Landscape Structures Affect Risk of Canine Distemper in Urban Wildlife

Urbanization rapidly changes landscape structure worldwide, thereby enlarging the human-wildlife interface. The emerging urban structures should have a key influence on the spread and distribution of wildlife diseases such as canine distemper, by shaping density, distribution and movements of wildlife. However, little is known about the role of urban structures as proxies for disease prevalence. To guide management, especially in densely populated cities, assessing the role of landscape structures in hampering or promoting disease prevalence is thus of paramount importance. Between 2008 and 2013, two epidemic waves of canine distemper hit the urban red fox (Vulpes vulpes) population of Berlin, Germany. The directly transmitted canine distemper virus (CDV) causes a virulent disease infecting a range of mammals with high host mortality, particularly in juveniles. We extracted information about CDV serological state (seropositive or seronegative), sex and age for 778 urban fox carcasses collected by the state laboratory Berlin Brandenburg. To assess the impact of urban landscape structure heterogeneity (e.g., richness) and shares of green and gray infrastructures at different spatial resolutions (areal of 28 ha, 78 ha, 314 ha) on seroprevalence we used Generalized Linear Mixed-Effects Models with binomial distributions. Our results indicated that predictors derived at a 28 ha resolution were most informative for describing landscape structure effects (AUC = 0.92). The probability to be seropositive decreased by 66% (0.6 to 0.2) with an increasing share of gray infrastructure (40 to 80%), suggesting that urbanization might hamper CDV spread in urban areas, owing to a decrease in host density (e.g., less foxes or raccoons) or an absence of wildlife movement corridors in strongly urbanized areas. However, less strongly transformed patches such as close-to-nature areas in direct proximity to water bodies were identified as high risk areas for CDV transmission. Therefore, surveillance and disease control actions targeting urban wildlife or human-wildlife interactions should focus on such areas. The possible underlying mechanisms explaining the prevalence distribution may be increased isolation, the absence of alternative hosts or an abiotic environment, all impairing the ability of CDV to persist without a host

Comparison of mosquito and fly derived DNA as a tool for sampling vertebrate biodiversity in suburban forests in Berlin, Germany

The use of invertebrate‐derived DNA (iDNA) is a promising non‐invasive tool to monitor wildlife. While most studies have been carried out in dense tropical and sub‐tropical forests and have focused on the use of a single category of invertebrates, this study compares the use of flies and mosquitoes‐derived DNA to assess vertebrate diversity in semi‐urban environments. We conducted our sampling in four different forest plots in Berlin, Germany. Pools of flies and non‐bloodfed mosquitoes were metabarcoded using 108‐bp vertebrate‐specific 12 S rRNA (12 S‐V5) and 94‐bp mammal‐specific 16 S rRNA (16Smam) mitochondrial markers, and individual bloodfed mosquitoes were sequenced using the 340‐bp vertebrate‐specific 12 S rRNA fragment (Mam‐12 S‐340). Most sequencing was only successful for mammal species. From the fly pools, we detected 10 mammal species using 16Smam, and six species using 12 S‐V5. From the non‐bloodfed mosquito pools, we only amplified putative contaminant DNA, indicating that mosquito females without visual signs of a blood meal carry no traces of vertebrate DNA. Finally, in the bloodfed mosquitoes, we identified four mammal species. We did not find significant differences in the proportion of mammal species detected regarding the total available number of species between sampling localities. Fly samples were easier to obtain and more abundant over the sampled localities compared to mosquito samples. We conclude that, while there are a few advantages in using mosquito blood meals, the use of flies in the detection of wildlife in a suburban environment is more effective in terms of collection of samples and detection of vertebrates, although this technique is limited to few mammal species in the urban environment

Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide

Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B*07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition

Arthropod abundance modulates bird community responses to urbanization

Aim We analysed the role of species interactions in wildlife community responses to urbanization. Specifically, we investigated non‐trophic associations within a bird community and the role of trophic interactions in the responses of bird species to the urbanization gradient. Location City‐state of Berlin, Central Europe. Methods Arthropod and bird abundances were sampled across the study area and analysed using hierarchical joint species distribution models (JSDMs). Urbanization gradient was defined by environmental predictors reflecting anthropogenic disturbances, for example noise level and human population density, as well as nature‐like features, for example tree cover and open green area. Relevant environmental predictors for each group and relevant spatial resolution were selected a priori using AICc. Arthropod abundances were modelled for the bird sampling transects and included as additional predictor variable in the bird community model. In this model, we used abundances and traits of 66 breeding bird species as response variables. Results Bird species responses to urbanization were captured by the interaction between invertebrate abundance and environmental predictors. We identified three groups of birds: the urban group (12 species) showed no decrease in abundance along the urbanization gradient and were not related to arthropods abundance; the woodland group (18 species) were positively related to tree cover and arthropod abundance, also in areas with high anthropogenic disturbance; and the nature group (36 species) were positively related to arthropod abundance, but the species abundance decreased sharply with increasing anthropogenic disturbance. All the non‐trophic associations found within the bird community were positive. Main conclusions Arthropod abundance clearly modulated birds’ responses to the urbanization gradient for most species. Especially at moderate levels of anthropogenic disturbance, the abundance of arthropods is key for the occurrence and abundance of bird species in urban areas. To maintain bird diversity in urban green areas, management measures should focus on maintaining and increasing invertebrate abundance

The Shaping of T Cell Receptor Recognition by Self-Tolerance

SummaryDuring selection of the T cell repertoire, the immune system navigates the subtle distinction between self-restriction and self-tolerance, yet how this is achieved is unclear. Here we describe how self-tolerance toward a trans-HLA (human leukocyte antigen) allotype shapes T cell receptor (TCR) recognition of an Epstein-Barr virus (EBV) determinant (FLRGRAYGL). The recognition of HLA-B8-FLRGRAYGL by two archetypal TCRs was compared. One was a publicly selected TCR, LC13, that is alloreactive with HLA-B44; the other, CF34, lacks HLA-B44 reactivity because it arises when HLA-B44 is coinherited in trans with HLA-B8. Whereas the alloreactive LC13 TCR docked at the C terminus of HLA-B8-FLRGRAYGL, the CF34 TCR docked at the N terminus of HLA-B8-FLRGRAYGL, which coincided with a polymorphic region between HLA-B8 and HLA-B44. The markedly contrasting footprints of the LC13 and CF34 TCRs provided a portrait of how self-tolerance shapes the specificity of TCRs selected into the immune repertoire

CD1a autoreactive T cells recognize natural skin oils that function as headless antigens

CD1a autoreactive T cells are common in human blood and skin, but the search for natural autoantigens has been confounded by background T cell responses to CD1 proteins and self lipids. After capturing CD1a-lipid complexes, we gently eluted ligands, while preserving unliganded CD1a for testing lipids from tissues. CD1a released hundreds of ligands of two types. Inhibitory ligands were ubiquitous membrane lipids with polar headgroups, whereas stimulatory compounds were apolar oils. CD1a autoantigens naturally accumulate in epidermis and sebum, where they were identified as squalene and skin waxes. T cell activation by skin oils suggests that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups. Oily autoantigens naturally coat the skin's surface, pointing to a new mechanism of barrier immunity

Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens

Crucial to Natural Killer T (NKT) cell function is the interaction between their T-cell receptor (TCR) and CD1d-antigen complex. However, the diversity of the NKT cell repertoire and the ensuing interactions with CD1d-antigen remain unclear. We describe an atypical population of CD1d-α-galactosylceramide (α-GalCer)-reactive human NKT cells that differ markedly from the prototypical TRAV10-TRAJ18-TRBV25-1(+) type I NKT cell repertoire. These cells express a range of TCR α- and β-chains that show differential recognition of glycolipid antigens. Two atypical NKT TCRs (TRAV21-TRAJ8-TRBV7-8 and TRAV12-3-TRAJ27-TRBV6-5) bind orthogonally over the A'-pocket of CD1d, adopting distinct docking modes that contrast with the docking mode of all type I NKT TCR-CD1d-antigen complexes. Moreover, the interactions with α-GalCer differ between the type I and these atypical NKT TCRs. Accordingly, diverse NKT TCR repertoire usage manifests in varied docking strategies and specificities towards CD1d-α-GalCer and related antigens, thus providing far greater scope for diverse glycolipid antigen recognition

HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells

Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01-NP199-207. The immunodominance hierarchies across these universal CD8+ T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8+ T-cell responses directed towards A2/M158 were generally immunodominant, A2/M158+CD8+ T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following ex vivo and in vitro analyses. A2/M158+CD8+ T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M158+CD8+ T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8+ T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8+ T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases

Lack of heterologous cross-reactivity towards HLA-A*02:01 restricted viral epitopes is underpinned by distinct αβT cell receptor signatures

αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M158, respectively) or with the hepatitis C and influenza viruses (NS31073 and NA231, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell αβTCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct αβTCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific

eLife

The functions of the TAF subunits of mammalian TFIID in physiological processes remain poorly characterised. In this study, we describe a novel function of TAFs in directing genomic occupancy of a transcriptional activator. Using liver-specific inactivation in mice, we show that the TAF4 subunit of TFIID is required for post-natal hepatocyte maturation. TAF4 promotes pre-initiation complex (PIC) formation at post-natal expressed liver function genes and down-regulates a subset of embryonic expressed genes by increased RNA polymerase II pausing. The TAF4-TAF12 heterodimer interacts directly with HNF4A and in vivo TAF4 is necessary to maintain HNF4A-directed embryonic gene expression at post-natal stages and promotes HNF4A occupancy of functional cis-regulatory elements adjacent to the transcription start sites of post-natal expressed genes. Stable HNF4A occupancy of these regulatory elements requires TAF4-dependent PIC formation highlighting that these are mutually dependent events. Local promoter-proximal HNF4A-TFIID interactions therefore act as instructive signals for post-natal hepatocyte differentiation