Histamine 1 Receptor Blockade Enhances Eosinophil-Mediated Clearance of Adult Filarial Worms

Filariae are tissue-invasive nematodes that cause diseases such as elephantiasis and river blindness. The goal of this study was to characterize the role of histamine during Litomosoides sigmodontis infection of BALB/c mice, a murine model of filariasis. Time course studies demonstrated that while expression of histidine decarboxylase mRNA increases throughout 12 weeks of infection, serum levels of histamine exhibit two peaks—one 30 minutes after primary infection and one 8 weeks later. Interestingly, mice treated with fexofenadine, a histamine receptor 1 inhibitor, demonstrated significantly reduced worm burden in infected mice compared to untreated infected controls. Although fexofenadine-treated mice had decreased antigen-specific IgE levels as well as lower splenocyte IL-5 and IFNγ production, they exhibited a greater than fourfold rise in eosinophil numbers at the tissue site where adult L. sigmodontis worms reside. Fexofenadine-mediated clearance of L. sigmodontis worms was dependent on host eosinophils, as fexofenadine did not decrease worm burdens in eosinophil-deficient dblGATA mice. These findings suggest that histamine release induced by tissue invasive helminths may aid parasite survival by diminishing eosinophilic responses. Further, these results raise the possibility that combining H1 receptor inhibitors with current anthelmintics may improve treatment efficacy for filariae and other tissue-invasive helminths.     

Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

Background

Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis.

Methodology/Principal Findings

Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.

Conclusions/Significance

Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.     

Contrasting genetic diversity and population structure among three sympatric Madagascan shorebirds: parallels with rarity,endemism, and dispersal

Understanding the relative contributions of intrinsic and extrinsic factors to population structure and genetic diversity is a central goal of conservation and evolutionary genetics. One way to achieve this is through comparative population genetic analysis of sympatric sister taxa, which allows evaluation of intrinsic factors such as population demography and life history while controlling for phylogenetic relatedness and geography. We used ten conserved microsatellites to explore the population structure and genetic diversity of three sympatric and closely related plover species in southwestern Madagascar: Kittlitz's plover (Charadrius pecuarius), white‐fronted plover (C. marginatus), and Madagascar plover (C. thoracicus). Bayesian clustering revealed strong population structure in the rare and endemic Madagascar plover, intermediate population structure in the white‐fronted plover, and no detectable population structure in the geographically widespread Kittlitz's plover. In contrast, allelic richness and heterozygosity were highest for the Kittlitz's plover, intermediate for the white‐fronted plover and lowest for the Madagascar plover. No evidence was found in support of the “watershed mechanism” proposed to facilitate vicariant divergence of Madagascan lemurs and reptiles, which we attribute to the vagility of birds. However, we found a significant pattern of genetic isolation by distance among populations of the Madagascar plover, but not for the other two species. These findings suggest that interspecific variation in rarity, endemism, and dispersal propensity may influence genetic structure and diversity, even in highly vagile species.     

Evidence of niche shift and global invasion potential of the Tawny Crazy ant,Nylanderia fulva

Analysis of an invasive species' niche shift between native and introduced ranges, along with potential distribution maps, can provide valuable information about its invasive potential. The tawny crazy ant, Nylanderia fulva, is a rapidly emerging and economically important invasive species in the southern United States. It is originally from east‐central South America and has also invaded Colombia and the Caribbean Islands. Our objectives were to generate a global potential distribution map for N. fulva, identify important climatic drivers associated with its current distribution, and test whether N. fulva's realized climatic niche has shifted across its invasive range. We used MaxEnt niche model to map the potential distribution of N. fulva using its native and invaded range occurrences and climatic variables. We used principal component analysis methods for investigating potential shifts in the realized climatic niche of N. fulva during invasion. We found strong evidence for a shift in the realized climatic niche of N. fulva across its invasive range. Our models predicted potentially suitable habitat for N. fulva in the United States and other parts of the world. Our analyses suggest that the majority of observed occurrences of N. fulva in the United States represent stabilizing populations. Mean diurnal range in temperature, degree days at ≥10°C, and precipitation of driest quarter were the most important variables associated with N. fulva distribution. The climatic niche expansion demonstrated in our study may suggest significant plasticity in the ability of N. fulva to survive in areas with diverse temperature ranges shown by its tolerance for environmental conditions in the southern United States, Caribbean Islands, and Colombia. The risk maps produced in this study can be useful in preventing N. fulva's future spread, and in managing and monitoring currently infested areas.     

A Naturally Occurring rev1-vpu Fusion Gene Does Not Confer a Fitness Advantage to HIV-1

Background

Pandemic strains of HIV-1 (group M) encode a total of nine structural (gag, pol, env), regulatory (rev, tat) and accessory (vif, vpr, vpu, nef) genes. However, some subtype A and C viruses exhibit an unusual gene arrangement in which the first exon of rev (rev1) and the vpu gene are placed in the same open reading frame. Although this rev1-vpu gene fusion is present in a considerable fraction of HIV-1 strains, its functional significance is unknown.

Results

Examining infectious molecular clones (IMCs) of HIV-1 that encode the rev1-vpu polymorphism, we show that a fusion protein is expressed in infected cells. Due to the splicing pattern of viral mRNA, however, these same IMCs also express a regular Vpu protein, which is produced at much higher levels. To investigate the function of the fusion gene, we characterized isogenic IMC pairs differing only in their ability to express a Rev1-Vpu protein. Analysis in transfected HEK293T and infected CD4+ T cells showed that all of these viruses were equally active in known Vpu functions, such as down-modulation of CD4 or counteraction of tetherin. Furthermore, the polymorphism did not affect Vpu-mediated inhibition of NF-кB activation or Rev-dependent nuclear export of incompletely spliced viral mRNAs. There was also no evidence for enhanced replication of Rev1-Vpu expressing viruses in primary PBMCs or ex vivo infected human lymphoid tissues. Finally, the frequency of HIV-1 quasispecies members that encoded a rev1-vpu fusion gene did not change in HIV-1 infected individuals over time.

Conclusions

Expression of a rev1-vpu fusion gene does not affect regular Rev and Vpu functions or alter HIV-1 replication in primary target cells. Since there is no evidence for increased replication fitness of rev1-vpu encoding viruses, this polymorphism likely emerged in the context of other mutations within and/or outside the rev1-vpu intergenic region, and may have a neutral phenotype.     

Processed and Unprocessed Red Meat and Risk of Colorectal Cancer: Analysis by Tumor Location and Modification by Time

Although the association between red meat consumption and colorectal cancer (CRC) is well established, the association across subsites of the colon and rectum remains uncertain, as does time of consumption in relation to cancer development. As these relationships are key for understanding the pathogenesis of CRC, they were examined in two large cohorts with repeated dietary measures over time, the Nurses’ Health Study (n = 87,108 women, 1980–2010) and Health Professionals Follow-up Study (n = 47,389 men, 1986–2010). Cox proportional hazards regression models generated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled by random-effects meta-analysis. In combined cohorts, there were 2,731 CRC cases (1,151 proximal colon, 816 distal colon, and 589 rectum). In pooled analyses, processed red meat was positively associated with CRC risk (per 1 serving/day increase: HR = 1.15, 95% CI: 1.01–1.32; P for trend 0.03) and particularly with distal colon cancer (per 1 serving/day increase; HR = 1.36; 95% CI: 1.09–1.69; P for trend 0.006). Recent consumption of processed meat (within the past 4 years) was not associated with distal cancer. Unprocessed red meat was inversely associated with risk of distal colon cancer and a weak non-significant positive association between unprocessed red meat and proximal cancer was observed (per 1 serving/day increase: distal HR = 0.75; 95% CI: 0.68–0.82; P for trend <0.001; proximal HR = 1.14, 95% CI: 0.92–1.40; P for trend 0.22). Thus, in these two large cohorts of US health professionals, processed meat intake was positively associated with risk of CRC, particularly distal cancer, with little evidence that higher intake of unprocessed red meat substantially increased risk of CRC. Future studies, particularly those with sufficient sample size to assess associations by subsites across the colon are needed to confirm these findings and elucidate potentially distinct mechanisms underlying the relationship between processed meat and subtypes of unprocessed red meat with CRC.     

New Insights into Plagiogrammaceae (Bacillariophyta) Based on Multigene Phylogenies and Morphological Characteristics with the Description of a New Genus and Three New Species

Plagiogrammaceae, a poorly described family of diatoms, are common inhabitants of the shallow marine littoral zone, occurring either in the sediments or as epiphytes. Previous molecular phylogenies of the Plagiogrammaceae were inferred but included only up to six genera: Plagiogramma, Dimeregramma, Neofragilaria, Talaroneis, Psammogramma and Psammoneis. In this paper, we describe a new plagiogrammoid genus, Orizaformis, obtained from Bohai Sea (China) and present molecular phylogenies of the family based on three and four genes (nuclear-encoded large and small subunit ribosomal RNAs and chloroplast-encoded rbcL and psbC). Also included in the new phylogenies is Glyphodesmis. The phylogenies suggest that the Plagiogrammaceae is composed of two major clades: one consisting of Talaroneis, Orizaformis and Psammoneis, and the second of Glyphodesmis, Psammogramma, Neofragilaria, Dimeregramma and Plagiogramma. In addition, we describe three new species within established genera: Psammoneis obaidii, which was collected from the Red Sea, Saudi Arabia; and Neofragilaria stilus and Talaroneis biacutifrons from the Mozambique Channel, Indian Ocean, and illustrate two new combination taxa: Neofragilaria anomala and Neofragilaria lineata. Our observations suggest that the biodiversity of the family is strongly needed to be researched, and the phylogenetic analyses provide a useful framework for future studies of Plagiogrammaceae.     

Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

Background

Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.

Hypothesis

We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.

Methods and Results

We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.

Conclusion

Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.