Cyclic lava effusion during the 2018 eruption of Kilauea Volcano.

Lava flows present a recurring threat to communities on active volcanoes, and volumetric eruption rate is one of the primary factors controlling flow behavior and hazard. The time scales and driving forces of eruption rate variability, however, remain poorly understood. In 2018, a highly destructive eruption occurred on the lower flank of Kilauea Volcano, Hawai'i, where the primary vent exhibited substantial cyclic eruption rates on both short (minutes) and long (tens of hours) time scales. We used multiparameter data to show that the short cycles were driven by shallow outgassing, whereas longer cycles were pressure-driven surges in magma supply triggered by summit caldera collapse events 40 kilometers upslope. The results provide a clear link between eruption rate fluctuations and their driving processes in the magmatic system.

The 2017-19 activity at Mount Agung in Bali (Indonesia): Intense unrest, monitoring, crisis response, evacuation, and eruption.

After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Group 1 innate lymphoid cells in Toxoplasma gondii infection.

Innate lymphoid cells (ILCs) are a group of lymphocytes that carry out important functions in immunity to infections and in organ homeostasis at epithelial barrier surfaces. ILCs are innate immune cells that provide an early source of cytokines to initiate immune responses against pathogens. Cytotoxic ILCs (i.e. conventional (c)NK cells) and several subsets of helper-like ILCs are the major branches of the ILC family. Conventional NK cells and group 1 ILCs share several characteristics such as surface receptors and the ability to produce IFN-γ upon activation, but they differ in their developmental paths and in their dependence on specific transcription factors. Infection of mice with the intracellular parasite Toxoplasma gondii is followed by a strong Th1-mediated immune response. Previous studies indicate that NK1.1+ cells contribute to the production of IFN-γ and TNF and cytotoxicity during acute T. gondii infection. Upon oral infection, the parasite infects intestinal enterocytes, and within the lamina propria, innate immune responses lead to initial parasite control although the infection disseminates widely and persists long-term in immune privileged sites despite adaptive immunity. Upon parasite entry into the small intestine, during the acute stage, ILC1 produce high levels of IFN-γ and TNF protecting barrier surfaces, thus essentially contributing to early parasite control. We will discuss here the role of innate lymphocytes during T. gondii infection in the context of the only recently appreciated diversity of ILC subsets.

Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity.

Natural killer (NK) cells attack many tumour cell lines, and are thought to have a critical role in anti-tumour immunity; however, the interaction between NK cells and tumour targets is poorly understood. The stimulatory lectin-like NKG2D receptor is expressed by NK cells, activated CD8+ T cells and by activated macrophages in mice. Several distinct cell-surface ligands that are related to class I major histocompatibility complex molecules have been identified, some of which are expressed at high levels by tumour cells but not by normal cells in adults. However, no direct evidence links the expression of these 'induced self' ligands with tumour cell rejection. Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1beta or H60 in several tumour cell lines results in potent rejection of the tumour cells by syngeneic mice. Rejection is mediated by NK cells and/or CD8+ T cells. The ligand-expressing tumour cells induce potent priming of cytotoxic T cells and sensitization of NK cells in vivo. Mice that are exposed to live or irradiated tumour cells expressing Rae1 or H60 are specifically immune to subsequent challenge with tumour cells that lack NKG2D ligands, suggesting application of the ligands in the design of tumour vaccines.

Strategies for target cell recognition by natural killer cells.

Stimulation of natural killer (NK) cells is regulated by a complex balance of inhibitory and stimulatory receptors expressed by NK cells. However, the interaction of stimulatory receptors and their ligands is poorly understood. One stimulatory receptor, NKG2D, is expressed by all NK cells, stimulated CD8+ T cells, gammadelta T cells and macrophages. Recently, progress has been made in defining cellular ligands for NKG2D. Four different families of ligands have been identified in mice and humans, all of which are distantly related to MHC class I molecules. Some of the ligands are upregulated in transformed and infected cells, provoking an attack by the innate and adaptive immune systems. It appears that these "induced-self" ligands recognized by the NKG2D receptor may be a precedent for a new strategy of target cell recognition by the immune system.

Regulation of type 2 nitric oxide synthase by type 1 interferons in macrophages infected with Leishmania major.

We recently reported that the infection of macrophages with Leishmania major led to the release of type 1 interferons (IFN-alpha /beta ). Moreover, at day 1 of infection of mice with L. major, IFN-alpha /beta was required for the expression of type 2 (inducible) NO synthase (NOS2 or iNOS) which, however, was restricted to a few macrophages in the dermis. Here, we further characterized the regulation of NOS2 by IFN-alpha /beta. Macrophages that were either simultaneously or sequentially exposed to L. major promastigotes and IFN-alpha /beta expressed NOS2 and anti-leishmanial activity. In contrast, when high amounts of IFN-alpha /beta were used or when IFN-alpha /beta was added to the macrophages 2 h prior to the parasites, almost no induction of NOS2 was observed. After pretreatment with IFN-alpha /beta, tyrosine phosphorylation and nuclear DNA binding of Stat1alpha, the degradation of the NF-kappaB inhibitor (IkappaBalpha and beta), and the nuclear translocation of NF-kappaB were strongly impaired compared with macrophages exposed to IFN-alpha /beta and L. major simultaneously. Thus, IFN-alpha /beta exerts agonistic or antagonistic effects on the expression of NOS2 in macrophages infected with a microbial pathogen, depending on the sequence of the stimuli and the amount of IFN-alpha /beta added. The limited number of NOS2-positive macrophages at day 1 of infection in vivo might result from a blockage of non-infected macrophages by IFN-alpha /beta that is released by neighboring infected cells.

Fibroblasts as host cells in latent leishmaniosis.

Intracellular parasites are known to persist lifelong in mammalian hosts after the clinical cure of the disease, but the mechanisms of persistence are poorly understood. Here, we show by confocal laser microscopy that in the draining lymph nodes of mice that had healed a cutaneous infection with Leishmania major, 40% of the persisting parasites were associated with fibroblasts forming the reticular meshwork of the lymph nodes. In vitro, both promastigotes and amastigotes of L. major infected primary skin or lymph node fibroblasts. Compared with macrophages, cytokine-activated fibroblasts had a reduced ability to express type 2 nitric oxide synthase and to kill intracellular L. major. These data identify fibroblasts as an important host cell for Leishmania during the chronic phase of infection and suggest that they might serve as safe targets for the parasites in clinically latent disease.

The role of nitric oxide in innate immunity.

Type 2 nitric oxide synthase (iNOS or NOS2) was originally described as an enzyme that is expressed in activated macrophages, generates nitric oxide (NO) from the amino acid L-arginine, and thereby contributes to the control of replication or killing of intracellular microbial pathogens. Since interferon (IFN)-gamma is the key cytokine for the induction of NOS2 in macrophages and the prototypic product of type 1 T-helper cells, high-level expression of NOS2 has been regarded to be mostly restricted to the adaptive phase of the immune response. In this review, we summarize data that demonstrate a prominent role of NOS2/NO also during innate immunity. During the early phase of infection with the intracellular pathogen Leishmania major, focally expressed NOS2/NO not only exerts antimicrobial activities but also controls the function of natural killer cells and the expression of cytokines such as IFN-gamma or transforming growth factor-beta. Some of these effects result from the function of NOS2/NO as an indispensable co-factor for the activation of Tyk2 kinase and, thus, for interleukin-12 and IFN-alpha/beta signaling in natural killer cells.

Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity.

Nitric oxide, nitric oxide derivatives and reactive oxygen intermediates are toxic molecules of the immune system which contribute to the control of microbial pathogens and tumors. There is recent evidence for additional functions of these oxygen metabolites in innate and adaptive immunity; these functions include the modulation of the cytokine response of lymphocytes and the regulation of immune cell apoptosis, as well as immunodeviating effects. Components of several signal transduction pathways have been identified as intracellular targets for reactive nitrogen and oxygen intermediates.

Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages.

Natural killer (NK) cells attack tumor and infected cells, but the receptors and ligands that stimulate them are poorly understood. Here we report the expression cloning of two murine ligands for the lectin-like receptor NKG2D. The two ligands, H-60 and Rae1 beta, are distant relatives of major histocompatibility complex class I molecules. NKG2D ligands are not expressed by most normal cells but are up-regulated on numerous tumor cells. We show that mouse NKG2D is expressed by NK cells, activated CD8+ T cells and activated macrophages. Expression of either NKG2D ligand by target cells triggers NK cell cytotoxicity and interferon-gamma secretion by NK cells, as well as nitric oxide release and tumor necrosis factor alpha transcription by macrophages. Thus, through their interaction with NKG2D, H-60 and Rae1 beta are newly identified potent stimulators of innate immunity.

Natural killer cells: stress out, turn on, tune in.

Natural killer cells attack tumor cells, infected cells and some normal cells, but the basis of their specificity is not completely understood. Recent studies indicate that epithelial tumor cells upregulate a stress-induced MHC class-I-like protein termed MICA, triggering NK cells via a recently described receptor called NKG2D.

Requirement for type 2 NO synthase for IL-12 signaling in innate immunity.

Interleukin-12 (IL-12) and type 2 NO synthase (NOS2) are crucial for defense against bacterial and parasitic pathogens, but their relationship in innate immunity is unknown. In the absence of NOS2 activity, IL-12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer (NK) cells for cytotoxicity or interferon-gamma (IFN-gamma) release, and failed to activate Tyk2 kinase and to tyrosine phosphorylate Stat4 (the central signal transducer of IL-12) in NK cells. Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.

IFN-gamma inhibits the production of latent transforming growth factor-beta1 by mouse inflammatory macrophages.

Transforming growth factor (TGF)-beta is a multifunctional cytokine, which in mammals exists in three isoforms (TGF-beta1, 2 and 3). It is synthesized by a variety of cells including macrophages, and exerts potent immunoregulatory effects such as the inhibition of Th1 development and the suppression or reversal of IFN-gamma-induced macrophage activation. In this study we analyzed the effect of IFN-gamma on the production of TGF-beta1 by thioglycolate-elicited mouse peritoneal macrophages under serum-free conditions. Untreated macrophages released TGF-beta1 in its latent form, which became detectable in a capture ELISA specific for active TGF-beta1 after acid activation of the culture supernatants. Treatment with IFN-gamma reduced the amount of latent TGF-beta1 in the culture supernatants in a dose-dependent fashion. The effect of IFN-gamma was confirmed by a newly developed Western blot system for the detection of mouse TGF-beta1 protein. IFN-gamma only weakly (16-24 %) reduced the levels TGF-beta1 mRNA at early and late time points of stimulation, and no evidence was obtained that IFN-gamma suppresses the secretion of latent TGF-beta1. Thus, inhibition of TGF-beta1 production by IFN-gamma is most likely due to decreased synthesis and/or stability of the TGF-beta1 protein, and might be important for the generation of fully activated macrophages and a Th1 response.

Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite.

Type 2 nitric oxide synthase (NOS2) is required for the Th1-dependent healing of infections with intracellular microbes, including Leishmania major. Here, we demonstrate the expression and define the function of NOS2 during the innate response to L. major. At day 1 of infection, genetic deletion or functional inactivation of NOS2 abolished the IFNgamma and natural killer cell response, increased the expression of TGFbeta, and caused parasite spreading from the skin and lymph node to the spleen, liver, bone marrow, and lung. Induction of NOS2 was dependent on IFNalpha/beta. Neutralization of IFNalpha/beta mimicked the phenotype of NOS2-/- mice. Thus, IFNalpha/beta and NOS2 are critical regulators of the innate response to L. major.

In vivo blocking of L-selectin rescues BALB/c mice from fatal Leishmania major infection.

Susceptibility and resistance to experimental Leishmania major (L. major) infection in mice are associated with a Th2- or Th1-type response, respectively. We have previously shown that immunological events occurring within the first 24 h after infection in the lymph node (LN) draining the site of parasite challenge are critical for the development of either type of T-cell responses. In the present study we manipulated these events by preventing the entry of naive lymphocytes into the draining LN by injecting BALB/c mice with a single dose of the anti-L-selectin mAb MEL-14 one day prior to infection with L. major. In contrast to control BALB/c mice, in MEL-14 treated animals the primary lesion healed 12 weeks after infection. The parasite load in the spleen and lymph nodes of MEL-14 treated mice was significantly reduced. The healing was found to be associated with an increased production of IFN-gamma and with a decrease in IL-4 production by LN cells. We observed a dramatic decrease in cellularity in the draining LN in Mel-14 treated L. major-infected mice within the first week of infection. Moreover, the cells in the LN of MEL-14 treated mice were highly enriched in activated cells as well as in cell influx in the draining LN after local L. major infection of BALB/c mice prevents fatal disease. The data suggest the MEL-14-induced enrichment of the draining LN in memory and activated cells is fundamental for the initiation of a protective Th1-type response.

Control of Leishmania major infection in BALB/c mice by inhibition of early lymphocyte entry into peripheral lymph nodes.

A single i.p. injection with the anti-CD62L (anti-L-selectin) mAb Mel-14 before parasite challenge protected BALB/c mice from the otherwise lethal infection with Leishmania major. The Mel-14 mAb treatment resulted in a significant (>90%) decrease in cellularity of the popliteal lymph node (PLN) with a decrease in the proportion of CD4+ cells and an increase of the proportion of B220+ cells. Furthermore, both activated cells (CD25+ and CD69+) and cells of the memory phenotype (CD45RBdull CD44high) were significantly enriched in PLN from Mel-14-treated BALB/c mice. After infection with L. major, the otherwise massive cellular infiltration in the draining PLN was completely blocked in the Mel-14-treated mice, and in these animals the high representation of both activated and memory cells in PLN remained characteristic for the first days of infection. The protective effect was found to be associated with a markedly increased production of IFN-gamma and with a decrease in IL-4 production upon restimulation of PLN and spleen cells with L. major Ag in vitro. The cured mice were found to be resistant against a secondary challenge with the parasites. These data suggest that the induction of a nonprotective Th2 response to L. major is associated with the entry of lymphocytes from the recirculating pool into the draining LN. The Mel-14-induced changes in the lymphoid microenvironment of the draining peripheral LN appear to favor the development of a protective Th1 cell-mediated immune response against the parasite.

Early parasite containment is decisive for resistance to Leishmania major infection.

We investigated the early spread of Leishmania major in various mouse strains. In BALB/c mice, which are extremely vulnerable to L. major infection, the parasites disseminated within 10-24 h from the site of subcutaneous footpad infection in to the popliteal lymph node, spleen, lung, liver and bone marrow. Application of recombinant (r)IL-12 prior to infection prevented the early dissemination of parasites into visceral organs and the animals healed the infection. In three mouse strains tested, C57BL/6, CBA/J and C3H/HeJ, which are all resistant to L. major infection, the parasites remained localized in the footpad and in the draining LN for 3 days without evidence of dissemination. In C57BL/6 mice, depletion of NK1.1+ cells or neutralization of interferon (IFN)-gamma prior to infection led to rapid parasite spreading with kinetics similar to those seen in susceptible animals. Depletion of either CD4+ or CD8+ T cells in vivo prior to infection did not alter the kinetics of dissemination in any mouse strain tested. Experiments with severe-combined immunodeficient mice provided further evidence that parasite containment depends on natural killer cells and IFN-gamma, but is independent of T cells. The finding that all resistant mouse strains restrict the spread of the parasites within the first 24 h after infection strongly suggests that early parasite containment is closely associated with a resistant phenotype. The data show that local restriction of parasites in the pre-T cell phase of the infection is mediated by the innate immune system and suggest that this function plays an important role in the development of a protective T cell response.