As shown by transcriptional analysis of blood samples from human volunteers, injection with synthetic dsRNA (an agonist of the TLR3 and MDA5 pattern recognition receptors) triggered up-regulation of genes involved in innate immune pathways, similar to those induced by vaccination with the efficacious yellow fever vaccine.

Live attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate (NHP) models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous wildtype SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node, but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in lymph node, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wildtype SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection, an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses.

Background With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing. Findings Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for high-performance computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA sequencing, chromatin immunoprecipitation sequencing, DNA sequencing, methylation sequencing, Hi-C, capture Hi-C, metagenomics, and Pacific Biosciences long-read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has already been configured on several servers, and a Docker image is also available to facilitate additional installations. Conclusions GenPipes offers genomics researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.

Dysfunction of virus-specific CD4 + T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4 + T cells specific for human immunodeficiency virus (HIV) from HIV-infected people prior and after initiation of antiretroviral therapy (ART). A follicular helper T cell (T FH cell)–like profile characterized HIV-specific CD4 + T cells in viraemic infection. HIV-specific CD4 + T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the T H 1, T H 17 and T H 22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with T FH cells but persistently low expression of genes associated with T H 1, T H 17 and T H 22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4 + T cells and involves both gain of function and loss of function.

We have developed an index based on macroscopic criteria to easily assess the health state of the eel swimbladder as a result of infection by the nematode Anguillicola crassus. In the sampling area (brackish lagoons of the French Mediterranean coast), 92% of the host sample (1,251 eels covering all size classes) showed pathological signs of infection. The general trend was for increasing damage as eel size increased, thus suggesting accumulation of pathological effects. We also revealed a non-linear relationship between the swimbladder index and the abundance of living worms. In particular, we showed that severely damaged swimbladders harboured very few living nematodes. We argue that the swimbladder degenerative index more closely reflects the parasite pressure than does classic parasite count. We found seasonal variation in the swimbladder index, with maximum damage occurring in July and thereafter a trend for healthy individuals. We discuss the possibility that the seasonal decrease in the swimbladder index could reflect the death of the more severely affected individuals during the warmest months.

Precocious egg production, i.e. progenesis, has been documented for a number of species in scattered reports throughout the trematode literature. The last 2 extensive studies on the subject date from Buttner in the early 1950s (in French) and from Tang in the early 1980s (in Chinese). Overall, 43 species were then known for their ability to produce eggs at the metacercarial stage while still in the second intermediate host. Here, we update the list, and document the existence of progenesis in a total of 79 digenean trematode species, for which we provide information on the taxonomy of the hosts, the facultative or obligate character of progenesis, relevant references, as well as some other pertinent biological information. We then review the subject by asking 7 questions of fundamental evolutionary importance. These include: What favours progenetic development? What are the associated costs and benefits? How are progenetic eggs released from the host? While exposing the various opinions of previous authors, we attempt to give a synthetic overview and stress on the importance of the metacercarial cyst wall (whether it is present, and if so its thickness) in the evolution and the adoption of a progenetic life-cycle.

Recombinant adenovirus vectors (rAds) are being investigated as vaccine delivery vehicles in pre-clinical and clinical studies. rAds constructed from different serotypes differ in receptor usage, tropism, and ability to activate cells, aspects of which likely contribute to their different immunogenicity profiles. Here, we compared the infectivity and cell stimulatory capacity of rAd serotype 5 (rAd5), rAd28 and rAd35 in association with their respective immunogenicity profiles. We found that rAd28 and rAd35 infected, and led to the in vitro maturation and activation, of both human and mouse dendritic cells (DCs) more efficiently compared to rAd5. In stark contrast to rAd5, rAd28 and rAd35 induced production of interferon alpha (IFNα) and stimulated interferon-related intracellular pathways. However, the in vivo immunogenicity of rAd28 and rAd35 was significantly lower than that of rAd5. Deletion of IFNα signaling during vaccination with rAd28 and rAd35 vectors increased the magnitude of the insert-specific T-cell response to levels induced by vaccination with rAd5 vector. The negative impact of IFNα signaling on the magnitude of the T cell response could be overcome by increasing the vaccine dose, which was also associated with greater polyfunctionality and a more favorable long-term memory phenotype of the CD8 T cell response in the presence of IFNα signaling. Taken together, our results demonstrate that rAd-induced IFNα production has multiple effects on T cell immunogenicity, the understanding of which should be considered in the design of rAd vaccine vectors.

Key Points• IRF8 K108E mutation causes dendritic cell depletion, defective antigen presentation, and anergic T cells.• IRF8 K108E mutant protein is functionally null and shows defective nuclear targeting and increased proteasomal degradation.We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8 K108E ) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD14 1 and CD161 monocytes, absence of CD11c 1 conventional dendritic cells (DCs) and CD11c 1 /CD123 1 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8 K108E patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD4 1 and CD8 1 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8 K108E are anergic.Biochemical characterization of the IRF8 K108E mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8. (Blood. 2014;124(12):1894-1904 IntroductionPrimary immunodeficiencies sometimes present with disseminated mycobacterial infection following neonatal vaccination with live Bacillus Calmette-Guérin (BCG). 1 In many cases, patients suffer from Mendelian susceptibility to mycobacterial disease, a syndrome caused by infection with weakly virulent mycobacteria such as BCG, with environmental mycobacteria, and/or recurrent infections with virulent mycobacteria (Mycobacterium tuberculosis) over the life course.2 Approximately half of patients with Mendelian susceptibility to mycobacterial disease have been shown to carry mutations in a small subset of genes involved in interferon (IFN) g-dependent early immune responses. 2,3 Other patients develop disseminated BCG disease as part of a broader pattern of susceptibility to infection (eg, severe combined immunodeficiency).We have previously reported an infant presenting with severe disseminated BCG infection, oral candidiasis, and severe respiratory viral infection. 4 Evaluation of the patient's blood cellular profile revealed an aberrant myeloid compartment; notably, a complete absence of CD14 1 and CD16 1 monocytes, absence of CD11c DCs, and prominent granulocytic hyperplasia. 4 The peripheral blood B-lymphocyte count was also increased in this patient. Production o...