Deer, predators, and the emergence of Lyme disease

Lyme disease is the most prevalent vector-borne disease in North America, and both the annual incidence and geographic range are increasing. The emergence of Lyme disease has been attributed to a century-long recovery of deer, an important reproductive host for adult ticks. However, a growing body of evidence suggests that Lyme disease risk may now be more dynamically linked to fluctuations in the abundance of small-mammal hosts that are thought to infect the majority of ticks. The continuing and rapid increase in Lyme disease over the past two decades, long after the recolonization of deer, suggests that other factors, including changes in the ecology of small-mammal hosts may be responsible for the continuing emergence of Lyme disease. We present a theoretical model that illustrates how reductions in small-mammal predators can sharply increase Lyme disease risk. We then show that increases in Lyme disease in the northeastern and midwestern United States over the past three decades are frequently uncorrelated with deer abundance and instead coincide with a range-wide decline of a key small-mammal predator, the red fox, likely due to expansion of coyote populations. Further, across four states we find poor spatial correlation between deer abundance and Lyme disease incidence, but coyote abundance and fox rarity effectively predict the spatial distribution of Lyme disease in New York. These results suggest that changes in predator communities may have cascading impacts that facilitate the emergence of zoonotic diseases, the vast majority of which rely on hosts that occupy low trophic levels.     

Helicobacter heilmannii sensu lato: An overview of the infection in humans

Helicobacter heilmannii sensu lato (H. heilmannii s.l.) is a group of gastric non-Helicobacter pylori Helicobacter species that are morphologically indistinguishable from each other. H. heilmannii s.l. infect the stomach of several animals and may have zoonotic potential. Although the prevalence of these infections in humans is low, they are associated with gastric pathology, including mucosa-associated lymphoid tissue lymphoma, making them a significant health issue. Here, the taxonomy, epidemiology, microbiology, diagnosis, and treatment of these infections will be reviewed. The gastric pathology associated with H. heilmannii s.l. infections in humans will also be addressed. Finally, the features of the complete bacterial genomes available and studies on species-specific pathogenesis will be reviewed. The understanding of the mechanisms that underlie gastric disease development mediated by the different bacterial species that constitute H. heilmannii s.l. is essential for developing strategies for prevention and treatment of these infections.     

Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia

The Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents have distinct infection courses, but both require cholesterol for growth. They acquire cholesterol from the environment and process it to form cholesterol glycolipids that are incorporated onto their membranes. To determine whether higher levels of serum cholesterol could enhance the organ burdens of B. burgdorferi and the spirochetemia of B. hispanica in laboratory mice, apolipoprotein E (apoE)-deficient and low-density lipoprotein receptor (LDLR)-deficient mice that produce large amounts of serum cholesterol were infected with both spirochetes. Both apoE- and LDLR-deficient mice infected with B. burgdorferi had an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity of B. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia of B. hispanica. In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice with B. hispanica resulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity with B. hispanica. Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease.Cholesterol is an essential structural component of the cell membrane of vertebrate animals, and it is required for membrane integrity and fluidity. In addition to being a component of the membrane, cholesterol is the precursor of steroid hormones and bile. In eukaryotic cells, cholesterol and sphingolipids are the main components of membrane microdomains known as lipid rafts. These microdomains are characterized as being more tightly packed than the surrounding bilayer and enriched with proteins involved in signaling (1–3).In the bloodstream of humans and other vertebrates, cholesterol is transported in lipoprotein complexes. Apolipoprotein E (apoE) binds cholesterol for transport through the circulatory system as apoE-containing chylomicrons and very-low-density lipoprotein (VLDL) particles. These apoE–cholesterol particles are internalized through the interaction with the low-density lipoprotein receptors (LDLRs). LDLR is one of the cell-surface receptors in cells that binds to apoE to clear the lipoprotein particles from the blood (4). Both apoE-deficient (apoE⁻) and LDLR-deficient (LDLR⁻) mice show elevated serum cholesterol levels and develop atherosclerotic plaques (5, 6). These mice are the most used mouse models for hyperlipidemia and atherosclerosis research.Lyme disease and relapsing-fever Borrelia have very distinct infection courses and niches in the host. In experimental mouse infections, relapsing-fever borreliae multiply in the blood, reaching high numbers (spirochetemia), until antibodies, mostly of the IgM class, clear the first peak, which is followed by several smaller peaks of antigenically variable organisms. Therefore, infection with Borrelia hispanica, an agent of relapsing fever, can be monitored by direct enumeration of the spirochetes from blood. Conversely, Borrelia burgdorferi, the agent of Lyme disease, does not have an overt spirochetemia, and it is difficult to detect in blood, but invades tissues including the skin, heart, and joints, where it can be quantified by molecular methods.The outer membrane of Borrelia is composed of phospholipids, including phosphatidylcholine and phosphatidylglycerol (7). The borreliae also have cholesterol glycolipids: cholesteryl 6-O-acyl-β-d-galactopyranoside and cholesteryl-β-d-galacto-pyranoside in B. burgdorferi; and 6-O-acylated cholesteryl β-d-glucopyranoside and cholesteryl β-d-glucopyranoside in relapsing-fever Borrelia. They also have noncholesterol glycolipids, monogalactosyl-diacylglycerol in B. burgdorferi and monoglucosyl-diacylglycerol in relapsing-fever Borrelia, as well as many lipoproteins (7–15). The presence of cholesterol is not common among prokaryotes, but it is increasingly being reported in bacterial pathogens other than Borrelia spp., including species of Helicobacter, Mycoplasma, Ehrlichia, Anaplasma, and Brachyspira (16–20).Recently, we demonstrated that B. burgdorferi acquires cholesterol from host cells (21). Cholesterol can remain free in the membrane or can be internalized and glycosylated by undetermined enzymes (22). Subsequently, cholesterol glycolipids are exported to the membrane, where they form lipid rafts (23, 24) that are cholesterol-rich domains with a selective presence of lipoproteins (25). The borreliae require cholesterol for growth and have to recruit it from the host because they cannot synthesize it. In this study, our goal was to determine whether serum hypercholesterolemia could lead to greater yields of bacteria in vivo by providing added cholesterol in a manner that would be accessible to the spirochetes. To this end, we infected apoE⁻ and LDLR⁻ mice that have increased levels of serum cholesterol with B. burgdorferi and B. hispanica. From these experiments, we concluded that infection of apoE⁻ and LDLR⁻ mice with B. burgdorferi resulted in greater severity of infection. In contrast, immune dysfunctions associated with deficiencies in the apoE⁻ mouse model, and not high cholesterol levels, led to increased severity in infection with relapsing-fever Borrelia.     

Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin

Adaptive modifications of heteromeric proteins may involve genetically based changes in single subunit polypeptides or parallel changes in multiple genes that encode distinct, interacting subunits. Here we investigate these possibilities by conducting a combined evolutionary and functional analysis of duplicated globin genes in natural populations of deer mice (Peromyscus maniculatus) that are adapted to different elevational zones. A multilocus analysis of nucleotide polymorphism and linkage disequilibrium revealed that high-altitude adaptation of deer mouse hemoglobin involves parallel functional differentiation at multiple unlinked gene duplicates: two α-globin paralogs on chromosome 8 and two β-globin paralogs on chromosome 1. Differences in O₂-binding affinity of the alternative β-chain hemoglobin isoforms were entirely attributable to allelic differences in sensitivity to 2,3-diphosphoglycerate (DPG), an allosteric cofactor that stabilizes the low-affinity, deoxygenated conformation of the hemoglobin tetramer. The two-locus β-globin haplotype that predominates at high altitude is associated with suppressed DPG-sensitivity (and hence, increased hemoglobin-O₂ affinity), which enhances pulmonary O₂ loading under hypoxia. The discovery that allelic differences in DPG-sensitivity contribute to adaptive variation in hemoglobin–O₂ affinity illustrates the value of integrating evolutionary analyses of sequence variation with mechanistic appraisals of protein function. Investigation into the functional significance of the deer mouse β-globin polymorphism was motivated by the results of population genetic analyses which revealed evidence for a history of divergent selection between elevational zones. The experimental measures of O₂-binding properties corroborated the tests of selection by demonstrating a functional difference between the products of alternative alleles.     

Helicobacter pylori:A chameleon-like approach to life

Helicobacter pylori(H.pylori)is widely adaptable for colonization in human stomachs in more than half of the world’s population.The microorganism is characterized by an unusual capability of arranging itself in both genotypic and phenotypic ways.Stressing conditions,including antimicrobial agents in sub-inhibitory concentrations,facilitate entering the viable but nonculturable state in which bacterial cells acquire the coccoid form.This morphotype represents an important strategy for bacterial survival in unsuitable conditions and also allows escape from the immune system.H.pylori is capable of forming biofilm outside and inside the host.For the bacterial population,the sessile growth mode represents an ideal environment for gene rearrangement,as it allows the acquiring of important tools aimed to improve bacterial"fitness"and species preservation.Biofilm formation in H.pylori in the human host also leads to recalcitrance to antibiotic treatment,thus hampering eradication.These lifestyle changes of H.pylori allow for a"safe haven"for its survival and persistence according to different ecological niches,and strongly emphasize the need for careful H.pylori surveillance to improve management of the infection.     

Zoonotic infections in communities of the James Bay Cree territory: An overview of seroprevalence

The Cree communities of James Bay are at risk for contracting infectious diseases transmitted by wildlife. Data from serological testing for a range of zoonotic infections performed in the general population (six communities), or trappers and their spouses (one community), were abstracted from four population-based studies conducted in Cree territory (Quebec) between 2005 and 2009. Evidence of exposure to Trichinella species, Toxoplasma gondii, Toxocara canis, Echinococcus granulosus, Leptospira species, Coxiella burnetii and Francisella tularensis was verified in all communities, whereas antibodies against Sin Nombre virus and California serogroup viruses (Jamestown Canyon and snowshoe hare viruses) were evaluated in three and six communities, respectively. Seroprevalence varied widely among communities: snowshoe hare virus (1% to 42%), F tularensis (14% to 37%), Leptospira species (10% to 27%), Jamestown Canyon virus (9% to 24%), C burnetii (0% to 18%), T gondii (4% to 12%), T canis (0% to 10%), E granulosus (0% to 4%) and Trichinella species (0% to 1%). No subject had serological evidence of Sin Nombre virus exposure. These data suggest that large proportions of the Cree population have been exposed to at least one of the targeted zoonotic agents. The Cree population, particularly those most heavily exposed to fauna, as well as the medical staff living in these regions, should be aware of these diseases. Greater awareness would not only help to decrease exposures but would also increase the chance of appropriate diagnostic testing.     

Helicobacter pylori and its reservoirs: A correlation with the gastric infection

Helicobacter pylori(H. pylori) has long been found to cause gastric diseases such as gastritis, gastric ulcers and gastric cancer. The transmission medium of this bacterium has yet to be determined, though several studies have speculated that the oral cavity is a reservoir for H. pylori. Others have also reported that the oral cavity may be a source of both transmission and gastric reinfection; however, such results are controversial. We reviewed the literature and selected studies that report an association among H. pylori detections in the oral cavity(dental plaque, saliva, tongue, tonsil tissue, root canals, oral mucosa) in humans and in animals, as well as in the human stomach. The oral cavity may be considered the main reservoir for H. pylori. There are a correlations between H. pylori infection in the oral cavity and periodontal disease, oral tissue inflammation, H. pylori transmission, and gastric reinfection. We believe that the mouth is a reservoir and that it plays a crucial role in both H. pylori transmission and gastric infection.     

Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis

Under conventional conditions, mice deficient in core 1-derived O-glycans (TM-IEC C1galt1^−/−), which have a defective mucus layer, experienced spontaneous inflammation of the colon. Analysis of fecal bacterial populations by pyrosequencing of 16S rRNA gene showed that disease in conventional TM-IEC C1galt1^−/− was associated with shifts in the microbiota manifested by increases in Lactobacillus and Clostridium species, and decreases in unclassified Ruminococcaceae and Lachnospiraceae. Under germ-free (GF) conditions, TM-IEC C1galt1^−/− presented decreased goblet cells, but did not develop inflammation. Monoassociation of GF TM-IEC C1galt1^−/− revealed that bacterial species differ significantly in their ability to induce inflammatory changes. Bacteroides thetaiotaomicron caused inflammation, while Lactobacillus johnsonii (enriched during colitis) did not. These observations demonstrate that not all microbiota shifts that correlate with disease contribute to pathogenesis.     

Laboratory Biosafety: Sentinel surveillance of Lyme disease risk in Canada, 2019: Results from the first year of the Canadian Lyme Sentinel Network (CaLSeN)

BackgroundLyme disease is an emerging vector-borne zoonotic disease of increasing public health importance in Canada. As part of its mandate, the Canadian Lyme Disease Research Network (CLyDRN) launched a pan-Canadian sentinel surveillance initiative, the Canadian Lyme Sentinel Network (CaLSeN), in 2019.ObjectivesTo create a standardized, national sentinel surveillance network providing a real-time portrait of the evolving environmental risk of Lyme disease in each province.MethodsA multicriteria decision analysis (MCDA) approach was used in the selection of sentinel regions. Within each sentinel region, a systematic drag sampling protocol was performed in selected sampling sites. Ticks collected during these active surveillance visits were identified to species, and Ixodes spp. ticks were tested for infection with Borrelia burgdorferi, Borrelia miyamotoi, Anaplasma phagocytophilum, Babesia microti and Powassan virus.ResultsIn 2019, a total of 567 Ixodes spp. ticks (I. scapularis [n=550]; I. pacificus [n=10]; and I. angustus [n=7]) were collected in seven provinces: British Columbia, Manitoba, Ontario, Québec, New Brunswick, Nova Scotia and Prince Edward Island. The highest mean tick densities (nymphs/100 m²) were found in sentinel regions of Lunenburg (0.45), Montréal (0.43) and Granby (0.38). Overall, the Borrelia burgdorferi prevalence in ticks was 25.2% (0%–45.0%). One I. angustus nymph from British Columbia was positive for Babesia microti, a first for the province. The deer tick lineage of Powassan virus was detected in one adult I. scapularis in Nova Scotia.ConclusionCaLSeN provides the first coordinated national active surveillance initiative for tick-borne disease in Canada. Through multidisciplinary collaborations between experts in each province, the pilot year was successful in establishing a baseline for Lyme disease risk across the country, allowing future trends to be detected and studied.     

Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: The role of genetics

Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.     

Interspecific introgressive origin of genomic diversity in the house mouse

We report on a genome-wide scan for introgression between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus), using samples from the ranges of sympatry and allopatry in Africa and Europe. Our analysis reveals wide variability in introgression signatures along the genomes, as well as across the samples. We find that fewer than half of the autosomes in each genome harbor all detectable introgression, whereas the X chromosome has none. Further, European mice carry more M. spretus alleles than the sympatric African ones. Using the length distribution and sharing patterns of introgressed genomic tracts across the samples, we infer, first, that at least three distinct hybridization events involving M. spretus have occurred, one of which is ancient, and the other two are recent (one presumably due to warfarin rodenticide selection). Second, several of the inferred introgressed tracts contain genes that are likely to confer adaptive advantage. Third, introgressed tracts might contain driver genes that determine the evolutionary fate of those tracts. Further, functional analysis revealed introgressed genes that are essential to fitness, including the Vkorc1 gene, which is implicated in rodenticide resistance, and olfactory receptor genes. Our findings highlight the extent and role of introgression in nature and call for careful analysis and interpretation of house mouse data in evolutionary and genetic studies.Classical laboratory mouse strains, as well as newly established wild-derived ones, are widely used by geneticists for answering a diverse array of questions (1). Understanding the genome contents and architecture of these strains is important for studies of natural variation and complex traits, as well as evolutionary studies in general (2). Mus spretus, a sister species of Mus musculus, impacts the findings in M. musculus investigations for at least two reasons. First, it was deliberately interbred with laboratory M. musculus strains to introduce genetic variation (3). Second, Mus musculus domesticus is partially sympatric (naturally cooccurring) with M. spretus (Fig. 1).Open in a separate windowFig. 1.Species ranges and samples used in our study. The species range of M. spretus is shown in green (4), and the species range of M. m. domesticus includes the blue regions, the range of M. spretus, and beyond (1). M. m. domesticus and M. spretus samples were obtained from locations marked with red circles and purple diamonds, respectively. The samples originated from within and outside the area of sympatry between the two species. (SI Appendix, Table S1, provides additional details about the samples used in our study.)Recent studies have examined admixture between subspecies of house mice (5–8), but have not studied introgression with M. spretus. In at least one case (5), the introgressive descent of the mouse genome was hidden due to data postprocessing that masked introgressed genomic regions as missing data. In another study reporting whole-genome sequencing of 17 classical laboratory strains (6), M. spretus was used as an outgroup for phylogenetic analysis. The authors were surprised to find that 12.1% of loci failed to place M. spretus as an outgroup to the M. musculus clade. The authors concluded that M. spretus was not a reliable outgroup but did not pursue their observation further. On the other hand, in a 2002 study (9), Orth et al. compiled data on allozyme, microsatellite, and mitochondrial variation in house mice from Spain (sympatry) and nearby countries in western and central Europe. Interestingly, allele sharing between the species was observed in the range of sympatry but not outside in the range of allopatry. The studies demonstrated the possibility of natural hybridization between these two sister species. Further, the study of Song et al. (10) demonstrated a recent adaptive introgression from M. spretus into some M. m. domesticus populations in the wild, involving the vitamin K epoxide reductase subcomponent 1 (Vkorc1) gene, which was later shown to be more widespread in Europe, albeit geographically restricted to parts of southwestern and central Europe (11).Major, unanswered questions arise from these studies. First, is the vicinity around the Vkorc1 gene an isolated case of adaptive introgression in the house mouse genome, or do many other such regions exist? Second, is introgression between M. spretus and M. m. domesticus common outside the range of sympatry? Third, have there been other hybridization events, and, in particular, more ancient ones? Fourth, what role do introgressed genes, and, more generally, genomic regions, play?To investigate these open questions, we used genome-wide variation data from 20 M. m. domesticus samples (wild and wild-derived) from the ranges of sympatry and allopatry, as well as two M. spretus samples. For detecting introgression, we used PhyloNet-HMM (12), a newly developed method for statistical inference of introgression in genomes while accounting for other evolutionary processes, most notably incomplete lineage sorting (ILS).Our analysis provides answers to the questions posed above. First, we find signatures of introgression between M. spretus and each of the M. m. domesticus samples. The amount of introgression varies across the autosomes of each genome, with a few chromosomes harboring all detectable introgression, and most of the chromosomes have none. We detected no introgression on the X chromosome. Further, the amount of introgression varied widely across the samples. Our analyses demonstrate introgression outside the range of sympatry. In fact, our results show more signatures of introgression in the genomes of allopatric samples from Europe than in sympatric samples from Africa. For the third question, we used the length distribution and sharing patterns of introgressed regions across the samples to show support for at least three hybridization events: an ancient hybridization event that predates the colonization of Europe by M. m. domesticus and two more recent events, one of which presumably occurred about 50 y ago and is related to warfarin resistance selection (10). For the fourth question, our functional analysis of the introgressed genes shows enrichment for certain categories, most notably olfaction—an essential trait for the fitness of rodents. Understanding the genomic architecture and evolutionary history of the house mouse has broad implications on various aspects of evolutionary, genetic, and biomedical research endeavors that use this model organism. The PhyloNet-HMM method (12) can be used to detect introgression in other eukaryotic species, further broadening the impact of this work.     

Gene-air pollution interaction and cardiovascular disease: a review

Genetic susceptibility is likely to play a role in response to air pollution. Hence, gene-environment interaction studies can be a tool for exploring the mechanisms and the importance of the pathway in the association between air pollution and a cardiovascular outcome.In this article, we present a systematic review of the studies that have examined gene-environment interactions in relation to the cardiovascular health effects of air pollutants.We identified 16 articles meeting our search criteria. Of these studies, most have focused on individual functional polymorphisms or individual candidate genes. Moreover, they were all based on 3 study populations that have been extensively investigated in relation to air pollution effects: the Normative Aging Study, Air Pollution and Inflammatory Response in Myocardial Infarction Survivors: Gene-Environment Interaction in a High Risk Group, and Multiethnic Study of Atherosclerosis.In conclusions, the studies differed substantially in both the cardiovascular outcomes examined and the polymorphisms examined, so there is little confirmation of results across cohorts. Gene-environment interaction studies can help explore the mechanisms and the potential pathway in the association between air pollution and a cardiovascular outcome; replication of findings and studies involving multiple cohorts would be needed to draw stronger conclusions.     

African apes as reservoirs of Plasmodium falciparum and the origin and diversification of the Laverania subgenus

We investigated two mitochondrial genes (cytb and cox1), one plastid gene (tufA), and one nuclear gene (ldh) in blood samples from 12 chimpanzees and two gorillas from Cameroon and one lemur from Madagascar. One gorilla sample is related to Plasmodium falciparum, thus confirming the recently reported presence in gorillas of this parasite. The second gorilla sample is more similar to the recently defined Plasmodium gaboni than to the P. falciparum–Plasmodium reichenowi clade, but distinct from both. Two chimpanzee samples are P. falciparum. A third sample is P. reichenowi and two others are P. gaboni. The other chimpanzee samples are different from those in the ape clade: two are Plasmodium ovale, and one is Plasmodium malariae. That is, we have found three human Plasmodium parasites in chimpanzees. Four chimpanzee samples were mixed: one species was P. reichenowi; the other species was P. gaboni in three samples and P. ovale in the fourth sample. The lemur sample, provisionally named Plasmodium malagasi, is a sister lineage to the large cluster of primate parasites that does not include P. falciparum or ape parasites, suggesting that the falciparum + ape parasite cluster (Laverania clade) may have evolved from a parasite present in hosts not ancestral to the primates. If malignant malaria were eradicated from human populations, chimpanzees, in addition to gorillas, might serve as a reservoir for P. falciparum.     

Edwardsiella tarda bacteremia. A rare but fatal water- and foodborne infection: Review of the literature and clinical cases from a single centre

BACKGROUND:Edwardsiella tarda bacteremia (ETB) can be a fatal disease in humans.OBJECTIVES:To determine the significant risk factors associated with death caused by ETB, and to examine the geographical, seasonal, environmental and dietary factors of the disease.METHODS:A retrospective, observational, case control study was performed. The PubMed MEDLINE and Japanese Medical Abstract Society (www.jamas.or.jp) databases were searched for ETB case reports and meeting abstracts. In additon, retrospective chart reviews of patients with ETB at the Tokyo Women’s Medical University Hospital (Tokyo, Japan) were conducted to evaluate the risk factors associated with death using multivariate analyses.RESULTS:The literature search yielded 46 publications, comprising 72 cases from the English (n=30), French (n=1), Spanish (n=1) and Japanese (n=14) literature. Five cases at the Tokyo Women’s Medical University Hospital were also included. Of the included 77 cases, the mean age was 61 years and 39% of patients were female; 77.2% of the cases occurred between June and November, and 45.5% were reported in Japan. Dietary factors (raw fish/meat exposure) were reported for 10.4% of patients and 12.9% reported environmental (ie, brackish water) exposure. The overall mortality rate was 44.6%; however, this rate increased to 61.1% for ETB patients with soft tissue infections. Liver cirrhosis was determined to be an independent risk factor associated with death (OR 12.0 [95% CI 2.46 to 58.6]; P=0.00213) using multivariate analyses.DISCUSSION:To our knowledge, the present analysis was the first and largest multi-language review of ETB. Clinical characteristics of ETB resemble those of Aeromonas, typhoid fever and Vibrio vulnificus infections, in addition to sharing similar risk factors.CONCLUSION:ETB should be categorized as a severe food- and waterborne infection, which results in high mortality for patients with liver cirrhosis.     

Usutu Virus: An Emerging Flavivirus in Europe

Usutu virus (USUV) is an African mosquito-borne flavivirus belonging to the Japanese encephalitis virus serocomplex. USUV is closely related to Murray Valley encephalitis virus, Japanese encephalitis virus, and West Nile virus. USUV was discovered in South Africa in 1959. In Europe, the first true demonstration of circulation of USUV was reported in Austria in 2001 with a significant die-off of Eurasian blackbirds. In the subsequent years, USUV expanded to neighboring countries, including Italy, Germany, Spain, Hungary, Switzerland, Poland, England, Czech Republic, Greece, and Belgium, where it caused unusual mortality in birds. In 2009, the first two human cases of USUV infection in Europe have been reported in Italy, causing meningoencephalitis in immunocompromised patients. This review describes USUV in terms of its life cycle, USUV surveillance from Africa to Europe, human cases, its cellular tropism and pathogenesis, its genetic relationship with other flaviviruses, genetic diversity among USUV strains, its diagnosis, and a discussion of the potential future threat to Asian countries.     

NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection

The human pathogens enteropathogenic (EPEC) and enterohemorrhagic Escherichia coli and the related mouse pathogen Citrobacter rodentium subvert a variety of host cell signaling pathways via their plethora of type III secreted effectors, including triggering of an early apoptotic response. EPEC-infected cells do not develop late apoptotic symptoms, however. In this study we demonstrate that the NleH family effectors, homologs of the Shigella effector kinase OspG, blocks apoptosis. During EPEC infection, NleH effectors inhibit elevation of cytosolic Ca²⁺ concentrations, nuclear condensation, caspase-3 activation, and membrane blebbing and promote cell survival. NleH1 alone is sufficient to prevent procaspase-3 cleavage induced by the proapoptotic compounds staurosporine, brefeldin A, and tunicamycin. Using C. rodentium, we found that NleH inhibits procaspase-3 cleavage at the bacterial attachment sites in vivo. A yeast two-hybrid screen identified the endoplasmic reticulum six-transmembrane protein Bax inhibitor-1 (BI-1) as an NleH-interacting partner. We mapped the NleH-binding site to the N-terminal 40 amino acids of BI-1. Knockdown of BI-1 resulted in the loss of NleH’s antiapoptotic activity. These results indicate that NleH effectors are inhibitors of apoptosis that may act through BI-1 to carry out their cytoprotective function.     

Rapid changes in the gut microbiome during human evolution

Humans are ecosystems containing trillions of microorganisms, but the evolutionary history of this microbiome is obscured by a lack of knowledge about microbiomes of African apes. We sequenced the gut communities of hundreds of chimpanzees, bonobos, and gorillas and developed a phylogenetic approach to reconstruct how present-day human microbiomes have diverged from those of ancestral populations. Compositional change in the microbiome was slow and clock-like during African ape diversification, but human microbiomes have deviated from the ancestral state at an accelerated rate. Relative to the microbiomes of wild apes, human microbiomes have lost ancestral microbial diversity while becoming specialized for animal-based diets. Individual wild apes cultivate more phyla, classes, orders, families, genera, and species of bacteria than do individual humans across a range of societies. These results indicate that humanity has experienced a depletion of the gut flora since diverging from Pan.The human microbiome is shaped by host genetics, environment, and lifestyle (1–3); thus, humanity''s unique evolutionary and cultural histories must have altered our associations with microorganisms (4). Despite intensive investigation of the microbiomes of humans spanning a range of geographic locations and cultures (5–7), how the composition of the microbiome has changed since humans diverged from other species, and since human populations diverged from one another, remains unclear, owing to a lack of knowledge about the microbiomes of ancestral hominid populations.Understanding how the composition of the human microbiome has changed over evolutionary time requires the inclusion of the microbiomes of phylogenetic outgroups (i.e., the African apes) into analyses of human microbiomes. Previous comparisons of the gut microbiomes of humans and the African apes have been restricted to just a few individuals per host species (8), precluding detection of the precise compositional differences that distinguish the microbiomes of the host species. Comparing the microbiomes of populations of chimpanzees, bonobos, gorillas, and humans while considering the phylogenetic relatedness among the hosts can reveal how the composition of the microbiome has changed since the host species diversified.Here we used a phylogenetic approach to identify the shifts in the composition of the microbiome that occurred along the lineages leading to the extant species of Homo and Pan. This analysis shows that humans across a range of cultures and geographies harbor microbiomes that are disproportionately divergent from those within wild apes. In particular, among the living hominid species, humans harbor uncharacteristically low levels of microbial diversity within their gut microbiomes.