Numerical Rule-Learning in Ring-Tailed Lemurs (Lemur Catta)

We investigated numerical discrimination and numerical rule-learning in ring-tailed lemurs (Lemur catta). Two ring-tailed lemurs were trained to respond to two visual arrays, each of which contained between one and four elements, in numerically ascending order. In Experiment 1, lemurs were trained with 36 exemplars of each of the numerosities 1–4 and then showed positive transfer to trial-unique novel exemplars of the values 1–4. In Experiments 2A and 2B, lemurs were tested on their ability to transfer an ascending numerical rule from the values 1–4 to novel values 5–9. Both lemurs successfully ordered the novel values with above chance accuracy. Accuracy was modulated by the ratio between the two numerical values suggesting that lemurs accessed the approximate number system when performing the task

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05).ResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome

SARS-CoV-2-specific T cell memory with common TCRαβ motifs is established in unvaccinated children who seroconvert after infection

As establishment of SARS-CoV-2-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analysed epitope-specific T cells directly ex vivo using seven HLA class-I and class-II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable spike-specific, but lower ORF1a- and N-specific memory T cell responses compared to adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naïve phenotypes and diverse TCRαβ repertoires. Our study demonstrates generation of SARS-CoV-2-specific T cell memory with common TCRαβ motifs in unvaccinated seroconverted children after their first virus encounter

Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan

CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158–66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections

Human CD8+ T cell cross-reactivity across influenza A, B and C viruses

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity

To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses

Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people

Robust SARS-CoV-2 T cell responses with common TCR?? motifs toward COVID-19 vaccines in patients with hematological malignancy impacting B cells

Immunocompromised hematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are, however, unclear, especially after 3 vaccine doses. We evaluated immune responses in hematology patients across three COVID-19 vaccination doses. Seropositivity was low after a first dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59%–75% after a second dose, and increased to 85% after a third dose. While prototypical antibody-secreting cells (ASCs) and T follicular helper (Tfh) cell responses were elicited in healthy participants, hematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T cells, together with their T cell receptor (TCR) repertoires, were robust in hematology patients, irrespective of B cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T cell immunity in hematology patients of varying diseases and treatments irrespective of B cell numbers and antibody response

Elucidating the Evolutionary Consequences of Sociality Through Genome-wide Analyses of Social and Solitary Mammals

Social affiliation and group living are seminal aspects of some of the most exciting and intensely studied topics in behavioral biology, from the field of human psychopathology to investigations of cooperation and reproductive skew in animal societies. Understanding how and why sociality evolves as an alternative to the much more common trait of solitary living has long been a topic of special interest among biologists, particularly in light of evidence that group living can impose a number of costs (e.g., increased exposure to pathogens or increased resource competition) that can negatively impact direct fitness. It is hypothesized that sociality only evolves when the benefits associated with cooperation outweigh the costs of competition. Social animals are therefore likely exposed to a unique set of evolutionary pressures as a result of the distinct costs and benefits inherent to their gregarious lifestyles, and social animals should consequently exhibit adaptations that specifically counterbalance the costs associated with sociality. For my dissertation, I set out to explore the evolutionary consequences of sociality by investigating patterns of genomic variation and change in social and solitary animals from a population-level and a broad, comparative perspective, respectively.The first two chapters of my dissertation serve as a comparative case study on the impacts of sociality on population structure in a novel rodent system. I present population-level genomic data from two species of pebble-mound mice (genus Pseudomys, family Muridae) endemic to mainland Australia: the solitary Queensland pebble-mound mouse (P. patrius) and the social Ngadji (P. chapmani). Like other pebble-mound mice, these focal species construct large aggregations of pebbles over their subterranean burrows that, although not necessary for survival, are required by females for mating. As a result of their distinct social systems, these closely related and ecologically similar congeners serve as compelling point of comparison. By characterizing patterns of genomic variation within each of these species, I demonstrate differences in population structure between the two species, particularly in relationship to pebble-mounds and kinship. In Chapter 1, I demonstrate that the Queensland pebble-mound mouse exhibits significant evidence of kin structure despite being solitary. In this particular case, kin structure seems to arise as a result of the spatially fixed resources (i.e., pebble-mounds) sought out by females. Because affiliations among close kin are very typical of social animals, these findings raise questions about how social and solitary animals might aggregate differently. These questions are then addressed in Chapter 2, where I demonstrate that the social Ngadji also exhibits kin stratification around pebble-mounds, but on a much broader scale than in the Queensland pebble-mound mouse. Beyond describing the molecular ecology of these two non-model species, this work demonstrates that population-level studies that utilize comparative frameworks of closely related and ecologically similar species can provide insights into the impacts of sociality on dispersal and mating system that might inform future studies on the ecological conditions and behavioral mechanisms underlying group living.Whereas the first two chapters consider the impacts of social system on general, population-level processes, the final chapter tests an explicit hypothesis about the evolutionary consequences of sociality on a broader comparative scale. Of all the proposed costs associated with group living, increased exposure to pathogens may be one of the most important: not only are pathogen exposure and disease susceptibility are two of the greatest influences on an individual’s reproductive success, but communicable diseases are known to thrive in communities characterized by group living and high rates of conspecific interaction. However, attempts to explicitly demonstrate the putative immunological consequences of sociality have historically proven difficult. For example, consider two ecologically similar species that share recent common ancestry but demonstrate distinct social organizations. One might attempt to characterize differences in immune pressures by measuring differences in pathogen exposure or parasite loads between the two species. However, divergence among species generally leads to divergence among their respective pathogens and parasites, such that measures of pathogen or parasite loads may become entirely incomparable between the two species. Similarly, this approach assumes that no adaptations (physiological, behavioral, or otherwise) have arisen since the divergence of the two species that might counteract their respective immune pressures. Rather than attempting to quantify the extent of immune-related evolutionary pressures by assessing pathogen or parasite prevalence, Chapter 3 characterizes the relative pathogen-mediated pressure acting on social and solitary species by assessing positive selection in immune orthologues from nine species across three divergent mammal lineages. These analyses demonstrate that relatively social and solitary mammals experience distinct evolutionary pressures, with group-living species experiencing faster rates of evolution at immune loci. When considered in conjunction with candidate loci studies in more limited taxonomic comparisons, these findings suggest that increased immune burden is one of the more common costs associated with sociality