Decision letter: The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

AbstractThe skin of vertebrates is the outermost organ of the body and serves as the first line of defense against external aggressions. In contrast to mammalian skin, that of teleost fish lacks keratinization and has evolved to operate as a mucosal surface containing a skin-associated lymphoid tissue (SALT). Thus far, IgT representing the prevalent immunoglobulin (Ig) in SALT have only been reported upon infection with a parasite. However, very little is known about the types of B cells and Igs responding to bacterial infection in the teleost skin mucosa, as well as the inductive or effector role of the SALT in such responses. To address these questions, here we analyzed the immune response of trout skin upon infection with one of the most widespread fish skin bacterial pathogens, Flavobacterium columnare. This pathogen induced strong skin innate immune and inflammatory responses at the initial phases of infection. More critically, we found that the skin mucus of fish having survived the infection contained significant IgT-but not IgM- or IgD-specific titers against the bacteria. Moreover, we demonstrate the local proliferation and production of IgT+ B-cells and specific IgT titers respectively within the SALT upon bacterial infection. Thus, our findings represent the first demonstration that IgT is the main Ig isotype induced by the skin mucosa upon bacterial infection, and that because of the large surface of the skin, its SALT probably represents a prominent IgT inductive site in fish.

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Microbial co-infection alters macrophage polarization, phagosomal escape, and microbial killing

Innate Immunity ◽

10.1177/1753425918760180 ◽

2018 ◽

Vol 24 (3) ◽

pp. 152-162 ◽

Cited By ~ 6

Author(s):

Nikita H Trivedi ◽

Jieh-Juen Yu ◽

Chiung-Yu Hung ◽

Richard P Doelger ◽

Christopher S Navara ◽

...

Keyword(s):

Bacterial Infection ◽

Macrophage Activation ◽

Secondary Infection ◽

Macrophage Polarization ◽

Innate Immune ◽

No Production ◽

Bacterial Killing ◽

Macrophage Response ◽

Endosomal Acidification ◽

J774 Cells

Macrophages are important innate immune cells that respond to microbial insults. In response to multi-bacterial infection, the macrophage activation state may change upon exposure to nascent mediators, which results in different bacterial killing mechanism(s). In this study, we utilized two respiratory bacterial pathogens, Mycobacterium bovis (Bacillus Calmette Guẻrin, BCG) and Francisella tularensis live vaccine strain (LVS) with different phagocyte evasion mechanisms, as model microbes to assess the influence of initial bacterial infection on the macrophage response to secondary infection. Non-activated (M0) macrophages or activated M2-polarized cells (J774 cells transfected with the mouse IL-4 gene) were first infected with BCG for 24–48 h, subsequently challenged with LVS, and the results of inhibition of LVS replication in the macrophages was assessed. BCG infection in M0 macrophages activated TLR2-MyD88 and Mincle-CARD9 signaling pathways, stimulating nitric oxide (NO) production and enhanced killing of LVS. BCG infection had little effect on LVS escape from phagosomes into the cytosol in M0 macrophages. In contrast, M2-polarized macrophages exhibited enhanced endosomal acidification, as well as inhibiting LVS replication. Pre-infection with BCG did not induce NO production and thus did not further reduce LVS replication. This study provides a model for studies of the complexity of macrophage activation in response to multi-bacterial infection.

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The pore-forming protein Aep1 is an innate immune molecule that prevents zebrafish from bacterial infection

Developmental & Comparative Immunology ◽

10.1016/j.dci.2018.01.003 ◽

2018 ◽

Vol 82 ◽

pp. 49-54 ◽

Cited By ~ 4

Author(s):

Lan-Lan Chen ◽

Jin Xie ◽

Dong-Dong Cao ◽

Ning Jia ◽

Ya-Juan Li ◽

...

Keyword(s):

Bacterial Infection ◽

Innate Immune ◽

Immune Molecule

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Innate immune cells and bacterial infection in zebrafish

The Zebrafish - Disease Models and Chemical Screens - Methods in Cell Biology ◽

10.1016/bs.mcb.2016.08.002 ◽

2017 ◽

pp. 31-60 ◽

Cited By ~ 13

Author(s):

J.W. Astin ◽

P. Keerthisinghe ◽

L. Du ◽

L.E. Sanderson ◽

K.E. Crosier ◽

...

Keyword(s):

Bacterial Infection ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells

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CF Monocyte Derived Macrophages Have an Attenuated Response to Extracellular Vesicles Secreted by Airway Epithelial Cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00621.2020 ◽

2021 ◽

Author(s):

Katja Koeppen ◽

Amanda B Nymon ◽

Roxanna Barnaby ◽

Zhongyou Li ◽

Thomas H Hampton ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Bacterial Infection ◽

Extracellular Vesicles ◽

Cell Types ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Immune Genes ◽

Innate Immune Genes

Mutations in CFTR alter macrophage responses, for example, by reducing their ability to phagocytose and kill bacteria. Altered macrophage responses may facilitate bacterial infection and inflammation in the lungs, contributing to morbidity and mortality in cystic fibrosis (CF). Extracellular vesicles (EVs) are secreted by multiple cell types in the lungs and participate in the host immune response to bacterial infection, but the effect of EVs secreted by CF airway epithelial cells (AEC) on CF macrophages is unknown. This report examines the effect of EVs secreted by primary AEC on monocyte derived macrophages (MDM) and contrasts responses of CF and WT MDM. We found that EVs generally increase pro-inflammatory cytokine secretion and expression of innate immune genes in MDM, especially when EVs are derived from AEC exposed to Pseudomonas aeruginosa, and that this effect is attenuated in CF MDM. Specifically, EVs secreted by P. aeruginosa exposed AEC induced immune response genes and increased secretion of pro-inflammatory cytokines, chemoattractants and chemokines involved in tissue repair by WT MDM, but these effects were less robust in CF MDM. We attribute attenuated responses by CF MDM to differences between CF and WT macrophages because EVs secreted by CF AEC or WT AEC elicited similar responses in CF MDM. Our findings demonstrate the importance of AEC EVs in macrophage responses and show that the Phe508del mutation in CFTR attenuates the innate immune response of MDM to EVs.

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The role of type 1 interferons in Gram-negative bacteria-induced coagulation

Blood ◽

10.1182/blood.2019002282 ◽

2020 ◽

Cited By ~ 4

Author(s):

Xinyu Yang ◽

Xiaoye Cheng ◽

Yiting Tang ◽

Xianhui Qiu ◽

Zhongtai Wang ◽

...

Keyword(s):

Immune Responses ◽

Bacterial Infection ◽

Innate Immune ◽

Coagulation Cascade ◽

Outer Cell ◽

Gram Negative Bacteria ◽

Innate Immune Responses ◽

Gram Negative ◽

Type 1 Interferons

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/βR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

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