Summary: The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.

Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses

The genus Legionella contains more than 50 species, of which at least 24 have been associated with human infection. The best-characterized member of the genus, Legionella pneumophila, is the major causative agent of Legionnaires' disease, a severe form of acute pneumonia. L. pneumophila is an intracellular pathogen, and as part of its pathogenesis, the bacteria avoid phagolysosome fusion and replicate within alveolar macrophages and epithelial cells in a vacuole that exhibits many characteristics of the endoplasmic reticulum (ER). The formation of the unusual L. pneumophila vacuole is a feature of its interaction with the host, yet the mechanisms by which the bacteria avoid classical endosome fusion and recruit markers of the ER are incompletely understood. Here we review the factors that contribute to the ability of L. pneumophila to infect and replicate in human cells and amoebae with an emphasis on proteins that are secreted by the bacteria into the Legionella vacuole and/or the host cell. Many of these factors undermine eukaryotic trafficking and signaling pathways by acting as functional and, in some cases, structural mimics of eukaryotic proteins. We discuss the consequences of this mimicry for the biology of the infected cell and also for immune responses to L. pneumophila infection.

https://www.antimicrobe.org/hisphoto/history/ClinMicroRev_Newton_LDpathogenesis2010.pdf

Molecular Pathogenesis of Infections Caused by Legionella pneumophila

Full Disclosure: The Perils and Promise of Transparency. By Archon Fung, Mary Graham, and David Weil. New York: Cambridge University Press, 2007. 282p. $28.00.One of the cornerstones of Woodrow Wilson's policy agenda, even before he formally sought the presidency, was transparency. To neutralize corporate misbehavior, for instance, he called for “turn[ing] the light” on corporations: “They don't like light. Turn it on so strong they can't stand it. Exposure is one of the best ways to whip them into line.” Although the authors of this superb work do not acknowledge Wilson's part in the evolutionary line of transparency policy, they do show by means of thorough and enlightening description and analysis the fruit finally borne of ideas like those Wilson espoused. Indeed, the authors tell a story of policy design that demonstrates the continuing value of careful legislative craftsmanship and policy refinement over time, based on feedback from administration and enforcement. It is a tale of effective legislative governance, particularly at the national level, that far too many American citizens, and even political leaders, believe is impossible or at least unlikely anymore.

Full Disclosure: The Perils and Promise of Transparency

Legionella pneumophila is the causative agent of human Legionnaire's disease. During infection, the bacterium invades macrophages and lung epithelial cells, and replicates intracellularly. However, little is known about its interaction with T cells. We investigated the ability of L. pneumophila to infect and stimulate the production of interleukin-8 (IL-8) in T cells. The objective of this study was to assess whether L. pneumophila interferes with the immune system by interacting and infecting T cells. Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T cells. On the other hand, wild-type L. pneumophila and Dot/Icm-deficient Legionella, but not flagellin-deficient Legionella or heat-killed Legionella induced IL-8 expression. L. pneumophila activated an IL-8 promoter through the NF-κB and AP-1 binding regions. Wild-type L. pneumophila but not flagellin-deficient Legionella activated NF-κB, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and transforming growth factor β-associated kinase 1 (TAK1). Transfection of dominant negative mutants of IκBα, IκB kinase, NF-κB-inducing kinase, TAK1, MyD88, and p38 MAPK inhibited L. pneumophila-induced IL-8 activation. Inhibitors of NF-κB, p38 MAPK, and JNK blocked L. pneumophila-induced IL-8 expression. In addition, c-Jun, JunD, cyclic AMP response element binding protein, and activating transcription factor 1, which are substrates of p38 MAPK and JNK, bound to the AP-1 site of the IL-8 promoter. Taken together, L. pneumophila induced a flagellin-dependent activation of TAK1, p38 MAPK, and JNK, as well as NF-κB and AP-1, which resulted in IL-8 production in human T cells, presumably contributing to the immune response in Legionnaire's disease.

/pdf/molecular-characterization-of-legionella-pneumophila-induced-h1gfzmayh4.pdf

Molecular characterization of Legionella pneumophila-induced interleukin-8 expression in T cells

In the respiratory system, the upper tract is colonized with commensal bacteria, whereas the lower tract is sterile. The respiratory system is continuously exposed to a variety of bacteria. To combat these intruders, the lung has developed a multifaceted system of defense. One of the most important

https://iai.asm.org/content/iai/77/2/568.full.pdf

Neutrophil recruitment to the lungs during bacterial pneumonia.

Legionella pneumophila (Lp), an important cause of morbidity and mortality from pneumonia, infects alveolar macrophages (AMs) and is recognized by several TLRs as well as Birc1e (NAIP5) and IL-1 converting enzyme-protease activating factor. We examined the role of TLR5 during the murine response to aerosolized Lp infection. At 4 h after infection, Tlr5 −/− mice had lower numbers of polymorphonuclear neutrophils (PMNs) in their broncho-alveolar lavage fluid in comparison to wild-type (WT) mice. At 24 and 72 h, the PMN recruitment was similar. WT mice infected with a flagellin-deficient strain (LpFlaA−) also showed an impaired early PMN response at 4 h compared with those infected with the WT strain. There was no consistent difference in bacterial counts at any of the time points when comparing the Tlr5 −/− and WT mice. However, at 6 days after infection, the Tlr5 −/− mice had increased leukocytic infiltrates in the alveolar and peribronchial interstitial spaces that were consistent with organizing pneumonia. We also examined the role of TLR5 during macrophage infection. In contrast to bone marrow-derived macrophages, AMs secreted TNF-α after stimulation with purified flagellin. In addition, WT, but not Tlr5 −/− , AMs produced TNF-α after stimulation with Lp. Live LpFlaA− did not induce TNF-α secretion in AM. These results suggested that AMs recognize Lp flagellin and that a majority of the Lp-induced TNF-α response is TLR5-mediated. Thus, TLR5 mediates recognition of Lp in AMs and performs a distinct role during the in vivo pulmonary immune response through regulation of early PMN recruitment and subsequent later development of pneumonia.

/pdf/altered-inflammatory-responses-in-tlr5-deficient-mice-1ukvyajixm.pdf

Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila

Abstract Cell-site simulators, also known as IMSI-catchers and stingrays, are used around the world by governments and criminals to track and eavesdrop on cell phones. Despite extensive public debate surrounding their use, few hard facts about them are available. For example, the richest sources of information on U.S. government cell-site simulator usage are from anonymous leaks, public records requests, and court proceedings. This lack of concrete information and the difficulty of independently obtaining such information hampers the public discussion. To address this deficiency, we build, deploy, and evaluate SeaGlass, a city-wide cellsite simulator detection network. SeaGlass consists of sensors that measure and upload data on the cellular environment to find the signatures of portable cell-site simulators. SeaGlass sensors are designed to be robust, low-maintenance, and deployable in vehicles for long durations. The data they generate is used to learn a city’s network properties to find anomalies consistent with cell-site simulators. We installed SeaGlass sensors into 15 ridesharing vehicles across two cities, collecting two months of data in each city. Using this data, we evaluate the system and show how SeaGlass can be used to detect signatures of portable cell-site simulators. Finally, we evaluate our signature detection methods and discuss anomalies discovered in the data.

https://sciendo.com/pdf/10.1515/popets-2017-0027

SeaGlass: Enabling City-Wide IMSI-Catcher Detection

Many have enthusiastically greeted the ability to search and view public records online as a great advance for transparency and accountability. Such ability, however, also creates value tensions with privacy and other important human values. In this paper, we report findings from a survey of 134 residents of the US Pacific Northwest on their awareness of and attitudes towards online access to political campaign records and real estate transaction histories, bringing to light some of the social implications of technological changes that increase ease of access to public records. We show that, while respondents often understood the reason behind making these records public, considerable concern about the current accessibility of these records exists, along with a precautionary indication that such open access may reduce public participation for some individuals.

/pdf/attitudes-toward-online-availability-of-us-public-records-5bgqiun95c.pdf

Attitudes toward online availability of US public records

Many have enthusiastically greeted the ability to search and view public records online as a great advance for transparency and accountability. Such ability, however, also creates value tensions with privacy and other important human values. In this paper, we report findings from a survey of 134 residents of the US Pacific Northwest on their awareness of and attitudes towards online access to political campaign records and real estate transaction histories, bringing to light some of the social implications of technological changes that increase ease of access to public records. We show that. while respondents often understood the reason behind making these records public, considerable concern about the current accessibility of these records exists, along with a precautionary indication that such open access may reduce public participation for some individuals.

/pdf/sunlight-or-sunburn-a-survey-of-attitudes-toward-online-xxjwwxk61g.pdf

Sunlight or sunburn: a survey of attitudes toward online availability of US public records

– Trust in current and historical calibration data is crucial. The recently proposed XML schema for digital calibration certificates (DCCs) provides machine-readability and a common exchange format to enhance this trust. We present a prototype web application developed in the programming language Links for storing and displaying a DCC using a relational database. In particular, we leverage the temporal database features that Links provides to capture different versions of a certificate and inspect differences between versions. The prototype is the starting point for developing software to support DCCs and the data with which they are populated and has underlined that DCCs are the tip of the iceberg in automating the management of digital calibration data, activity that includes data provenance and tracking of modifications.

https://www.imeko.org/publications/tc6-2022/IMEKO-TC6-2022-024.pdf

Ian Smith

Papers

Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila

SeaGlass: Enabling City-Wide IMSI-Catcher Detection

Attitudes toward online availability of US public records

Sunlight or sunburn: a survey of attitudes toward online availability of US public records

Supporting provenance of digital calibration certificates with temporal databases