Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection

Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-κB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFα) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFα synthesis in a manner that involved transcriptional repression of the TNFα promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFα promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFα cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFα production. Moreover, because Tat activates both RelB and TNFα in microglia, and because Tat induces inflammatory TNFα synthesis via NF-κB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-κB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND

Scrub typhus ecology: a systematic review of Orientia in vectors and hosts

Abstract Scrub typhus, caused by Orientia tsutsugamushi, is an important and neglected vector-borne zoonotic disease with an expanding known distribution. The ecology of the disease is complex and poorly understood, impairing discussion of public health interventions. To highlight what we know and the themes of our ignorance, we conducted a systematic review of all studies investigating the pathogen in vectors and non-human hosts. A total of 276 articles in 7 languages were included, with 793 study sites across 30 countries. There was no time restriction for article inclusion, with the oldest published in 1924. Seventy-six potential vector species and 234 vertebrate host species were tested, accounting for over one million trombiculid mites (‘chiggers’) and 83,000 vertebrates. The proportion of O. tsutsugamushi positivity was recorded for different categories of laboratory test and host species. Vector and host collection sites were geocoded and mapped. Ecological data associated with these sites were summarised. A further 145 articles encompassing general themes of scrub typhus ecology were reviewed. These topics range from the life-cycle to transmission, habitats, seasonality and human risks. Important gaps in our understanding are highlighted together with possible tools to begin to unravel these. Many of the data reported are highly variable and inconsistent and minimum data reporting standards are proposed. With more recent reports of human Orientia sp. infection in the Middle East and South America and enormous advances in research technology over recent decades, this comprehensive review provides a detailed summary of work investigating this pathogen in vectors and non-human hosts and updates current understanding of the complex ecology of scrub typhus. A better understanding of scrub typhus ecology has important relevance to ongoing research into improving diagnostics, developing vaccines and identifying useful public health interventions to reduce the burden of the disease.</jats:p

MEDIAN EYE IN LARVAE OF HYDRYPHANTES RUBER (DE GEER, 1778) (ACARIFORMES: HYDRYPHANTIDAE)

Median eye in larva of the water mite Hydryphantes ruber (De Geer, 1778) was investigated by means of light-optical and electron-microscopical (SEM and TEM) methods. The median eye is a single organ situated at the dorsal body surface under a slightly thickened and protruded cuticle in the middle of the dorsal shield. The median eye is a simply organized structure and is composed of small retinula cells with everted mostly isolated rhabdomeres looking to the cuticle. Each rhabdomere consists of irregularly arranged microvilli. The basal nuclear zones of these cells are occupied by electron-dense pigment granules. Two laterally situated nerves are composed of five axons each that suggest the paired origin of the median eye. Epidermal cells reach in lipid inclusions totally enclose the eye and are underlain by a flat basal lamina. Retinula cells contact to each other and to the epidermal cells by septate junctions. The larval median eye appears to be rather similar to median eye in adult mites of this species studied previously (Mischke 1981)

Stylostome of the trombiculid mite larvaeNeotrombicula talmiensis (Schluger, 1955) (Acariformes, Trombiculidae) feeding on two host species in the Russian Far East

Shatrov, Andrey B., Antonovskaia, Anastasia A. (2021): Stylostome of the trombiculid mite larvaeNeotrombicula talmiensis (Schluger, 1955) (Acariformes, Trombiculidae) feeding on two host species in the Russian Far East. Acarologia 61 (2): 412-431, DOI: 10.24349/acarologia/20214442, URL: http://dx.doi.org/10.24349/acarologia/2021444

OBSERVATION ON SILK PRODUCTION AND MORPHOLOGY OF SILK IN WATER MITES (ACARIFORMES: HYDRACHNIDIA)

Adults of the following water mite species — Piona coccinea (C.L. Koch, 1836), Limnesia undulata (O.F. Müller, 1776), Limnesia maculata (O.F. Müller, 1776), Limnesia undulatoides (Davids, 1997), Hydryphantes ruber (de Geer, 1778) and Mideopsis orbicularis (O.F. Müller, 1776) maintaining in the laboratory for several months were shown to permanently produce various amount of silk in the form of long thin unbrunched threads. Morphology of these threads are similar in all studied species — they are stright, rigid, mostly hollow tubes of two dimension categories: thin 730±130 nm, and thick 1–2.5 μm in diameter. Predominance of different thread types varies freely in different mite species. Specific staining reveals neither DNA nor microbial walls in threads composition, so the microbial origin of threads is excluded. Staining with Calcofluor White M2R fluorochrome definitely indicates that these threads belong to arthropod silk. Organization of the threads is found to be simplest among known spiders and insect’s silks. The observed silk formation does not correspond to the mite reproduction activity because has lasted from late summer till mid autumn where mites have already completed producing both eggs and spermatophores. Possible functions of the silk are discussed