GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections

Kim, Jin‐Kyung; Kim, Yi Sak; Lee, Hyemi; Jin, Hyo Sun; Neupane, Chiranjivi; Kim, Sup; Lee, Sang‐Hee; Min, Jung‐Joon; Sasai, Miwa; Jeong, Jae-Ho; Choe, Seong-Kyu; Yamamoto, Masahiro; Choy, Hyon E.; Park, Jin Bong; Jo, Eun-Kyeong

doi:10.1038/s41467-018-06487-5

Cited by 144 publications

(117 citation statements)

References 70 publications

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“…22 GABA signaling promotes autophagy activation, which improves phagosome maturation and promotes host protection against infections. 23 To our knowledge, the beneficial effect of hypnotics on clinical outcome has not been reported previously in the management of COVID-19 patients.…”

Section: Discussionmentioning

confidence: 75%

Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China

Chen

et al. 2020

Preprint

141

179

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Background With evidence of sustained transmission in more than 190 countries, coronavirus disease 2019 (COVID-19) has been declared a global pandemic. As such, data are urgently needed about risk factors associated with clinical outcomes. Methods A retrospective chart review of 323 hospitalized patients with COVID-19 in Wuhan was conducted. Patients were classified into three disease severity groups (non-severe, severe, and critical), based on their initial clinical presentation. Clinical outcomes were designated as favorable and unfavorable, based on disease progression and response to treatments. Logistic regression models were performed to identify factors associated with clinical outcomes, and logrank test was conducted for the association with clinical progression. Results Current standard treatments did not show significant improvement on patient outcomes in the study. By univariate logistic regression model, 27 risk factors were significantly associated with clinical outcomes. Further, multivariate regression indicated that age over 65 years, smoking, critical disease status, diabetes, high hypersensitive troponin I (>0.04 pg/mL), leukocytosis (>10 x 109/L) and neutrophilia (>75 x 109/L) predicted unfavorable clinical outcomes. By contrast, the use of hypnotics was significantly associated with favorable outcomes. Survival analysis also confirmed that patients receiving hypnotics had significantly better survival. Conclusions To our knowledge, this is the first indication that hypnotics could be an effective ancillary treatment for COVID-19. We also found that novel risk factors, such as higher hypersensitive troponin I, predicted poor clinical outcomes. Overall, our study provides useful data to guide early clinical decision making to reduce mortality and improve clinical outcomes of COVID-19.

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Section: Discussionmentioning

confidence: 75%

Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China

Chen

et al. 2020

Preprint

141

179

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“…Interestingly, the activation of GABAergic signaling is positively implicated in the treatment of these conditions, but based to our knowledge, the potential relation of autophagy and GABAergic signaling in inflammatory conditions have not been investigated so far. Besides the role of GABA in the induction of antimicrobial autophagy 18 , our group as well as studies from other groups reported the potential of some Lactobacillus species to stimulate or suppress autophagy [19][20][21] . In addition, the role of autophagy in immunomodulatory effects of GABA-producing probiotic strain have not been investigated.…”

mentioning

confidence: 99%

“…However, the relation between GABA-producing LAB and their immunomodulatory properties has not been investigated previously. Considering recent findings on potential linkage of GABA signaling and autophagy 18 , we hypothesized that the direct immunomodulatory activity of GABA produced by L. brevis BGZLS10-17 include the regulation of autophagy within these immune cells.…”

mentioning

confidence: 99%

GABA potentiate the immunoregulatory effects of Lactobacillus brevis BGZLS10-17 via ATG5-dependent autophagy in vitro

Bajić

Đokić

Dinić

et al. 2020

Sci Rep

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The characterization of mechanisms involved in the positive effects of probiotic bacteria in various pathophysiological conditions is a prerogative for their safe and efficient application in biomedicine. We have investigated the immunological effects of live bacteria-free supernatant collected from GABAproducing Lactobacillus brevis BGZLS10-17 on Concanavalin A-stimulated mesenteric lymph node cells (MLNC), an in vitro model of activated immune cells. We have shown that GABA containing and GABA-free supernatant of Lactobacillus brevis BGZLS10-17 have strong immunoregulatory effects on MLNC. Further, GABA produced by this strain exhibit additional inhibitory effects on proliferation, IFN-γ and IL-17 production by MLNC, and the expression of MHCII and CD80 on antigen presenting cells. At the other hand, GABA-containing supernatants displayed the strongest stimulatory effects on the expression of immunoregulatory molecules, such as Foxp3 + , IL-10, TGF-β, CTLA4 and SIRP-α. By looking for the mechanisms of actions, we found that supernatants produced by BGZLS10-17 induce autophagy in different MLNC, such as CD4 + and CD8 + T lymphocytes, NK and NKT cells, as well as antigen presenting cells. Further, we showed that the stimulation of Foxp3 + , IL-10 and TGF-β expression by BGZLS10-17 produced GABA is completely mediated by the induction of ATG5 dependent autophagy, and that other molecules in the supernatants display GABA-, ATG5-, Foxp3 +-, IL-10-and TGF-β-independent, immunoregulatory effects.

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“…Additionally, ~25-fold upregulation of GABAergic neurotransmission upon blood feeding in the midgut highlights its possible functionality in the regulation innate immune response by activating the autophagy response as a result of gut flora expansion following blood feeding (Fig. 5d) [61].…”

Section: Fig 4: Innate Physiological Status Differentially Modulatesmentioning

confidence: 97%

Microbiome-Gut-Brain-Axis communication influences metabolic switch in the mosquitoAnopheles culicifacies

Sharma

Tevatiya

et al. 2019

Preprint

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A well coordinated neuro-olfactory regulation is essential for a successful host seeking and blood feeding behavior of adult female mosquitoes. Although, the crucial role of mosquito tiny brain during host selection/choice is of prime interest but how blood meal uptake modulate brain functions which consequently empower the cognition in mosquitoes remains unclear. Here we report that blood meal induced gut 'metabolic switch' shift brain function from external communication to inter-organ management. An exclusive induction of oxidation reduction associated proteins and enhancement of brain's energy metabolism indicate the active functioning of the brain probably to maintain physiological homeostasis. A spatial and temporal change in the expression pattern of neuro-signaling molecules and other neuro-modulators in the brain designate that a guided neuro-stimulation and endocrine regulation is enough to manage the brain-distant organ communication. Analogous to brain, significant modulation of the neuro-modulator receptor genes in the gut signifies its function as 'Second Brain' during metabolic switch in mosquitoes. Furthermore, quantitative analysis of neuro-transmitters (NTs)revealed that the gut of mosquitoes is one of the potent source of NTs during altered metabolic conditions. Finally, quantitative data on NTs dynamics of naïve and aseptic mosquitoes establish the concept of microbiome-gut-brainaxis communication in adult female mosquitoes. Graphical abstract:Introduction:Central nervous system i.e. the brain is a privileged organ in shaping animal's behavior from lower to higher taxa of which insect's tiny brain is famous for performing amazingly sophisticated behavior. Thus, insects are either enough smart to squeeze more information from limited number of neurons or they use some different algorithms to process information in their microscopic brain system [1]. In particular to mosquitoes, while navigating towards a vertebrate host for blood feeding the brain engagement of adult female mosquitoes is more complex than any other insect species [2][3][4][5]. A crucial interaction of olfactory derived odorant binding proteins (OBPs) and olfactory receptors (Ors) with the environmental guided chemical cues may have direct impact on mosquito's behavioural properties [6,7]. But how this chemical information influences decision Results & DiscussionHypothesis: Since, neuro system is a versatile centre of chemical information exchange, we hypothesize a minor change in the innate physiological status may have strong impact on mosquito's day to day life. Importantly blood meal uptake causes a drastic metabolic changes, which we named "gut metabolic switch", engages multiple organs simultaneously. We hypothesize that upon blood feeding mosquitoes' brain functions may shift from external communication to internal management such as (a) initiation of diuresis b) finding a resting site for digestion of blood meal in the midgut; (c) distribution of amino acids, generated through the degradation of protein rich blood meal; ...

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GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections

Cited by 144 publications

References 70 publications

Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China

Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China

GABA potentiate the immunoregulatory effects of Lactobacillus brevis BGZLS10-17 via ATG5-dependent autophagy in vitro

Microbiome-Gut-Brain-Axis communication influences metabolic switch in the mosquitoAnopheles culicifacies

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