Long-Distance Wind-Dispersal of Spores in a Fungal Plant Pathogen: Estimation of Anisotropic Dispersal Kernels from an Extensive Field Experiment

Given its biological significance, determining the dispersal kernel (i.e., the distribution of dispersal distances) of spore-producing pathogens is essential. Here, we report two field experiments designed to measure disease gradients caused by sexually- and asexually-produced spores of the wind-dispersed banana plant fungus Mycosphaerella fijiensis. Gradients were measured during a single generation and over 272 traps installed up to 1000 m along eight directions radiating from a traceable source of inoculum composed of fungicide-resistant strains. We adjusted several kernels differing in the shape of their tail and tested for two types of anisotropy. Contrasting dispersal kernels were observed between the two types of spores. For sexual spores (ascospores), we characterized both a steep gradient in the first few metres in all directions and rare long-distance dispersal (LDD) events up to 1000 m from the source in two directions. A heavy-tailed kernel best fitted the disease gradient. Although ascospores distributed evenly in all directions, average dispersal distance was greater in two different directions without obvious correlation with wind patterns. For asexual spores (conidia), few dispersal events occurred outside of the source plot. A gradient up to 12.5 m from the source was observed in one direction only. Accordingly, a thin-tailed kernel best fitted the disease gradient, and anisotropy in both density and distance was correlated with averaged daily wind gust. We discuss the validity of our results as well as their implications in terms of disease diffusion and management strategy

La réaction d’hémagglutination (Réaction de Middlebrook-Dubos ) dans la paratuberculose bovine (Entérite chronique hypertrophiante, maladie de Johne)

Gernez-Rieux Charles, Tacquet Albert, Gaumont R., Verge Jean, Cauchy Laurent. La réaction d'hémagglutination (Réaction de Middlebrook-Dubos) dans la paratuberculose bovine (Entérite chronique hypertrophiante, maladie de Johne). In: Bulletin de l'Académie Vétérinaire de France tome 103 n°9, 1950. pp. 465-468

Invited perspectives: Mountain roads in Nepal at a new crossroads

In Nepal and many developing countries around the world, roads are vehicles for development for communities in rural areas. By reducing travel time on foot, opportunities are opened for quicker transportation of goods and better access to employment, education, health care and markets. Roads also fuel migration and numerous social changes, both positive and negative. Poorly constructed roads in mountainous areas of Nepal have increased erosion and landslide risk as they often cut through fragile geology, destabilizing slopes and altering local hydrological conditions, with costs to lives and livelihoods. The convergence of the newly constituted decentralized Nepali government with China's Belt and Road Initiative is likely to bring more roads to rural communities. The new provincial government administrations now have the opportunity to develop policies and practices, which can realign the current trend of poorly engineered, inefficient and hazardous road construction toward a more sustainable trajectory. This commentary provides an overview of some of the obstacles along the way for a more sustainable road network in Nepal and illustrates how good governance, development and landslide risk are intertwined. The opinion presented in this brief commentary lends little hope that Nepal's current pathway of unsustainable road construction will provide the country with the much-needed sustainable road network, unless checks and balances are put in place to curb noncompliance with existing laws and policies.</p

Secondary contact and admixture between independently invading populations of the Western corn rootworm, diabrotica virgifera virgifera in Europe

The western corn rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae), is one of the most destructive pests of corn in North America and is currently invading Europe. The two major invasive outbreaks of rootworm in Europe have occurred, in North-West Italy and in Central and South-Eastern Europe. These two outbreaks originated from independent introductions from North America. Secondary contact probably occurred in North Italy between these two outbreaks, in 2008. We used 13 microsatellite markers to conduct a population genetics study, to demonstrate that this geographic contact resulted in a zone of admixture in the Italian region of Veneto. We show that i) genetic variation is greater in the contact zone than in the parental outbreaks; ii) several signs of admixture were detected in some Venetian samples, in a Bayesian analysis of the population structure and in an approximate Bayesian computation analysis of historical scenarios and, finally, iii) allelic frequency clines were observed at microsatellite loci. The contact between the invasive outbreaks in North-West Italy and Central and South-Eastern Europe resulted in a zone of admixture, with particular characteristics. The evolutionary implications of the existence of a zone of admixture in Northern Italy and their possible impact on the invasion success of the western corn rootworm are discussed

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD

AKT activity orchestrates marginal zone B cell development in mice and humans.

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D &lt;sup&gt;+&lt;/sup&gt; CD27 &lt;sup&gt;+&lt;/sup&gt; B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD &lt;sup&gt;+&lt;/sup&gt; CD27 &lt;sup&gt;-&lt;/sup&gt; and memory IgD &lt;sup&gt;-&lt;/sup&gt; CD27 &lt;sup&gt;+&lt;/sup&gt; B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans

J Virol

In this placebo-controlled phase II randomized clinical trial, 103 HIV-1 infected patients under c-ART (combined antiretroviral treatment) were randomized 2:1 to receive 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag and gp160) at Week (W)0, W4 and W12 followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol and Nef at W20 and W24 or placebos. Analytical treatment interruption (ATI) was performed between W36 to W48.At W28, vaccinees experienced an increase in functional CD4(+) T cell responses measured (P\textbackslashtextless0.001 for each cytokine compared to W0) predominantly against Gag and Pol/Env and an increase in HIV-specific CD8(+) T cells producing IL-2 and TNF-α (P=0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T cell subsets by mass cytometry in a subpopulation showed an increase of W28/W0 ratio for memory CD8(+) T cells co-expressing exhaustion and senescence markers such as PD-1/TIGIT (P=0.004) and CD27/CD57 (P=0.044) in vaccinees compared to placebo. During ATI, all patients experienced viral rebound with a maximum observed HIV RNA level at W42 (median: 4.63 log(10) cp/ml; IQR 4.00-5.09) without any difference between arms. No patient resumed c-ART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed.These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need of combined immunomodulatory strategies.IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU®-MultiHIV B clade) followed by a boost vaccination by a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients while on combined antiretroviral therapy. We show that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1 infected individuals and healthy volunteers who received each vaccine component individually. Compared to placebo group, vaccines elicited strong and polyfunctional HIV-specific CD4(+) and CD8(+) T cell responses. However, these immune responses presenting some qualitative defects were not able to control viremia following antiretroviral treatment interruption as no difference in HIV viral rebound was observed in vaccine and placebo groups. Several lessons were learned from these results pointing out the urgent need to combine the vaccine strategies with other immune-based interventions

Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae

Evolution of Highly Polymorphic T Cell Populations in Siblings with the Wiskott-Aldrich Syndrome

Population level evolutionary processes can occur within a single organism when the germ line contains a mutation that confers a cost at the level of the cell. Here we describe how multiple compensatory mutations arose through a within-individual evolutionary process in two brothers with the immune deficiency Wiskott-Aldrich Syndrome (WAS). As a result, both brothers have T lymphocyte populations that are highly polymorphic at the locus of the germ line defect, and no single allele achieves fixation. WASP, the gene product affected in this disease, is specific to white blood cells where it is responsible for regulating actin cytoskeleton dynamics in a wide range of cellular responses. The brothers inherited a rare allele predicted to result in truncated WASP lacking the carboxy-terminal VCA domains, the region that directly catalyzes actin filament generation. Although the brothers' T cell populations are highly polymorphic, all share a corrective effect relative to the inherited allele in that they restore the VCA domain. This indicates massive selection against the truncated germ line allele. No single somatic allele becomes fixed in the circulating T cell population of either brother, indicating that a regulated step in maturation of the affected cell lineage is severely compromised by the germ line allele. Based on the finding of multiple somatic mutations, the known maturation pathway for T-lineage cells and the known defects of T cells and precursor thymocytes in mice with truncated WASP, we hypothesize that the presence of truncated WASP (WASPΔVCA) confers an extreme disadvantage in early developing thymocytes, above and beyond the known cost of absence of full-length WASP, and that the disadvantage likely occurs through dominant negative competition of WASPΔVCA with N-WASP, a protein that otherwise partially compensates for WASP absence in developing thymocytes