50 research outputs found
Adaptation of avian influenza virus to a swine host
The emergence of pathogenic RNA viruses into new hosts can have dramatic consequences for both livestock and public health. Here we characterize the viral genetic changes that were observed in a previous study which experimentally adapted a field isolate of duck influenza virus to swine respiratory cells. Both pre-existing and mutations were selected during this adaptation. We compare the growth dynamics of the adapted virus with those of the original strain as well as all possible reassortants using reverse genetics. This full factorial design showed that viral gene segments are involved in complex epistatic interactions on virus fitness, including negative and sign epistasis. We also identify two point mutations at positions 67 and 113 of the HA2 subunit of the hemagglutinin protein conferring a fast growth phenotype on the naïve avian virus in swine cells. These HA2 mutations enhance the pH dependent, HA-mediated membrane fusion. A global H1 maximum-likelihood phylogenetic analysis, combined with comprehensive ancestry reconstruction and tests for directional selection, confirmed the field relevance of the mutation at position 113 of HA2. Most notably, this mutation was associated with the establishment of the H1 ‘avian-like’ swine influenza lineage, regarded as the most likely to cause the next influenza pandemic in humans. This multidisciplinary approach to study the genetics of viral adaptation provides unique insights on the underlying processes leading to influenza emergence in a new host species, and identifies specific targets for future surveillance and functional studies.This work was supported by a grant from DEFRA and HEFCE under the Veterinary Training and Research Initiative to the Cambridge Infectious Diseases Consortium (VB, LT), the French Ministry of Agriculture and INRA (VB, AT, J-LG), BBSRC grants BB/H014306/1 (LT) and BB/G00479X/1 (LT, JL), and the Medical Research Council Methodology Research Programme grant MR/J013862/1 (SDWF)
Genotypic characterisation of Avian paramyxovirus type-1 viruses isolated from aquatic birds in Uganda
Avian paramyxovirus type-1 (APMV-1) viruses of the lentogenic pathotypes are often isolated from wild aquatic birds and may mutate to high pathogenicity when they cross into poultry and cause debilitating Newcastle disease. This study characterised AMPV-1 isolated from fresh faecal droppings from wild aquatic birds roosting sites in Uganda. Fresh faecal samples from wild aquatic birds at several waterbodies in Uganda were collected and inoculated into 9–10-day-old embryonated chicken eggs. After isolation, the viruses were confirmed as APMV-1 by APMV-1-specific polymerase chain reaction (PCR). The cleavage site of the fusion protein gene for 24 representative isolates was sequenced and phylogenetically analysed and compared with representative isolates of the different APMV-1 genotypes in the GenBank database. In total, 711 samples were collected from different regions in the country from which 72 isolates were recovered, giving a prevalence of 10.1%. Sequence analysis of 24 isolates revealed that the isolates were all lentogenic, with the typical 111GGRQGR’L117 avirulent motif. Twenty-two isolates had similar amino acid sequences at the cleavage site, which were different from the LaSota vaccine strain by a silent nucleotide substitution T357C. Two isolates, NDV/waterfowl/Uganda/MU150/2011 and NDV/waterfowl/Uganda/MU186/2011, were different from the rest of the isolates in a single amino acid, with aspartate and alanine at positions 124 and 129, respectively. The results of this study revealed that Ugandan aquatic birds indeed harbour APMV-1 that clustered with class II genotype II strains and had limited genetic diversity
Expression profile of human Fc receptors in mucosal tissue: implications for antibody-dependent cellular effector functions targeting HIV-1 transmission
The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the initial events in mucosal transmission and dissemination warrants further mechanistic studies
Human Macrophages and Dendritic Cells Can Equally Present MART-1 Antigen to CD8+ T Cells after Phagocytosis of Gamma-Irradiated Melanoma Cells
Dendritic cells (DC) can achieve cross-presentation of naturally-occurring
tumor-associated antigens after phagocytosis and processing of dying tumor
cells. They have been used in different clinical settings to vaccinate cancer
patients. We have previously used gamma-irradiated MART-1 expressing melanoma
cells as a source of antigens to vaccinate melanoma patients by injecting
irradiated cells with BCG and GM-CSF or to load immature DC and use them as
a vaccine. Other clinical trials have used IFN-gamma activated macrophage
killer cells (MAK) to treat cancer patients. However, the clinical use of
MAK has been based on their direct tumoricidal activity rather than on their
ability to act as antigen-presenting cells to stimulate an adaptive antitumor
response. Thus, in the present work, we compared the fate of MART-1 after
phagocytosis of gamma-irradiated cells by clinical grade DC or MAK as well
as the ability of these cells to cross present MART-1 to CD8+
T cells. Using a high affinity antibody against MART-1, 2A9, which specifically
stains melanoma tumors, melanoma cell lines and normal melanocytes, the expression
level of MART-1 in melanoma cell lines could be related to their ability to
stimulate IFN-gamma production by a MART-1 specific HLA-A*0201-restricted
CD8+ T cell clone. Confocal microscopy with Alexa Fluor®647-labelled
2A9 also showed that MART-1 could be detected in tumor cells attached and/or
fused to phagocytes and even inside these cells as early as 1 h and up to
24 h or 48 h after initiation of co-cultures between gamma-irradiated melanoma
cells and MAK or DC, respectively. Interestingly, MART-1 was cross-presented
to MART-1 specific T cells by both MAK and DC co-cultured with melanoma gamma-irradiated
cells for different time-points. Thus, naturally occurring MART-1 melanoma
antigen can be taken-up from dying melanoma cells into DC or MAK and both
cell types can induce specific CD8+ T cell cross-presentation
thereafter
A Worldwide Test of the Predictive Validity of Ideal Partner Preference-Matching
©American Psychological Association, [2024]. This paper is not the copy of record and may not exactly replicate the authoritative document published in the APA journal. The final article is available, upon publication, at: [ARTICLE DOI]”Ideal partner preferences (i.e., ratings of the desirability of attributes like attractiveness or intelligence) are the source of numerous foundational findings in the interdisciplinary literature on human mating. Recently, research on the predictive validity of ideal partner preference-matching (i.e., do people positively evaluate partners who match versus mismatch their ideals?) has become mired in several problems. First, articles exhibit discrepant analytic and reporting practices. Second, different findings emerge across laboratories worldwide, perhaps because they sample different relationship contexts and/or populations. This registered report—partnered with the Psychological Science Accelerator—uses a highly powered design (N=10,358) across 43 countries and 22 languages to estimate preference-matching effect sizes. The most rigorous tests revealed significant preference-matching effects in the whole sample and for partnered and single participants separately. The “corrected pattern metric” that collapses across 35 traits revealed a zero-order effect of β=.19 and an effect of β=.11 when included alongside a normative preference-matching metric. Specific traits in the “level metric” (interaction) tests revealed very small (average β=.04) effects. Effect sizes were similar for partnered participants who reported ideals before entering a relationship, and there was no consistent evidence that individual differences moderated any effects. Comparisons between stated and revealed preferences shed light on gender differences and similarities: For attractiveness, men’s and (especially) women’s stated preferences underestimated revealed preferences (i.e., they thought attractiveness was less important than it actually was). For earning potential, men’s stated preferences underestimated—and women’s stated preferences overestimated—revealed preferences. Implications for the literature on human mating are discussed.Unfunde
Impact of depleting therapeutic monoclonal antibodies on the host adaptive immunity: a bonus or a malus?
Clinical responses to anti-tumor monoclonal antibody (mAb) treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti-tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti-tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens