Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella

Intracellular pathogens and endogenous danger signals in the cytosol engage NOD-like receptors (NLRs), which assemble inflammasome complexes to activate caspase-1 and promote the release of proinflammatory cytokines IL-1β and IL-18. However, the NLRs that respond to microbial pathogens in vivo are poorly defined. We show that the NLRs NLRP3 and NLRC4 both activate caspase-1 in response to Salmonella typhimurium. Responding to distinct bacterial triggers, NLRP3 and NLRC4 recruited ASC and caspase-1 into a single cytoplasmic focus, which served as the site of pro–IL-1β processing. Consistent with an important role for both NLRP3 and NLRC4 in innate immune defense against S. typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo.

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Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF- B and MAPK signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1403252111 ◽

2014 ◽

Vol 111 (20) ◽

pp. 7385-7390 ◽

Cited By ~ 125

Author(s):

N. H. Philip ◽

C. P. Dillon ◽

A. G. Snyder ◽

P. Fitzgerald ◽

M. A. Wynosky-Dolfi ◽

...

Keyword(s):

Mapk Signaling ◽

Immune Defense ◽

Innate Immune ◽

Caspase 8 ◽

Caspase 1 ◽

Innate Immune Defense

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During Aspergillus infection, neutrophil, monocyte-derived DC, and plasmacytoid DC enhance innate immune defense through CXCR3-dependent crosstalk

10.1101/2020.05.05.079517 ◽

2020 ◽

Author(s):

Yahui Guo ◽

Shinji Kasahara ◽

Anupam Jhingran ◽

Nicholas L. Tosini ◽

Bing Zhai ◽

...

Keyword(s):

Dendritic Cells ◽

Host Defense ◽

Immune Defense ◽

Innate Immune ◽

Type I ◽

Dependent Manner ◽

Interferon Signaling ◽

Nadph Oxidase Activity ◽

Innate Immune Defense ◽

Effector Activity

SummaryAspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically anti-viral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1/Card9- and type I and III interferon-signaling dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.

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Critical Role For Muc5b In Innate Immune Defense In Vivo

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5105 ◽

2012 ◽

Author(s):

Christopher M. Evans ◽

Michelle Roy ◽

Melissa L. McElwee ◽

Ryan Boerner ◽

Victoria N. Mdoe ◽

...

Keyword(s):

Critical Role ◽

Immune Defense ◽

Innate Immune ◽

Innate Immune Defense

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The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

Frontiers in Immunology ◽

10.3389/fimmu.2020.00965 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 4

Author(s):

Graham A. D. Blyth ◽

Liam Connors ◽

Cristina Fodor ◽

Eduardo R. Cobo

Keyword(s):

Host Defense ◽

Immune Defense ◽

Innate Immune ◽

Host Defense Peptides ◽

Enteropathogenic Bacteria ◽

Innate Immune Defense ◽

Defense Peptides

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Salmonella and Reactive Oxygen Species: A Love-Hate Relationship

Journal of Innate Immunity ◽

10.1159/000496370 ◽

2019 ◽

Vol 11 (3) ◽

pp. 216-226 ◽

Cited By ~ 9

Author(s):

Mikael Rhen

Keyword(s):

Reactive Oxygen ◽

Immune Defense ◽

Innate Immune ◽

Intracellular Pathogens ◽

Oxygen Species ◽

Phagocytic Cells ◽

Innate Defense ◽

Innate Immune Defense ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Salmonella enterica represents an enterobacterial species including numerous serovars that cause infections at, or initiated at, the intestinal epithelium. Many serovars also act as facultative intracellular pathogens with a tropism for phagocytic cells. These bacteria not only survive in phagocytes but also undergo de facto replication therein. Phagocytes, through the activities of phagocyte NADPH-dependent oxidase and inducible nitric oxide synthase, are very proficient in converting molecular oxygen to reactive oxygen (ROS) and nitrogen species (RNS). These compounds represent highly efficient effectors of the innate immune defense. Salmonella is by no means resistant to these effectors, which may stand in contrast to the host niches chosen. To cope with this paradox, these bacteria rely on an array of detoxification and repair systems. Combination these systems allows for a high enough tolerance to ROS and RNS to enable establishment of infection. In addition, salmonella possesses protein factors that have the potential to dampen the infection-associated inflammation, which evidently results in a reduced exposure to ROS and RNS. This review attempts to summarize the activities and strategies by which salmonella tries to cope with ROS and RNS and how the bacterium can make use of these innate defense factors.

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Critical coordination of innate immune defense against Toxoplasma gondii by dendritic cells responding via their Toll-like receptors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1011549108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 278-283 ◽

Cited By ~ 74

Author(s):

Baidong Hou ◽

Alicia Benson ◽

Lili Kuzmich ◽

Anthony L. DeFranco ◽

Felix Yarovinsky

Keyword(s):

Dendritic Cells ◽

Toxoplasma Gondii ◽

Host Defense ◽

Adaptor Protein ◽

T Cell Response ◽

Immune Defense ◽

Innate Immune ◽

Microbial Pathogens ◽

Toll Like Receptors ◽

Inflammatory Monocytes

Toll-like receptors (TLRs) play an important role in host defense against a variety of microbial pathogens. We addressed the mechanism by which TLRs contribute to host defense against the lethal parasite Toxoplasma gondii by using mice with targeted inactivation of the TLR adaptor protein myeloid differentiation primary response gene 88 (MyD88) in different innate cell types. Lack of MyD88 in dendritic cells (DCs), but not in macrophages or neutrophils, resulted in high susceptibility to the T. gondii infection. In the mice deficient in MyD88 in DCs, the early IL-12 response by DCs was ablated, the IFN-γ response by natural killer cells was delayed, and the recruited inflammatory monocytes were incapable of killing the T. gondii parasites. The T-cell response, although attenuated in these mice, was sufficient to eradicate the parasite during the chronic stage, provided that defects in DC activation were compensated by IL-12 treatment early after infection. These results demonstrate a central role of DCs in orchestrating the innate immune response to an intracellular pathogen and establish that defects in pathogen recognition by DCs can predetermine sensitivity to infection.

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Trefoil Factor Family (TFF) Peptides and their Different Roles in the Mucosal Innate Immune Defense and More: An Update

Current Medicinal Chemistry ◽

10.2174/0929867328666210215114140 ◽

2021 ◽

Vol 28 ◽

Author(s):

Werner Hoffmann

Keyword(s):

Cysteine Residue ◽

Immune Defense ◽

Innate Immune ◽

Molecular Forms ◽

Trefoil Factor ◽

Gastric Mucus ◽

Innate Immune Defense ◽

Trefoil Factor Family

: Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa; whereas TFF3 is rather widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue; whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but binds also Deleted in Malignant Brain Tumors/gp340 (DMBT1gp340) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1gp340 are secreted from most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of microorganisms. Such a function could be well be supported by DMBT1gp340. In contrast, the TFF2/MUC6 complex probably stabilizes physically the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3-FCGBP might play also a role in blood vessels.

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Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense

Science ◽

10.1126/science.aay8085 ◽

2020 ◽

Vol 370 (6514) ◽

pp. eaay8085 ◽

Cited By ~ 4

Author(s):

Marta Bosch ◽

Miguel Sánchez-Álvarez ◽

Alba Fajardo ◽

Ronan Kapetanovic ◽

Bernhard Steiner ◽

...

Keyword(s):

Host Defense ◽

Lipid Droplets ◽

Acid Metabolism ◽

Cell Metabolism ◽

Innate Immune ◽

Eukaryotic Cells ◽

Metabolic Adaptation ◽

Intracellular Pathogens ◽

Defense Proteins ◽

Danger Signals

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

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Autophagy—A Story of Bacteria Interfering with the Host Cell Degradation Machinery

Pathogens ◽

10.3390/pathogens10020110 ◽

2021 ◽

Vol 10 (2) ◽

pp. 110

Author(s):

Anna K. Riebisch ◽

Sabrina Mühlen ◽

Yan Yan Beer ◽

Ingo Schmitz

Keyword(s):

Escherichia Coli ◽

Staphylococcus Aureus ◽

Immune Response ◽

Mycobacterium Tuberculosis ◽

Listeria Monocytogenes ◽

Salmonella Typhimurium ◽

Innate Immune ◽

Intracellular Pathogens ◽

Response Mechanism ◽

Pathogenic Escherichia Coli

Autophagy is a highly conserved and fundamental cellular process to maintain cellular homeostasis through recycling of defective organelles or proteins. In a response to intracellular pathogens, autophagy further acts as an innate immune response mechanism to eliminate pathogens. This review will discuss recent findings on autophagy as a reaction to intracellular pathogens, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Staphylococcus aureus, and pathogenic Escherichia coli. Interestingly, while some of these bacteria have developed methods to use autophagy for their own benefit within the cell, others have developed fascinating mechanisms to evade recognition, to subvert the autophagic pathway, or to escape from autophagy.

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