William Bishai and colleagues report that cyclic-di-adenosine monophosphate produced during infection with Mycobacterium tuberculosis induces IFN-β and contributes to the innate sensing of tuberculosis. Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense1,2,3. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)4-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)5-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS)6,7, but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.

Kimchi is a traditional Korean vegetable product that is naturally fermented by various microorganisms present in the raw materials. Among these microorganisms, lactic acid bacteria dominate the fermentation process. Natural fermentation with unsterilized raw materials leads to the growth of various lactic acid bacteria, resulting in variations in the taste and quality of kimchi, which may make it difficult to produce industrial-scale kimchi with consistent quality. The use of starter cultures has been considered as an alternative for the industrial production of standardized kimchi, and recent trends suggest that the demand for starter cultures is on the rise. However, several factors should be carefully considered for the successful application of starter cultures for kimchi fermentation. In this review, we summarize recent studies on kimchi starter cultures, describe practical problems in the application of industrial-scale kimchi production, and discuss the directions for further studies.

During human latent tuberculosis infection, Mycobacterium tuberculosis likely resides within the nutrientstarved environment of caseous lung granuloma

The occurrence of atopic dermatitis (AD), a chronic inflammatory skin disease, has been increasing steadily in children and adults in recent decades. In this study, we evaluated the ability of the lactic acid bacterium Weissella cibaria WIKIM28 isolated from gatkimchi, a Korean fermented vegetable preparation made from mustard leaves, to suppress the development of AD induced by 2,4-dinitrochlorobenzene in a murine model. Oral administration of W. cibaria WIKIM28 reduced AD-like skin lesions, epidermal thickening, and serum immunoglobulin E levels. Furthermore, the production of type 2 helper T (Th2) cytokines such as interleukin (IL)-4, IL-5, and IL-13 decreased in peripheral lymph node cells. Moreover, the intake of W. cibaria WIKIM28 increased the proportion of CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cells in mesenteric lymph nodes (MLNs) and IL-10 levels in polyclonally stimulated MLN cells. In conclusion, the oral administration of W. cibaria WIKIM28 isolated from gatkimchi ameliorated AD-like symptoms by suppressing allergic Th2 responses and inducing Treg responses. These results suggest that W. cibaria WIKIM28 may be applicable as a probiotic for the prevention and amelioration of AD.

Mycobacterium tuberculosis SigF is homologous to stress response and sporulation sigma factors in many bacteria. Consistent with a possible role in mycobacterial survival under stress conditions, M. tuberculosis sigF is strongly induced within cultured human macrophages and upon nutrient starvation, and SigF has been implicated in M. tuberculosis entry into stationary phase. On the other hand, SigF appears to contribute to the immune pathology of tuberculosis (TB), and a sigF -deficient mutant has altered cell membrane properties. Using an M. tuberculosis sigF deletion mutant, we show here that sigF is not required for bacillary survival under nutrient starvation conditions and within activated murine macrophages or for extracellular persistence in an in vivo granuloma model of latent TB infection. Using a chemically inducible recombinant strain to conditionally overexpress sigF , we did not observe arrest or retardation of growth in exponentially growing cultures or reduced susceptibility to rifampin and isoniazid. Consistent with our hypothesis that SigF may mediate TB immunopathogenesis by altering cell membrane properties, we found that overexpression of sigF resulted in the differential regulation of many cell wall-associated proteins, including members of the MmpL, PE, and PPE families, several of which have been shown to influence host-pathogen interactions. The most highly upregulated gene by quantitative reverse transcription-PCR at all time points following sigF induction was Rv3301c ( phoY1 ), which encodes a probable transcriptional regulatory protein homologous to PhoU proteins involved in regulation of phosphate uptake. Using in vitro transcription analysis, we show that SigF directly regulates phoY1 , whose proposed promoter sequence is GGATTG-N ₁₆ -GGGTAT.

Kimchi fermentation depends on diverse lactic acid bacteria, which convert raw materials into numerous metabolites that contribute to the taste of food. Amino acids and saccharides are important primary metabolites. Arginine is nearly exhausted during kimchi fermentation, whereas the concentrations of other amino acids are reported not to increase or decrease dramatically. These phenomena could imply that arginine is an important nutritional component among the amino acids during kimchi fermentation. In this study, we investigated the arginine-catabolism pathway of seven lactic acid bacteria isolated from kimchi and evaluated the products of arginine catabolism (citrulline and ornithine) associated with the bacteria. The arginine content dramatically decreased in cultures of Lactobacillus brevis and Weissella confusa from 300 μg/mL of arginine to 0.14 ± 0.19 and 1.3 ± 0.01 μg/mL, respectively, after 6 h of cultivation. Citrulline and ornithine production by L. brevis and W. confusa showed a pattern that was consistent with arginine catabolism. Interestingly, Pediococcus pentosaceus, Lactobacillus plantarum, Leuconostoc mesenteroides, and Leuconostoc lactis did not show increased citrulline levels after arginine was added. The ornithine contents were higher in all bacteria except for L. lactis after adding arginine to the culture. These results were consistent with the absence of the arginine deiminase gene among the lactic acid bacteria. Arginine consumption and ornithine production were monitored and compared with lactic acid bacteria by metagenomics analysis, which showed that the increment of ornithine production correlated positively with lactic acid bacteria growth.