Non-canonical activation of IRE1α during infection enhances macrophage fungicidal activity.

While the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding.

The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α.

The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood.

Reducing Stress PERKs up Anti-tumor Immunity.

Myeloid-derived suppressor cells (MDSCs) can promote tumor progression. In this issue of Immunity, Mohamed et al. show that the unfolded protein response sensor, PERK, enhances MDSC-mediated immunosuppression through the NRF2 transcription factor, preventing oxidative damage, mitochondrial DNA release, and DNA sensor-STING-dependent type I interferon production.

Metabolism of the Gram-Positive Bacterial Pathogen .

Bacterial metabolism represents the biochemical space that bacteria can manipulate to produce energy, reducing equivalents and building blocks for replication. Gram-positive pathogens, such as , show remarkable flexibility, which allows for exploitation of diverse biological niches from the soil to the intracytosolic space. Although the human host represents a potentially rich source for nutrient acquisition, competition for nutrients with the host and hostile host defenses can constrain bacterial metabolism by various mechanisms, including nutrient sequestration.

Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses.

The innate immune system senses microbial ligands through pattern recognition and triggers downstream signaling cascades to promote inflammation and immune defense mechanisms. Emerging evidence suggests that cells also recognize alterations in host processes induced by infection as triggers. Protein ubiquitination and deubiquitination are post-translational modification processes essential for signaling and maintenance of cellular homeostasis, and infections can cause global alterations in the host ubiquitin proteome.

Glycolysis Is an Intrinsic Factor for Optimal Replication of a Norovirus.

The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics and energetic profiling of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus (MNV) infection.

Invasion of the Brain by Is Mediated by InlF and Host Cell Vimentin.

is a facultative intracellular bacterial pathogen that is frequently associated with food-borne infection. Of particular concern is the ability of to breach the blood-brain barrier, leading to life-threatening meningitis and encephalitis. The mechanisms used by bacterial pathogens to infect the brain are not fully understood.

Anti-infective Activity of 2-Cyano-3-Acrylamide Inhibitors with Improved Drug-Like Properties against Two Intracellular Pathogens.

Due to the rise of antibiotic resistance and the small number of effective antiviral drugs, new approaches for treating infectious diseases are urgently needed. Identifying targets for host-based therapies represents an emerging strategy for drug discovery. The ubiquitin-proteasome system is a central mode of signaling in the eukaryotic cell and may be a promising target for therapies that bolster the host's ability to control infection.

Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined.

Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity.

The global spread of anti-microbial resistance requires urgent attention, and diverse alternative strategies have been suggested to address this public health concern. Host-directed immunomodulatory therapies represent one approach that could reduce selection for resistant bacterial strains. Recently, the small molecule deubiquitinase inhibitor WP1130 was reported as a potential anti-infective drug against important human food-borne pathogens, notably Listeria monocytogenes and noroviruses.

Caspase-2 mediates a Brucella abortus RB51-induced hybrid cell death having features of apoptosis and pyroptosis.

Programmed cell death (PCD) can play a crucial role in tuning the immune response to microbial infection. Although PCD can occur in different forms, all are mediated by a family of proteases called caspases. Caspase-2 is the most conserved caspase, however, its function in cell death is ill-defined.

Regulation of bacterial pathogenesis by intestinal short-chain Fatty acids.

The human gut microbiota is inextricably linked to health and disease. One important function of the commensal organisms living in the intestine is to provide colonization resistance against invading enteric pathogens. Because of the complex nature of the interaction between the microbiota and its host, multiple mechanisms likely contribute to resistance.

More than a pore: the cellular response to cholesterol-dependent cytolysins.

Targeted disruption of the plasma membrane is a ubiquitous form of attack used in all three domains of life. Many bacteria secrete pore-forming proteins during infection with broad implications for pathogenesis. The cholesterol-dependent cytolysins (CDC) are a family of pore-forming toxins expressed predominately by Gram-positive bacterial pathogens.

Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections.

We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T cells.

Fatty acids regulate stress resistance and virulence factor production for Listeria monocytogenes.

Fatty acids (FAs) are the major structural component of cellular membranes, which provide a physical and chemical barrier that insulates intracellular reactions from environmental fluctuations. The native composition of membrane FAs establishes the topological and chemical parameters for membrane-associated functions and is therefore modulated diligently by microorganisms especially in response to environmental stresses. However, the consequences of altered FA composition during host-pathogen interactions are poorly understood.

Membrane damage during Listeria monocytogenes infection triggers a caspase-7 dependent cytoprotective response.

The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated.

A small molecule deubiquitinase inhibitor increases localization of inducible nitric oxide synthase to the macrophage phagosome and enhances bacterial killing.

Macrophages are key mediators of antimicrobial defense and innate immunity. Innate intracellular defense mechanisms can be rapidly regulated at the posttranslational level by the coordinated addition and removal of ubiquitin by ubiquitin ligases and deubiquitinases (DUBs). While ubiquitin ligases have been extensively studied, the contribution of DUBs to macrophage innate immune function is incompletely defined.

Branched-chain fatty acids promote Listeria monocytogenes intracellular infection and virulence.

Anteiso-branched-chain fatty acids (BCFA) represent the dominant group of membrane fatty acids and have been established as crucial determinants in resistance against environmental stresses in Listeria monocytogenes, a facultative intracellular pathogen. Here, we investigate the role of anteiso-BCFA in L. monocytogenes virulence by using mutants deficient in branched-chain alpha-keto acid dehydrogenase (BKD), an enzyme complex involved in the synthesis of BCFA.

XIAP regulates cytosol-specific innate immunity to Listeria infection.

The inhibitor of apoptosis protein (IAP) family has been implicated in immune regulation, but the mechanisms by which IAP proteins contribute to immunity are incompletely understood. We show here that X-linked IAP (XIAP) is required for innate immune control of Listeria monocytogenes infection. Mice deficient in XIAP had a higher bacterial burden 48 h after infection than wild-type littermates, and exhibited substantially decreased survival.

Homeostatic maintenance of pathogen-containing vacuoles requires TBK1-dependent regulation of aquaporin-1.

Membranes are an integral component of many cellular functions and serve as a barrier to keep pathogenic bacteria from entering the nutrient-rich host cytosol. TANK-binding-kinase-1 (TBK1), a kinase of the IkappaB kinase family, is required for maintaining integrity of pathogen-containing vacuoles (PCV) upon bacterial invasion of host cells. Here we investigate how vacuolar integrity is maintained during bacterial infection, even in the presence of bacterial membrane damaging agents.

LplA1-dependent utilization of host lipoyl peptides enables Listeria cytosolic growth and virulence.

The bacterial pathogen Listeria monocytogenes replicates within the cytosol of mammalian cells. Mechanisms by which the bacterium exploits the host cytosolic environment for essential nutrients are poorly defined. L.