination-inhibiting antibody activity, and neutralizing antibody titers, than the Alum-adjuvanted formulation. Moreover, this combination adjuvant shifted the immune response toward a Th1-biased immune response. Importantly, the Alum/CpG 1018-formulated vaccine could confer better protective immunity against H7N9 challenge than that adjuvanted with Alum alone. Notably, the addition of CpG 1018 to the Alum-adjuvanted H7N9 whole-virion vaccine exhibited an antigen-sparing effect without compromising vaccine efficacy. These findings have significant implications for improving Alum-adjuvanted influenza vaccines using the approved adjuvant CpG 1018 for pandemic preparedness.

Keywords: Aluminum hydroxide; CpG 1018; H7N9; TLR9 agonist; whole-virion vaccine

DOI: https://doi.org/10.1080/22221751.2023.2249130