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The goal of a successful immune response is to clear the pathogen while sparing host tissues from damage associated with pathogen replication and active immunity. Regulatory T cells (Treg) have been implicated in maintaining this balance as they contribute both to the organization of immune responses as well as restriction of inflammation and immune activation to limit immunopathology. To determine if Treg abundance prior to pathogen encounter can be used to predict the success of an antiviral immune response, we used genetically diverse mice from the collaborative cross infected with West Nile virus (WNV). We identified collaborative cross lines with extreme Treg abundance at steady state, either high or low, and used mice with these extreme phenotypes to demonstrate that baseline Treg quantity predicted the magnitude of the CD8 T cell response to WNV infection, although higher numbers of baseline Tregs were associated with reduced CD8 T cell functionality in terms of TNF and granzyme B expression. Finally, we found that abundance of CD44+ Tregs in the spleen at steady state was correlated with an increased early viral load within the spleen without an association with clinical disease. Thus, we propose that Tregs participate in disease tolerance in the context of WNV infection by tuning an appropriately focused and balanced immune response to control the virus while at the same time minimizing immunopathology and clinical disease. We hypothesize that Tregs limit the antiviral CD8 T cell function to curb immunopathology at the expense of early viral control as an overall host survival strategy.

Despite the pandemic, on-going efforts to evaluate student perceptions of their curricula improving their abilities across different areas needs to be continued. This study examined one business school’s undergraduate curriculum. Twelve individual item goals of this curriculum closely corresponded to what employers look for on college students’ resumes (NACE, 2021). Ninety-three Fall 2021 graduating business seniors filled out a survey asking their perceptions about the business school’s curriculum improving their abilities on these twelve goals. To date, these individual attributes have not been analyzed together in prior studies to produce a smaller set of research scales. A factor analysis of these twelve individual items resulted in keeping nine of these items, creating two new reliable and distinct scales for future research, labeled as Professional Development (5 items) and Quantitative Skills (4 items). Significant positive relationships between these two scales and two outcomes, student satisfaction and employment preparation, were subsequently found. In addition, a new short multi-item, reliable Employment Preparedness scale was developed. After controlling for record-based student demographics (gender, race, state residency) and school-related variables (GPA, transfer student, quantitative/qualitative major), Quantitative Skills accounted for significant variance in both outcomes, while Professional Development accounted for only student satisfaction.

Background A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. Methods We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. Results Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. Conclusions These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.

Background Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines, as well as the early identification of individuals with the highest risk that may require supportive treatment. Methods We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, SARS-coronavirus, and West Nile virus. Results CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality following infection and strains exhibiting no mortality. We then used comprehensive pre-infection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. Conclusions These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease., Author summary In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection have brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune responses are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of Stimulator of Interferon Genes (STING) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING is required for effective programming of the innate and adaptive immune response to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.

Flaviviruses are hematophagous arthropod-viruses that pose global challenges to human health. Like Zika virus, West Nile Virus (WNV) is a flavivirus for which no approved vaccine exists [1]. The role host genetics play in early detection and response to WNV still remains largely unexplained. In order to capture the impact of genetic variation on innate immune responses, we studied gene expression following WNV infection using the collaborative cross (CC). The CC is a mouse genetics resource composed of hundreds of independently bred, octo-parental recombinant inbred mouse lines [2]. To accurately capture the host immune gene expression signatures of West Nile infection, we used the nanostring platform to evaluate expression in spleen tissue isolated from CC mice infected with WNV over a time course of 4, 7, and 12 days' post-infection [3]. Nanostring is a non-amplification based digital method to quantitate gene expression that uses color-coded molecular barcodes to detect hundreds of transcripts in a sample. Using this approach, we identified unique gene signatures in spleen tissue at days 4, 7, and 12 following WNV infection, which delineated distinct differences between asymptomatic and symptomatic CC lines. We also identified novel immune genes. Data was deposited into the Gene Expression Omnibus under accession GSE86000.

Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines, as well as the early identification of individuals with the highest risk that may require supportive treatment. Here, we completed a large screen of mice from the Collaborative Cross (CC) that we infected with influenza, SARS-coronavirus, and West Nile virus. CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality following infection and strains exhibiting no mortality to these infections. We then used comprehensive pre-infection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans., Author Summary Much experimental work has been directed at understanding the host immune response to flavivirus infections such as West Nile virus (WNV) using mouse models of infection. While valuable information has certainly been secured using these methods, a limitation to studies with traditional inbred mouse models is that they lack the genetic diversity of the human population, and consequently this limits our ability to study particular states of disease that aren’t replicated in traditional inbred mice. For instance, despite reports of chronic WNV infection in humans, a mouse model of chronic infection is lacking. Here, we report the discovery of a mouse model of chronic WNV infection using the Collaborative Cross, a panel of reproducible recombinant inbred mouse strains with a high degree of standing genetic variation. Further, we find that chronic disease is associated with altered innate immunity and increased regulatory T cell frequency, and we find that chronically infected mice have lower expression of genes associated with cytolysis. Thus, in addition to discovery of a new chronic infection model that may be useful for other neuroinvasive infections, we provide an immunologic mechanism by which chronic virus infection can be established.

West Nile Virus (WNV) is an emerging neuroinvasive flavivirus that causes serious encephalitis disease that is lethal in 6% of human cases. The immunopathology of WNV infection has been well-studied in C57BL/6J mice, but the model lacks the diversity in susceptibility and outcomes that are observed in humans, thus limiting its usefulness as a model to understand the host genetics and overall breadth of WNV infection outcomes and immune response. We are using the Collaborative Cross (CC) mouse model to evaluate the pathobiology and immune regulation that underlies WNV disease progression and neuroinvasion. Our studies reveal that the CC model captures the diversity in susceptibility and outcomes of WNV observed in humans. We generated a standardized histology scoring system to evaluate viral localization and immunopathology of WNV infection in tissue including brain isolates from CC lines. Our studies show a diverse array of histological phenotypes that link with the susceptibility and disease outcomes of the CC mice with WNV infection. Time course studies also showed variation in the temporal progression of viral induced-pathology and immunopathogenesis among different CC lines. Our findings show that the CC model of WNV is a relevant and powerful mouse model for mechanistic studies of WNV infection and neuropathology. Application of the CC model to genetic mapping of quantitative trait loci that impart immune regulation of WNV infection will be presented.

Using classical test theory, 6 cognitive scales were constructed to address the need for measurement instruments that are reliable and have adequate representation of the difficulty range for both healthy older adults and patients with dementia

Six newly constructed cognitive scales with strong reliability for both Alzheimer's disease (AD) patients and healthy older adults were used to examine the pattern of deficits in AD. The performance of 31 patients with mild to moderate probable AD was impaired on all scales (p < .0005) relative to that of 31 age‐ and education‐matched normal controls. In the AD patients, the scales revealed profound, equivalent deficits in secondary verbal and nonverbal memory. Nonmemory deficits were most severe on a measure of executive function (mazes), which was followed by verbal reasoning, visual‐spatial reasoning and vocabulary. From these results, we hypothesized that primary dysfunction of frontal association areas may exceed that of parietal areas in AD. The relationship of this hypothesis to findings from previous studies of neu‐ropathological changes, cerebral glucose metabolism, and cognitive deficits in AD is discussed.