The NLRP12 inflammasome recognizes Yersinia pestis.

Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1ß, which are generated through caspase-1-activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1ß production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-γ production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-κB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis.

A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling.

Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-ß and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2.

TRIM13 is a negative regulator of MDA5-mediated type I interferon production.

UNLABELLED: Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are essential intracellular detectors of viral RNA. They contribute to the type I interferon (IFN) response that is crucial for host defense against viral infections. Given the potent antiviral and proinflammatory activities elicited by the type I IFNs, induction of the type I IFN response is tightly regulated. Members of the tripartite motif (TRIM) family of proteins have recently emerged as key regulators of antiviral immunity. We show that TRIM13, an E3 ubiquitin ligase, is expressed in immune cells and is upregulated in bone marrow-derived macrophages upon stimulation with inducers of type I IFN. TRIM13 interacts with MDA5 and negatively regulates MDA5-mediated type I IFN production in vitro, acting upstream of IFN regulatory factor 3. We generated Trim13(-/-) mice and show that upon lethal challenge with encephalomyocarditis virus (EMCV), which is sensed by MDA5, Trim13(-/-) mice produce increased amounts of type I IFNs and survive longer than wild-type mice. Trim13(-/-) murine embryonic fibroblasts (MEFs) challenged with EMCV or poly(I · C) also show a significant increase in beta IFN (IFN-ß) levels, but, in contrast, IFN-ß responses to the RIG-I-detected Sendai virus were diminished, suggesting that TRIM13 may play a role in positively regulating RIG-I function. Together, these results demonstrate that TRIM13 regulates the type I IFN response through inhibition of MDA5 activity and that it functions nonredundantly to modulate MDA5 during EMCV infection. IMPORTANCE: The type I interferon (IFN) response is crucial for host defense against viral infections, and proper regulation of this pathway contributes to maintaining immune homeostasis. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are intracellular detectors of viral RNA that induce the type I IFN response. In this study, we show that expression of the gene tripartite motif 13 (Trim13) is upregulated in response to inducers of type I IFN and that TRIM13 interacts with both MDA5 and RIG-I in vitro. Through the use of multiple in vitro and in vivo model systems, we show that TRIM13 is a negative regulator of MDA5-mediated type I IFN production and may also impact RIG-I-mediated type I IFN production by enhancing RIG-I activity. This places TRIM13 at a key junction within the viral response pathway and identifies it as one of the few known modulators of MDA5 activity.

Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.

Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer.

Serine/threonine acetylation of TGFß-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling.

The Gram-negative bacteria Yersinia pestis, causative agent of plague, is extremely virulent. One mechanism contributing to Y. pestis virulence is the presence of a type-three secretion system, which injects effector proteins, Yops, directly into immune cells of the infected host. One of these Yop proteins, YopJ, is proapoptotic and inhibits mammalian NF-κB and MAP-kinase signal transduction pathways. Although the molecular mechanism remained elusive for some time, recent work has shown that YopJ acts as a serine/threonine acetyl-transferase targeting MAP2 kinases. Using Drosophila as a model system, we find that YopJ inhibits one innate immune NF-κB signaling pathway (IMD) but not the other (Toll). In fact, we show YopJ mediated serine/threonine acetylation and inhibition of dTAK1, the critical MAP3 kinase in the IMD pathway. Acetylation of critical serine/threonine residues in the activation loop of Drosophila TAK1 blocks phosphorylation of the protein and subsequent kinase activation. In addition, studies in mammalian cells show similar modification and inhibition of hTAK1. These data present evidence that TAK1 is a target for YopJ-mediated inhibition.

Excess astrophysical photons from a 0.1-1 keV cosmic axion background.

Primordial decays of string theory moduli at z~10(12) naturally generate a dark radiation cosmic axion background with 0.1-1 keV energies. This cosmic axion background can be detected through axion-photon conversion in astrophysical magnetic fields to give quasithermal excesses in the extreme ultraviolet and soft x-ray bands. Substantial and observable luminosities may be generated even for axion-photon couplings <<10(-11) GeV(-1). We propose that axion-photon conversion may explain the observed excess emission of soft x rays from galaxy clusters, and may also contribute to the diffuse unresolved cosmic x-ray background. We list a number of correlated predictions of the scenario.

Neonatal herpes simplex presenting as a zosteriform eruption.

Herpes simplex virus (HSV) infection in newborn infants is a potentially devastating disease leading to death and disability. Skin, eye and mouth (SEM) infections account for approximately half of the cases in the USA. The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection, prompt interventions and life-saving management; however, less than half of neonates with proven disease present with characteristic vesicular lesions. Furthermore, if SEM infections are not treated promptly, there is significant risk of progression to central nervous system and disseminated disease. We present a case of HSV-2 infection in a neonate with an atypical zosteriform eruption on day 3 of life. This case demonstrates that neonatal HSV can unusually present in a zosteriform rash. By elucidating this unique presentation, we highlight atypical HSV skin presentation and emphasise on the importance of earlier diagnosis and antiviral treatment to prevent the associated morbidity and mortality.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Neural Monitoring for Robotic Abdominal Wall Reconstruction.

INTRODUCTION: Positioning-related neural injuries are an inherent risk in surgery, particularly in robotic-assisted abdominal wall reconstruction because of unique patient positioning and increased operative times. The implementation of intraoperative neurophysiological monitoring should be considered in such cases. METHODS: This was a two-armed study with one prospective intervention group and one retrospective control group. All patients underwent robotic abdominal wall reconstruction at an academic center. The prospective arm underwent robotic reconstruction from January through July 2019. The retrospective database reviewed patients who underwent the same procedure from August 2015 through July 2018. Factors assessed included: demographics (age, gender, body mass index, comorbidities), surgical details (American Society of Anesthesiologists class, procedure, operative time, positioning), outcomes (length of stay, 30-d readmission, reoperation), and any new-onset intraoperative or postoperative neuropathy. Patients were seen in the clinic postoperatively at weeks 1 and 6. RESULTS: Ten patients were included in the prospective arm. All received intraoperative neurophysiological monitoring using somatosensory evoked potentials. They were compared with 47 patients in the retrospective arm who underwent surgery without intraoperative neurophysiological monitoring. One position-related neural response from baseline was detected intraoperatively in the prospective arm; however, there were no peripheral neurological symptoms present postoperatively. Two patients in the control group developed transient peripheral neuropathies that resolved within 6 weeks. Demographics, surgical procedures, and length of surgery were similar in both groups. The prospective group had a higher rate of preoperative neuropathy and intraoperative use of vasopressors. CONCLUSION: Incorporation of neurophysiological monitoring in robotic surgery is feasible and may lead to the prevention and reduction in positioning-related injuries.

An update on alopecia areata.

PURPOSE OF REVIEW: Alopecia areata is one of the most frequent organ-restricted autoimmune diseases, yet its pathogenesis is still unclear. In addition, although alopecia areata often results in significant psychological distress, effective treatment is lacking. RECENT FINDINGS: New potential susceptibility loci have been implicated, but the strongest evidence points to certain class II human leukocyte antigen alleles. There is new evidence for the collapse of hair follicle immune privilege as a key step in the pathogenesis of alopecia areata. There is also new basic science evidence for stress as a contributing factor in the development of alopecia areata. Few treatments for alopecia areata have been well evaluated in randomized trials. SUMMARY: Although multiple potential susceptibility loci have been implicated, the genetics of alopecia areata is still unclear. The role of any potential environmental contributors is also unclear. Quality evidence for efficacy of currently used treatments for alopecia areata is lacking.

Voriconazole-induced blistering in the setting of graft versus host disease: A report of 2 patients.

Voriconazole is a newer triazole antifungal agent with a wide spectrum of activity against yeast, fungi and molds including many Candida, Aspergillus, and Fusarium species. Its use continues to increase, particularly in immunocompromised patients, owing to its broad coverage, availability in both intravenous and oral preparations, and safety profile. The detection of adverse events in these patients may be complicated by their preexisting comorbidities and polypharmacy. We describe 2 patients with hematologic malignancies status post allogeneic bone marrow transplantation who developed blistering eruptions on the extremities related to voriconazole use. A history of graft versus host disease in each patient confounded and delayed the diagnosis. It is imperative to recognize voriconazole-induced blistering as a separate and distinct entity in such patients with a history of graft versus host disease, since delayed withdrawal of voriconazole use could result in unnecessary and potentially dangerous increases in immunosuppressive therapy.

Enhanced growth of myelodysplastic colonies in hypoxic conditions.

OBJECTIVE: To determine the response of bone marrow progenitor cells from patients with myelodysplastic syndromes (MDS) to culture in physiologic oxygen tension. METHODS: Methylcellulose progenitor assays using both unfractionated bone marrow mononuclear cells (MNCs) and purified CD34(+) progenitors were performed in atmospheric oxygen (18.6% O(2)) or one of two levels of hypoxia (1% and 3% O(2)). Assays were performed using normal donor marrow, MDS patient marrow, acute myelogenous leukemia marrow or peripheral blood blasts, chronic phase chronic myelogenous leukemia (CML) marrow MNCs, and blast crisis CML peripheral blood. RESULTS: The majority of MDS samples showed decreased colony-forming units (CFU) in 18.6% O(2) compared to normal controls, as expected. However, in either 1% or 3% O(2), 9 of 13 MDS samples demonstrated augmentation of CFUs beyond that observed in normal controls, with 6 of 13 demonstrating a greater than ninefold augmentation. This effect is cell autonomous, as it persisted after purification of CD34(+) progenitor cells. Additionally, the augmented response to physiologic oxygen tension is specific to MDS, as it was not observed in either acute or chronic myelogenous leukemia samples. CONCLUSION: These results suggest that the reported decrease in MDS CFUs reflects greater sensitivity of MDS progenitors or their progeny to the nonphysiologic oxygen tensions routinely used in vitro, rather than a true decrease in progenitor frequency. Importantly, these experiments for the first time describe an experimental system that can be used to study the growth of primary cells from patients with MDS.

Small neutrino mass from large compactification volumes.

We present an argument in which the scale approximately 0.1 eV associated with neutrino masses naturally appears in a class of (very) large volume compactifications, being tied to a supersymmetry scale of 10(3) GeV and a string scale of 10(11) GeV. The masses are of the Majorana type, and there is no right-handed neutrino within the low-energy field theory. The suppression scale 10(14) GeV is independent of the masses of the heavy states that are integrated out. These kinds of constructions appear naturally in type IIB flux compactifications. However, the arguments that lead to this result rely only on a few geometrical features of the compactification manifold and, hence, can be used independently of string theory.

Skin lesions in the neonate.

Neonatal skin provides physical protection and assists in fluid balance,immunosurveillance, and thermoregulation; thus, playing a vital role in the newborn's transition from an aqueous to an air-dominant environment. Worried parents often seek medical attention from their child's physician regarding skin lesions. Thus,a working knowledge of both normal and abnormal cutaneous lesions of the neonate is required to properly address these issues. In this article, the authors briefly discuss transient benign lesions,pustular and vesicular infections, "birthmarks" (vascular and pigmentary lesions), common congenital abnormalities, select blistering disorders, and various other skin conditions.

YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction.

The Yersinia pestis virulence factor YopJ is a potent inhibitor of the NF-kappaB and MAPK signalling pathways, however, its molecular mechanism and relevance to pathogenesis are the subject of much debate. In this report, we characterize the effects of this type III effector protein on bone fide signalling events downstream of Toll-like receptors (TLRs), critical sensors in innate immunity. YopJ inhibited TLR-mediated NF-kappaB and MAP kinase activation, as suggested by previous studies. In addition, induction of the TLR-mediated interferon response was blocked by YopJ, indicating that YopJ also inhibits IRF3 signalling. Examination of the NF-kappaB signalling pathway in detail suggested that YopJ acts at the level of TAK1 (MAP3K7) activation. Further studies revealed a YopJ-dependent decrease in the ubiquitination of TRAF3 and TRAF6. These data support the hypothesis that YopJ is a deubiquitinating protease that acts on TRAF proteins to prevent or remove the K63-polymerized ubiquitin conjugates required for signal transduction. Our data do not directly address the alternative hypothesis that YopJ is an acetyltransferase that acts on the activation loop of IKK and MKK proteins, but support the conclusion that the critical function of YopJ is to deubiquinate TRAF proteins.

Seeing an invisible axion in the supersymmetric particle spectrum.

I describe how under favorable circumstances, the existence of an invisible axion could correlate with a distinctive CERN Large Hadron Collider sparticle spectrum, in particular, through a gluino approximately ln(M(P)/m(3/2)) times heavier than other gauginos.

Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.

At mammalian body temperature, the plague bacillus Yersinia pestis synthesizes lipopolysaccharide (LPS)-lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity. To address the effect of weak TLR4 stimulation on virulence, we modified Y. pestis to produce a potent TLR4-stimulating LPS. Modified Y. pestis was completely avirulent after subcutaneous infection even at high challenge doses. Resistance to disease required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and convalescent mice were protected from both subcutaneous and respiratory challenge with wild-type Y. pestis. Despite the presence of other established immune evasion mechanisms, the modified Y. pestis was unable to cause systemic disease, demonstrating that the ability to evade the LPS-induced inflammatory response is critical for Y. pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria.