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Cell Host & Microbe

Ian Setliff, Wyatt J McDonnell, Nagarajan Raju, Robin G Bombardi, Amyn A Murji, Cathrine Scheepers, Rutendo Ziki, Charissa Mynhardt, Bryan E Shepherd, Alusha A Mamchak, Nigel Garrett, Salim Abdool Karim, Simon A Mallal, James E Crowe, Lynn Morris, Ivelin S Georgiev
Characterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of "public" antibody clonotypes that were shared among multiple HIV-infected individuals...
May 28, 2018: Cell Host & Microbe
Kevin Wiehe, Todd Bradley, R Ryan Meyerhoff, Connor Hart, Wilton B Williams, David Easterhoff, William J Faison, Thomas B Kepler, Kevin O Saunders, S Munir Alam, Mattia Bonsignori, Barton F Haynes
HIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages...
May 25, 2018: Cell Host & Microbe
Isabella Cristina Hirako, Patrícia Aparecida Assis, Natália Satchiko Hojo-Souza, George Reed, Helder Nakaya, Douglas Taylor Golenbock, Roney Santos Coimbra, Ricardo Tostes Gazzinelli
The Plasmodium cell cycle, wherein millions of parasites differentiate and proliferate, occurs in synchrony with the vertebrate host's circadian cycle. The underlying mechanisms are unknown. Here we addressed this question in a mouse model of Plasmodium chabaudi infection. Inflammatory gene expression and carbohydrate metabolism are both enhanced in interferon-γ (IFNγ)-primed leukocytes and liver cells from P. chabaudi-infected mice. Tumor necrosis factor α (TNFα) expression oscillates across the host circadian cycle, and increased TNFα correlates with hypoglycemia and a higher frequency of non-replicative ring forms of trophozoites...
May 17, 2018: Cell Host & Microbe
Julien Thézé, Tony Li, Louis du Plessis, Jerome Bouquet, Moritz U G Kraemer, Sneha Somasekar, Guixia Yu, Mariateresa de Cesare, Angel Balmaseda, Guillermina Kuan, Eva Harris, Chieh-Hsi Wu, M Azim Ansari, Rory Bowden, Nuno R Faria, Shigeo Yagi, Sharon Messenger, Trevor Brooks, Mars Stone, Evan M Bloch, Michael Busch, José E Muñoz-Medina, Cesar R González-Bonilla, Steven Wolinsky, Susana López, Carlos F Arias, David Bonsall, Charles Y Chiu, Oliver G Pybus
The Zika virus (ZIKV) epidemic in the Americas established ZIKV as a major public health threat and uncovered its association with severe diseases, including microcephaly. However, genetic epidemiology in some at-risk regions, particularly Central America and Mexico, remains limited. We report 61 ZIKV genomes from this region, generated using metagenomic sequencing with ZIKV-specific enrichment, and combine phylogenetic, epidemiological, and environmental data to reconstruct ZIKV transmission. These analyses revealed multiple independent ZIKV introductions to Central America and Mexico...
May 15, 2018: Cell Host & Microbe
Yoichiro Fujioka, Shinya Nishide, Toyoyuki Ose, Tadaki Suzuki, Izumi Kato, Hideo Fukuhara, Mari Fujioka, Kosui Horiuchi, Aya O Satoh, Prabha Nepal, Sayaka Kashiwagi, Jing Wang, Mika Horiguchi, Yuko Sato, Sarad Paudel, Asuka Nanbo, Tadaaki Miyazaki, Hideki Hasegawa, Katsumi Maenaka, Yusuke Ohba
Influenza A virus (IAV) infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV infection has remained unidentified. Here, we show that HA binds to the voltage-dependent Ca2+ channel Cav 1.2 to trigger intracellular Ca2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca2+ channel blockers (CCBs) or by knockdown of Cav 1.2. The CCB diltiazem also inhibited virus replication in vivo...
May 10, 2018: Cell Host & Microbe
Vitaly Sedlyarov, Ruth Eichner, Enrico Girardi, Patrick Essletzbichler, Ulrich Goldmann, Paula Nunes-Hasler, Ismet Srndic, Anna Moskovskich, Leonhard X Heinz, Felix Kartnig, Johannes W Bigenzahn, Manuele Rebsamen, Pavel Kovarik, Nicolas Demaurex, Giulio Superti-Furga
Macrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization...
May 8, 2018: Cell Host & Microbe
Peng Zhang, Jason Gorman, Hui Geng, Qingbo Liu, Yin Lin, Yaroslav Tsybovsky, Eden P Go, Barna Dey, Tsion Andine, Alice Kwon, Mit Patel, Deepali Gururani, Ferzan Uddin, Christina Guzzo, Raffaello Cimbro, Huiyi Miao, Krisha McKee, Gwo-Yu Chuang, Loïc Martin, Francesca Sironi, Mauro S Malnati, Heather Desaire, Edward A Berger, John R Mascola, Michael A Dolan, Peter D Kwong, Paolo Lusso
The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades...
June 13, 2018: Cell Host & Microbe
Jingshu Zhang, Yun Lan, Ming Yuan Li, Mart Matthias Lamers, Maxime Fusade-Boyer, Elizabeth Klemm, Christoph Thiele, Joseph Ashour, Sumana Sanyal
Ubiquitylation is one of the most versatile protein post-translational modifications and is frequently altered during virus infections. Here we employed a functional proteomics screen to identify host proteins that are differentially ubiquitylated upon dengue virus (DENV) infection. Among the several differentially modified proteins identified in infected cells was AUP1, a lipid droplet-localized type-III membrane protein, which exists predominantly in the mono-ubiquitylated form. AUP1 associated with DENV NS4A and relocalized from lipid droplets to autophagosomes upon infection...
June 13, 2018: Cell Host & Microbe
Chen Chen, Brittney N Nguyen, Gabriel Mitchell, Shally R Margolis, Darren Ma, Daniel A Portnoy
Listeriolysin O (LLO) is a cholesterol-dependent cytolysin that mediates escape of Listeria monocytogenes from a phagosome, enabling growth of the bacteria in the host cell cytosol. LLO contains a PEST-like sequence that prevents it from killing infected cells, but the mechanism involved is unknown. We found that the LLO PEST-like sequence was necessary to mediate removal of LLO from the interior face of the plasma membrane, where it coalesces into discrete puncta. LLO interacts with Ap2a2, an adaptor protein involved in endocytosis, via its PEST-like sequence, and Ap2a2-dependent endocytosis is required to prevent LLO-induced cytotoxicity...
June 13, 2018: Cell Host & Microbe
Yogesh Bhattarai, Brianna B Williams, Eric J Battaglioli, Weston R Whitaker, Lisa Till, Madhusudan Grover, David R Linden, Yasutada Akiba, Karunya K Kandimalla, Nicholas C Zachos, Jonathan D Kaunitz, Justin L Sonnenburg, Michael A Fischbach, Gianrico Farrugia, Purna C Kashyap
Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4 R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion...
June 13, 2018: Cell Host & Microbe
Vanessa Zuzarte-Luís, Maria M Mota
Parasites undergo complex life cycles that comprise a wide variety of cellular differentiation events in different host compartments and transmission across multiple hosts. As parasites depend on host resources, it is not surprising they have developed efficient mechanisms to sense alterations and adapt to the available resources in a wide range of environments. Here we provide an overview of the nutritional needs of different parasites throughout their diverse life stages and highlight recent insights into strategies that both hosts and parasites have developed to meet these nutritional requirements needed for defense, survival, and replication...
June 13, 2018: Cell Host & Microbe
Christopher A Lopez, Eric P Skaar
Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed "nutritional immunity." In response, bacteria have evolved elegant strategies to access metals and counteract this host defense...
June 13, 2018: Cell Host & Microbe
Aleksandr Milshteyn, Dominic A Colosimo, Sean F Brady
Natural products have long played a pivotal role in the development of therapeutics for a variety of diseases. Traditionally, soil and marine environments have provided a rich reservoir from which diverse chemical scaffolds could be discovered. Recently, the human microbiome has been recognized as a promising niche from which secondary metabolites with therapeutic potential have begun to be isolated. In this Review, we address how the expansive history of identifying bacterial natural products in other environments is informing the approaches being brought to bear on the study of the human microbiota...
June 13, 2018: Cell Host & Microbe
Allison Agus, Julien Planchais, Harry Sokol
The gut microbiota is a crucial actor in human physiology. Many of these effects are mediated by metabolites that are either produced by the microbes or derived from the transformation of environmental or host molecules. Among the array of metabolites at the interface between these microorganisms and the host is the essential aromatic amino acid tryptophan (Trp). In the gut, the three major Trp metabolism pathways leading to serotonin (5-hydroxytryptamine), kynurenine (Kyn), and indole derivatives are under the direct or indirect control of the microbiota...
June 13, 2018: Cell Host & Microbe
Kassem Makki, Edward C Deehan, Jens Walter, Fredrik Bäckhed
Food is a primordial need for our survival and well-being. However, diet is not only essential to maintain human growth, reproduction, and health, but it also modulates and supports the symbiotic microbial communities that colonize the digestive tract-the gut microbiota. Type, quality, and origin of our food shape our gut microbes and affect their composition and function, impacting host-microbe interactions. In this review, we will focus on dietary fibers, which interact directly with gut microbes and lead to the production of key metabolites such as short-chain fatty acids, and discuss how dietary fiber impacts gut microbial ecology, host physiology, and health...
June 13, 2018: Cell Host & Microbe
Charles Chiu
Three recent Science articles (Chen et al., 2018; Gootenberg et al., 2018; Myhrvold et al., 2018) describe the use of CRISPR-Cas technology to develop point-of-care diagnostics that directly detect viruses from clinical samples. These tests could radically transform approaches to diagnosing infectious diseases at the bedside and in the field.
June 13, 2018: Cell Host & Microbe
James B Munro
No immunogen has been found that elicits a broadly neutralizing antibody (bNAb) response sufficient for development into an HIV vaccine. In this issue of Cell Host and Microbe, Zhang et al. (2018) rationally design an HIV envelope glycoprotein variant that provides new hope that such an immunogen may be attainable.
June 13, 2018: Cell Host & Microbe
Markus Hoffmann, Stefan Pöhlmann
Influenza A viruses attach to sialic acids on host cells. In this issue of Cell Host & Microbe, Fujioka et al. (2018) show that binding to a specific sialylated cellular protein facilitates infection: engagement of sialic acids linked to the Ca2+ channel CaV 1.2 induces Ca2+ oscillations, which promote infectious entry.
June 13, 2018: Cell Host & Microbe
Sarah E Reece, Kimberley F Prior
Successive synchronized cycles of Plasmodium replication in the host's blood causes the symptoms of malaria and fuels disease transmission. In this issue of Cell Host & Microbe, Hirako et al. (2018) reveal that host circadian rhythms of inflammation and metabolism are responsible for the timing of cycles of parasite replication.
June 13, 2018: Cell Host & Microbe
Keith Ireton
Listeriolysin O (LLO) perforates host vacuoles, allowing Listeria monocytogenes to escape to the cytosol. How cytosolic LLO prevents cell lysis was not understood. In this issue of Cell Host & Microbe, Chen et al. (2018) show that a PEST sequence prevents cytotoxicity by mediating LLO endocytosis from the plasma membrane.
June 13, 2018: Cell Host & Microbe
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