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PLoS Pathogens

Manalee Vishnu Surve, Smita Bhutda, Akshay Datey, Anjali Anil, Shalini Rawat, Athira Pushpakaran, Dipty Singh, Kwang Sik Kim, Dipshikha Chakravortty, Anirban Banerjee
Outcome of host-pathogen encounter is determined by the complex interplay between protective bacterial and host defense strategies. This complexity further amplifies with the existence of cell-to-cell phenotypic heterogeneity in pathogens which remains largely unexplored. In this study, we illustrated that heterogeneous expression of pneumolysin (Ply), a pore-forming toxin of the meningeal pathogen, S. pneumoniae (SPN) gives rise to stochastically different bacterial subpopulations with variable fate during passage across blood-brain barrier (BBB)...
July 16, 2018: PLoS Pathogens
Albin Fontaine, Sebastian Lequime, Isabelle Moltini-Conclois, Davy Jiolle, Isabelle Leparc-Goffart, Robert Charles Reiner, Louis Lambrechts
The kinetics of arthropod-borne virus (arbovirus) transmission by their vectors have long been recognized as a powerful determinant of arbovirus epidemiology. The time interval between virus acquisition and transmission by the vector, termed extrinsic incubation period (EIP), combines with vector mortality rate and vector competence to determine the proportion of infected vectors that eventually become infectious. However, the dynamic nature of this process, and the amount of natural variation in transmission kinetics among arbovirus strains, are poorly documented empirically and are rarely considered in epidemiological models...
July 13, 2018: PLoS Pathogens
Jie Geng, Anita J Zaitouna, Malini Raghavan
Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides present in the cytosol of cells are transported into the ER via the transporter associated with antigen processing (TAP). In the ER, peptides are assembled with MHC-I molecules via the peptide-loading complex (PLC)...
July 11, 2018: PLoS Pathogens
Lucas E Cavallin, Qi Ma, Julian Naipauer, Sachin Gupta, Mani Kurian, Paola Locatelli, Paolo Romanelli, Mehrdad Nadji, Pascal J Goldschmidt-Clermont, Enrique A Mesri
Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) Most KSHV infected spindle cells of KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis...
July 9, 2018: PLoS Pathogens
Chyntia Carolina Díaz Acosta, André Alves Dias, Thabatta Leal Silveira Andrezo Rosa, Leonardo Ribeiro Batista-Silva, Patricia Sammarco Rosa, Thiago Gomes Toledo-Pinto, Fabrício da Mota Ramalho Costa, Flávio Alves Lara, Luciana Silva Rodrigues, Katherine Antunes Mattos, Euzenir Nunes Sarno, Patrícia Torres Bozza, Christophe Guilhot, Márcia de Berrêdo-Pinho, Maria Cristina Vidal Pessolani
Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner...
July 6, 2018: PLoS Pathogens
Carlos F De La Cruz-Herrera, Kathy Shire, Umama Z Siddiqi, Lori Frappier
Many cellular processes pertinent for viral infection are regulated by the addition of small ubiquitin-like modifiers (SUMO) to key regulatory proteins, making SUMOylation an important mechanism by which viruses can commandeer cellular pathways. Epstein-Barr virus (EBV) is a master at manipulating of cellular processes, which enables life-long infection but can also lead to the induction of a variety of EBV-associated cancers. To identify new mechanisms by which EBV proteins alter cells, we screened a library of 51 EBV proteins for global effects on cellular SUMO1 and SUMO2 modifications (SUMOylation), identifying several proteins not previously known to manipulate this pathway...
July 6, 2018: PLoS Pathogens
Adam S Dingens, Priyamvada Acharya, Hugh K Haddox, Reda Rawi, Kai Xu, Gwo-Yu Chuang, Hui Wei, Baoshan Zhang, John R Mascola, Bridget Carragher, Clinton S Potter, Julie Overbaugh, Peter D Kwong, Jesse D Bloom
Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery...
July 5, 2018: PLoS Pathogens
Lindsay McDonald, Mathieu Cayla, Alasdair Ivens, Binny Mony, Paula MacGregor, Eleanor Silvester, Kirsty McWilliam, Keith R Matthews
Trypanosoma brucei, the agents of African trypanosomiasis, undergo density-dependent differentiation in the mammalian bloodstream to prepare for transmission by tsetse flies. This involves the generation of cell-cycle arrested, quiescent, stumpy forms from proliferative slender forms. The signalling pathway responsible for the quorum sensing response has been catalogued using a genome-wide selective screen, providing a compendium of signalling protein kinases phosphatases, RNA binding proteins and hypothetical proteins...
June 25, 2018: PLoS Pathogens
Christina Yacoob, Miles Darnell Lange, Kristen Cohen, Kanan Lathia, Junli Feng, Jolene Glenn, Sara Carbonetti, Brian Oliver, Vladimir Vigdorovich, David Noah Sather, Leonidas Stamatatos
Broadly neutralizing HIV-1 antibodies (bNAbs) isolated from infected subjects display protective potential in animal models. Their elicitation by immunization is thus highly desirable. The HIV-1 envelope glycoprotein (Env) is the sole viral target of bnAbs, but is also targeted by binding, non-neutralizing antibodies. Env-based immunogens tested so far in various animal species and humans have elicited binding and autologous neutralizing antibodies but not bNAbs (with a few notable exceptions). The underlying reasons for this are not well understood despite intensive efforts to characterize the binding specificities of the elicited antibodies; mostly by employing serologic methodologies and monoclonal antibody isolation and characterization...
June 22, 2018: PLoS Pathogens
Young C Shin, Georg F Bischof, William A Lauer, Lucas Gonzalez-Nieto, Eva G Rakasz, Gregory M Hendricks, David I Watkins, Mauricio A Martins, Ronald C Desrosiers
The properties of the human immunodeficiency virus (HIV) pose serious difficulties for the development of an effective prophylactic vaccine. Here we describe the construction and characterization of recombinant (r), replication-competent forms of rhesus monkey rhadinovirus (RRV), a gamma-2 herpesvirus, containing a near-full-length (nfl) genome of the simian immunodeficiency virus (SIV). A 306-nucleotide deletion in the pol gene rendered this nfl genome replication-incompetent as a consequence of deletion of the active site of the essential reverse transcriptase enzyme...
June 18, 2018: PLoS Pathogens
Louis S Ates, Fadel Sayes, Wafa Frigui, Roy Ummels, Merel P M Damen, Daria Bottai, Marcel A Behr, Jeroen W J van Heijst, Wilbert Bitter, Laleh Majlessi, Roland Brosch
Tuberculosis is the deadliest infectious disease worldwide. Although the BCG vaccine is widely used, it does not efficiently protect against pulmonary tuberculosis and an improved tuberculosis vaccine is therefore urgently needed. Mycobacterium tuberculosis uses different ESX/Type VII secretion (T7S) systems to transport proteins important for virulence and host immune responses. We recently reported that secretion of T7S substrates belonging to the mycobacteria-specific Pro-Glu (PE) and Pro-Pro-Glu (PPE) proteins of the PGRS (polymorphic GC-rich sequences) and MPTR (major polymorphic tandem repeat) subfamilies required both a functional ESX-5 system and a functional PPE38/71 protein for secretion...
June 18, 2018: PLoS Pathogens
Frederico Alisson-Silva, Janet Z Liu, Sandra L Diaz, Lingquan Deng, Mélanie G Gareau, Ronald Marchelletta, Xi Chen, Victor Nizet, Nissi Varki, Kim E Barrett, Ajit Varki
While infectious agents have typical host preferences, the noninvasive enteric bacterium Vibrio cholerae is remarkable for its ability to survive in many environments, yet cause diarrheal disease (cholera) only in humans. One key V. cholerae virulence factor is its neuraminidase (VcN), which releases host intestinal epithelial sialic acids as a nutrition source and simultaneously remodels intestinal polysialylated gangliosides into monosialoganglioside GM1. GM1 is the optimal binding target for the B subunit of a second virulence factor, the AB5 cholera toxin (Ctx)...
June 18, 2018: PLoS Pathogens
Man Shun Fu, Carolina Coelho, Carlos M De Leon-Rodriguez, Diego C P Rossi, Emma Camacho, Eric H Jung, Madhura Kulkarni, Arturo Casadevall
Cryptococcus neoformans is a facultative intracellular pathogen and its interaction with macrophages is a key event determining the outcome of infection. Urease is a major virulence factor in C. neoformans but its role during macrophage interaction has not been characterized. Consequently, we analyzed the effect of urease on fungal-macrophage interaction using wild-type, urease-deficient and urease-complemented strains of C. neoformans. The frequency of non-lytic exocytosis events was reduced in the absence of urease...
June 15, 2018: PLoS Pathogens
Maria Fernanda Laranjeira-Silva, Wanpeng Wang, Tamika K Samuel, Fernando Y Maeda, Vladimir Michailowsky, Iqbal Hamza, Zhongchi Liu, Norma W Andrews
Iron is essential for many cellular processes, but can generate highly toxic hydroxyl radicals in the presence of oxygen. Therefore, intracellular iron accumulation must be tightly regulated, by balancing uptake with storage or export. Iron uptake in Leishmania is mediated by the coordinated action of two plasma membrane proteins, the ferric iron reductase LFR1 and the ferrous iron transporter LIT1. However, how these parasites regulate their cytosolic iron concentration to prevent toxicity remains unknown...
June 15, 2018: PLoS Pathogens
Madushi Wanaguru, David J Barry, Donald J Benton, Nicola J O'Reilly, Kate N Bishop
The murine leukaemia virus (MLV) Gag cleavage product, p12, is essential for both early and late steps in viral replication. The N-terminal domain of p12 binds directly to capsid (CA) and stabilises the mature viral core, whereas defects in the C-terminal domain (CTD) of p12 can be rescued by addition of heterologous chromatin binding sequences (CBSs). We and others hypothesised that p12 tethers the pre-integration complex (PIC) to host chromatin ready for integration. Using confocal microscopy, we have observed for the first time that CA localises to mitotic chromatin in infected cells in a p12-dependent manner...
June 15, 2018: PLoS Pathogens
Eric J G Pollitt, Piotr T Szkuta, Nicola Burns, Simon J Foster
Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections...
June 14, 2018: PLoS Pathogens
Cristina Faralla, Effie E Bastounis, Fabian E Ortega, Samuel H Light, Gabrielle Rizzuto, Salvatorre Nocadello, Wayne F Anderson, Jennifer R Robbins, Julie A Theriot, Anna I Bakardjiev
During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such as Listeria monocytogenes, present a unique opportunity for learning how the placenta carries out its protective function. We previously identified the L. monocytogenes protein Internalin P (InlP) as a secreted virulence factor critical for placental infection. Here, we show that InlP, but not the highly similar L...
May 30, 2018: PLoS Pathogens
Hong-Ru Chen, Chiao-Hsuan Chao, Ching-Chuan Liu, Tzong-Shiann Ho, Huey-Pin Tsai, Guey-Chuen Perng, Yee-Shin Lin, Jen-Ren Wang, Trai-Ming Yeh
Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients...
April 27, 2018: PLoS Pathogens
Quang Tien Phan, Tamara Sipka, Catherine Gonzalez, Jean-Pierre Levraud, Georges Lutfalla, Mai Nguyen-Chi
Understanding the roles of neutrophils and macrophages in fighting bacterial infections is a critical issue in human pathologies. Although phagocytic killing has been extensively studied, little is known about how bacteria are eliminated extracellularly in live vertebrates. We have recently developed an infection model in the zebrafish embryo in which leukocytes cannot reach the injected bacteria. When Escherichia coli bacteria are injected within the notochord, both neutrophils and macrophages are massively recruited during several days, but do not infiltrate the infected tissue presumably because of its tough collagen sheath...
July 2018: PLoS Pathogens
Hsin-Ping Chiu, Han Chiu, Chao-Fu Yang, Yi-Ling Lee, Feng-Lan Chiu, Hung-Chih Kuo, Ren-Jye Lin, Yi-Ling Lin
CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses mainly through RNA degradation, translation inhibition and innate immune responses. So far, only one flavivirus, yellow fever virus, has been reported to be ZAP-resistant. Here, we investigated the antiviral potential of human ZAP (isoform ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). Infection of JEV but not DENV or ZIKV was blocked by ZAP overexpression, and depletion of endogenous ZAP enhanced JEV replication...
July 2018: PLoS Pathogens
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