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Proceedings of the National Academy of Sciences

Tue, 11/13/2018 - 15:16
Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule...
Tue, 11/06/2018 - 13:41
The gut metabolic landscape is complex and is influenced by the microbiota, host physiology, and enteric pathogens. Pathogens have to exquisitely monitor the biogeography of the gastrointestinal tract to find a suitable niche for colonization. To dissect the important metabolic pathways that influence virulence of enterohemorrhagic Escherichia coli (EHEC), we...
Tue, 10/02/2018 - 12:06
Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar...
Tue, 09/18/2018 - 12:52
Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other...
Tue, 09/18/2018 - 12:52
Diarrheal diseases are still one of the biggest global health burdens. According to the World Health Organization (WHO), diarrhea ranks as the ninth cause of death worldwide, being the fourth among children. One of the most prevalent diarrheagenic pathogens is enterotoxigenic Escherichia coli (ETEC) (1). ETEC’s classic virulence mechanisms include...
Tue, 08/07/2018 - 14:31
Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD...
Tue, 07/31/2018 - 12:01
The type 6 secretion system (T6SS) is a nanomachine used by many Gram-negative bacteria, including Vibrio cholerae, to deliver toxic effector proteins into adjacent eukaryotic and bacterial cells. Because the activity of the T6SS is dependent on direct contact between cells, its activity is limited to bacteria growing on solid...
Tue, 07/24/2018 - 13:56
The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of...
Tue, 07/10/2018 - 12:36
Initial attachment and subsequent colonization of the intestinal epithelium comprise critical events allowing enteric pathogens to survive and express their pathogenesis. In enterotoxigenic Escherichia coli (ETEC), these are mediated by a long proteinaceous fiber termed type IVb pilus (T4bP). We have reported that the colonization factor antigen/III (CFA/III), an operon-encoded...
Tue, 07/03/2018 - 16:26
While the structure and regulatory networks that govern type-six secretion system (T6SS) activity of Vibrio cholerae are becoming increasingly clear, we know less about the role of T6SS in disease. Under laboratory conditions, V. cholerae uses T6SS to outcompete many Gram-negative species, including other V. cholerae strains and human commensal...
Tue, 06/26/2018 - 12:16
Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method,...
Tue, 06/26/2018 - 12:16
Sensing and responding to environmental changes is essential for bacteria to adapt and thrive, and nucleotide-derived second messengers are central signaling systems in this process. The most recently identified bacterial cyclic dinucleotide second messenger, 3′, 3′-cyclic GMP-AMP (cGAMP), was first discovered in the El Tor biotype of Vibrio cholerae. The...
Tue, 05/22/2018 - 12:06
AGRICULTURAL SCIENCES Correction for “Ion-beam irradiation, gene identification, and marker-assisted breeding in the development of low-cadmium rice,” by Satoru Ishikawa, Yasuhiro Ishimaru, Masato Igura, Masato Kuramata, Tadashi Abe, Takeshi Senoura, Yoshihiro Hase, Tomohito Arao, Naoko K. Nishizawa, and Hiromi Nakanishi, which was first published November 6, 2012; 10.1073/pnas.1211132109 (Proc...
Tue, 05/22/2018 - 12:06
Capsules are surface layers of hydrated capsular polysaccharides (CPSs) produced by many bacteria. The human pathogen Salmonella enterica serovar Typhi produces “Vi antigen” CPS, which contributes to virulence. In a conserved strategy used by bacteria with diverse CPS structures, translocation of Vi antigen to the cell surface is driven by...
Tue, 04/17/2018 - 14:36
Host-associated microbiota help defend against bacterial pathogens; however, the mechanisms by which pathogens overcome this defense remain largely unknown. We developed a zebrafish model and used live imaging to directly study how the human pathogen Vibrio cholerae invades the intestine. The gut microbiota of fish monocolonized by symbiotic strain Aeromonas...
Tue, 04/17/2018 - 14:36
Our studies of the SNP rs8060947 determine that the A allele is associated with increased invasion of Salmonella enterica serovar Typhi and increased susceptibility to typhoid fever (1). Gilchrist et al. (2) now provide evidence that the A allele is also associated with increased risk for bacteremia, and the association...
Tue, 04/17/2018 - 14:36
Performing a genome-wide association study of Salmonella enterica serovar Typhi (S. Typhi) invasion, Alvarez et al. (1) identify a trait-associated SNP, rs8060947, in VAC14. rs8060947 is an expression quantitative trait locus for VAC14 RNA expression, and carriage of the A allele is associated with reduced VAC14 RNA and protein expression,...
Tue, 03/13/2018 - 13:26
Salmonella enterica serovar Typhimurium ST313 is a relatively newly emerged sequence type that is causing a devastating epidemic of bloodstream infections across sub-Saharan Africa. Analysis of hundreds of Salmonella genomes has revealed that ST313 is closely related to the ST19 group of S. Typhimurium that cause gastroenteritis across the world....
Tue, 03/06/2018 - 12:21
The facultative human pathogen Vibrio cholerae changes its transcriptional profile upon oral ingestion by the host to facilitate survival and colonization fitness. Here, we used a modified version of recombination-based in vivo expression technology to investigate gene silencing during the in vivo passage, which has been understudied. Using a murine...
Tue, 12/19/2017 - 13:41
In a pet food factory in Reno, NV, researchers from IBM Research and Mars, Inc. are conducting an experiment that may someday revolutionize food safety. For more than two years, they’ve taken regular samples of poultry meal—a protein-rich mash of chicken parts—as it enters the factory on its way to...
Tue, 11/28/2017 - 13:26
Bacterial cells modulate transcription in response to changes in iron availability. The ferric uptake regulator (Fur) senses intracellular iron availability and plays a central role in maintaining iron homeostasis in Bacillus subtilis. Here we utilized FrvA, a high-affinity Fe2+ efflux transporter from Listeria monocytogenes, as an inducible genetic tool to...
Tue, 09/19/2017 - 12:06
Campylobacter jejuni, a leading cause of bacterial gastroenteritis, is naturally competent. Like many competent organisms, C. jejuni restricts the DNA that can be used for transformation to minimize undesirable changes in the chromosome. Although C. jejuni can be transformed by C. jejuni-derived DNA, it is poorly transformed by the same...
Tue, 09/19/2017 - 12:06
Heavy metals from urban runoff preserved in sedimentary deposits record long-term economic and industrial development via the expansion and contraction of a city’s infrastructure. Lead concentrations and isotopic compositions measured in the sediments of the harbor of Ostia—Rome’s first harbor—show that lead pipes used in the water supply networks of...
Tue, 09/12/2017 - 16:40
The enteroinvasive bacterium Shigella is a facultative intracellular bacterium known, in vitro, to invade a large diversity of cells through the delivery of virulence effectors into the cell cytoplasm via a type III secretion system (T3SS). Here, we provide evidence that the injection of T3SS effectors does not necessarily result...
Tue, 09/12/2017 - 16:40
Genetic variant tied to risk of typhoid fever Salmonella bacteria. Image courtesy of Flickr/National Institute of Allergy and Infectious Diseases. Worldwide, Salmonella enterica serovar Typhi (S. Typhi) causes around 20 million typhoid infections every year, and 1–5% of infected individuals chronically carry the pathogen, notable among which is the storied...
Tue, 09/05/2017 - 12:50
Picornaviruses use internal ribosome entry sites (IRESs) to translate their genomes into protein. A typical feature of these IRESs is their ability to bind directly to the eukaryotic initiation factor (eIF) 4G component of the eIF4F cap-binding complex. Remarkably, the hepatitis A virus (HAV) IRES requires eIF4E for its translation,...
Tue, 08/29/2017 - 12:15
Cyclic di-3′,5′-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism in Listeria monocytogenes by inhibiting its pyruvate carboxylase (LmPC), a biotin-dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT)...
Tue, 07/11/2017 - 12:59
Trained in both human medical and veterinary sciences, Xiang-Jin Meng has made numerous contributions to the field of comparative viral pathogenesis. His achievements concerning emerging, reemerging, and zoonotic viral diseases include the discovery of swine and avian hepatitis E viruses (HEV) and the invention of a commercial vaccine against porcine...
Tue, 06/27/2017 - 14:09
Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several...
Tue, 06/20/2017 - 12:04
The Picornaviridae are a diverse family of RNA viruses including many pathogens of medical and veterinary importance. Classically considered “nonenveloped,” recent studies show that some picornaviruses, notably hepatitis A virus (HAV; genus Hepatovirus) and some members of the Enterovirus genus, are released from cells nonlytically in membranous vesicles. To better...
Tue, 06/13/2017 - 12:29
Listeria monocytogenes is a common food-borne pathogen that can disseminate from the intestine and infect multiple organs. Here, we used sequence tag-based analysis of microbial populations (STAMP) to investigate L. monocytogenes population dynamics during infection. We created a genetically barcoded library of murinized L. monocytogenes and then used deep sequencing...
Tue, 05/30/2017 - 12:39
XIAP-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human neoplasms. However, the molecular mechanism underlying its proapoptotic function remains largely undefined. Here, we report that XAF1 induction by heavy metals triggers an apoptotic switch of stress response by destabilizing metallothionein 2A (MT2A). XAF1 directly...
Tue, 04/18/2017 - 12:47
Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB1) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB1-induced HCCs are poorly understood. Herein, it...
Tue, 04/11/2017 - 13:39
Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need...
Tue, 02/28/2017 - 11:40
The toxigenic classical and El Tor biotype Vibrio cholerae serogroup O1 strains are generated by lysogenization of host-type–specific cholera toxin phages (CTX phages). Experimental evidence of the replication and transmission of an El Tor biotype-specific CTX phage, CTX-1, has explained the evolution of V. cholerae El Tor biotype strains. The...
Tue, 01/24/2017 - 12:24
Hepatitis A virus (HAV) infects ∼1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10,...
Tue, 01/17/2017 - 15:48
CELL BIOLOGY Correction for “DNA polymerase ζ limits chromosomal damage and promotes cell survival following aflatoxin exposure,” by Ying-Chih Lin, Nichole Owen, Irina G. Minko, Sabine S. Lange, Liang Li, Michael P. Stone, Richard D. Wood, Amanda K. McCullough, and R. Stephen Lloyd, which appeared in issue 48, November 29,...
Tue, 01/10/2017 - 13:16
Domoic acid is a potent neurotoxin produced by certain marine microalgae that can accumulate in the foodweb, posing a health threat to human seafood consumers and wildlife in coastal regions worldwide. Evidence of climatic regulation of domoic acid in shellfish over the past 20 y in the Northern California Current...
Tue, 12/27/2016 - 13:37
In Salmonella enterica serovar Typhimurium, Mg2+ limitation induces transcription of the mgtA Mg2+ transport gene, but the mechanism involved is unclear. The 5′ leader of the mgtA mRNA contains a 17-codon, proline-rich ORF, mgtL, whose translation regulates the transcription of mgtA [Park S-Y et al. (2010) Cell 142:737–748]. Rapid translation...
Tue, 12/20/2016 - 13:10
Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could...
Tue, 12/06/2016 - 12:51
The study of the isotopic fractionation of endogen elements and toxic heavy metals in living organisms for biomedical applications, and for metabolic and toxicological studies, is a cutting-edge research topic. This paper shows that human neuroblastoma cells incorporated small amounts of uranium (U) after exposure to 10 µM natural U,...
Tue, 11/29/2016 - 11:48
Vibrio cholerae has caused seven cholera pandemics since 1817, imposing terror on much of the world, but bacterial strains are currently only available for the sixth and seventh pandemics. The El Tor biotype seventh pandemic began in 1961 in Indonesia, but did not originate directly from the classical biotype sixth-pandemic...
Tue, 11/29/2016 - 11:48
Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B1 (AFB1) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB1-N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening...
Tue, 10/25/2016 - 13:24
All of the heme-degrading enzymes that have been characterized to date require molecular oxygen as a cosubstrate. Escherichia coli O157:H7 has been shown to express heme uptake and transport proteins, as well as use heme as an iron source. This enteric pathogen colonizes the anaerobic space of the lower intestine...
Tue, 10/18/2016 - 12:32
The rise of inorganic–biological hybrid organisms for solar-to-chemical production has spurred mechanistic investigations into the dynamics of the biotic–abiotic interface to drive the development of next-generation systems. The model system, Moorella thermoacetica–cadmium sulfide (CdS), combines an inorganic semiconductor nanoparticle light harvester with an acetogenic bacterium to drive the...
Tue, 10/04/2016 - 13:10
Sequence analyses of pathogen genomes facilitate the tracking of disease outbreaks and allow relationships between strains to be reconstructed and virulence factors to be identified. However, these methods are generally used after an outbreak has happened. Here, we show that support vector machine analysis of bovine E. coli O157 isolate...
Tue, 09/20/2016 - 11:46
Infections due to clonal expansion of highly virulent bacterial strains are clear and present threats to human and animal health. Association of genetic changes with disease is now a routine, but identification of causative mutations that enable disease remains difficult. Campylobacter jejuni is an important zoonotic pathogen transmitted to humans...
Tue, 09/06/2016 - 12:56
Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small...
Tue, 07/26/2016 - 13:56
Memory γδ T cells are important for the clearance of Listeria monocytogenes infection in the intestinal mucosa. However, the mechanisms by which memory γδ T cells provide protection against secondary oral infection are poorly understood. Here we used a recombinant strain of L. monocytogenes that efficiently invades the intestinal epithelium...
Tue, 07/12/2016 - 14:10
It is estimated that ∼2.7 million tons poly(carbonate)s (PCs) are produced annually worldwide. In 2008, retailers pulled products from store shelves after reports of bisphenol A (BPA) leaching from baby bottles, reusable drink bottles, and other retail products. Since PCs are not typically recycled, a need for the repurposing of...

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