Cat COVID, CMV and Chemokines, Oh My!

Cytomegalovirus (CMV) is an important pathogen infecting most humans worldwide. CMV infection within immunocompromised individuals can cause severe morbidity and potential mortality. Disease during CMV infection is due to virus dissemination and subsequent inflammation. Host immune cells lie at the intersection potentially mediating both. The CMV-encoded viral chemokine vCXCL-1 is a proposed virulence factor in mouse models increasing immune cell recruitment and disease. However, the primary immune cell mediator is undetermined. To identify targets, Chapter 2 examines CXCR2 expression (receptor for vCXCL-1) among various mouse tissues and human peripheral blood under steady-state conditions. In vitro, isoforms of HCMV’s vCXCL-1 induce differential outcomes even when acting upon the same cells/receptors (termed functional selectivity), the in vivo consequences of which are unknown. In Chapter 3, recombinant MCMVs expressing vCXCL-1 in vivo, as well as purified chemokine in vitro, and protein modeling in silico help further characterize functional differences between viral and host chemokines. We additionally identified a conserved, unique region within the C-terminus of vCXCL-1. These observations provide the basis for future studies of CMV pathogenesis. Following recruitment to a site of infection, viral uptake occurs infecting migrated cells. Prevention of viral entry is an attractive therapeutic target to lessen viral burden and disease. However, there are limitations in relating in vitro assays to in vivo, as MCMV derived in vivo displays altered entry phenotypes rendering attachment and entry inhibitors less effective. In Chapters 4 and 5 we further characterized differences between in vitro and in vivo derived MCMV. In Chapter 4, in vitro and in vivo virus display different dependencies on cell surface heparan sulfate proteoglycans (HS) for attachment, with in vivo virus less dependent on HS and potentially utilizing different moieties. Chapter 5 further demonstrates in vivo virus’ reduced HS interaction. In vivo virus was additionally found to be of a uniform size and contain submicron particle distributions (potentially extracellular vesicles) different from in vitro derived virus. While submicron particles did not appear to play a role to enhance infection in vitro, their exact role is unknown. These advances can hopefully better inform development of anti-CMV therapeutics

Circumpolar Diversity and Geographic Differentiation of mtDNA in the Critically Endangered Antarctic Blue Whale (Balaenoptera musculus intermedia)

To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work.\ud This is the publisher’s final pdf. The published article is copyrighted by the Public Library of Science and can be found at: http://www.plosone.org/home.action.The Antarctic blue whale (Balaenoptera musculus intermedia) was hunted to near extinction between 1904 and 1972, declining from an estimated initial abundance of more than 250,000 to fewer than 400. Here, we describe mtDNA control region diversity and geographic differentiation in the surviving population of the Antarctic blue whale, using 218 biopsy samples collected under the auspices of the International Whaling Commission (IWC) during research cruises from 1990-2009. Microsatellite genotypes and mtDNA sequences identified 166 individuals among the 218 samples and documented movement of a small number of individuals, including a female that traveled at least 6,650 km or 131 degrees longitude over four years. mtDNA sequences from the 166 individuals were aligned with published sequences from 17 additional individuals, resolving 52 unique haplotypes from a consensus length of 410 bp. From this minimum census, a rarefaction analysis predicted that only 72 haplotypes (95% CL, 64, 86) have survived in the contemporary population of Antarctic blue whales. However, haplotype diversity was relatively high (0.968 +/- 0.004), perhaps as a result of the longevity of blue whales and the relatively recent timing of the bottleneck. Despite the potential for circumpolar dispersal, we found significant differentiation in mtDNA diversity (F-ST = 0.032, p<0.005) and microsatellite alleles (F-ST = 0.005, p<0.05) among the six Antarctic Areas historically used by the IWC for management of blue whales

One planet regions: planetary health at the local level

One of the key lessons that can be learnt from the history of public health is that many major public health advances—from clean drinking water to tobacco control—have been led at the local level. As we enter the Anthropocene, and strive to embrace an ecosocial approach that can address the implications for population health of the global ecological changes humans are creating,1 once again much of the leadership and action will need to occur at the local level

Critical considerations for the practical utility of health equity tools: a concept mapping study

Background Promoting health equity within health systems is a priority and challenge worldwide. Health equity tools have been identified as one strategy for integrating health equity considerations into health systems. Although there has been a proliferation of health equity tools, there has been limited attention to evaluating these tools for their practicality and thus their likelihood for uptake. Methods Within the context of a large program of research, the Equity Lens in Public Health (ELPH), we conducted a concept mapping study to identify key elements and themes related to public health leaders and practitioners’ views about what makes a health equity tool practical and useful. Concept mapping is a participatory mixed-method approach to generating ideas and concepts to address a common concern. Participants brainstormed responses to the prompt “To be useful, a health equity tool should…” After participants sorted responses into groups based on similarity and rated them for importance and feasibility, the statements were analyzed using multidimensional scaling, then grouped using cluster analysis. Pattern matching graphs were constructed to illustrate the relationship between the importance and feasibility of statements, and go-zone maps were created to guide subsequent action. Results The process resulted in 67 unique statements that were grouped into six clusters: 1) Evaluation for Improvement; 2) User Friendliness; 3) Explicit Theoretical Background; 4) Templates and Tools 5) Equity Competencies; and 6) Nothing about Me without Me- Client Engaged. The result was a set of concepts and themes describing participants’ views of the practicality and usefulness of health equity tools. Conclusions These thematic clusters highlight the importance of user friendliness and having user guides, templates and resources to enhance use of equity tools. Furthermore, participants’ indicated that practicality was not enough for a tool to be useful. In addition to practical characteristics of the tool, a useful tool is one that encourages and supports the development of practitioner competencies to engage in equity work including critical reflections on power and institutional culture as well as strategies for the involvement of community members impacted by health inequities in program planning and delivery. The results of this study will be used to inform the development of practical criteria to assess health equity tools for application in public health

Exiting the Anthropocene : Achieving personal and planetary health in the 21st century

Planetary health provides a perspective of ecological interdependence that connects the health and vitality of individuals, communities, and Earth's natural systems. It includes the social, political, and economic ecosystems that influence both individuals and whole societies. In an era of interconnected grand challenges threatening health of all systems at all scales, planetary health provides a framework for cross-sectoral collaboration and unified systems approaches to solutions. The field of allergy is at the forefront of these efforts. Allergic conditions are a sentinel measure of environmental impact on human health in early life-illuminating how ecological changes affect immune development and predispose to a wider range of inflammatory noncommunicable diseases (NCDs). This shows how adverse macroscale ecology in the Anthropocene penetrates to the molecular level of personal and microscale ecology, including the microbial systems at the foundations of all ecosystems. It provides the basis for more integrated efforts to address widespread environmental degradation and adverse effects of maladaptive urbanization, food systems, lifestyle behaviors, and socioeconomic disadvantage. Nature-based solutions and efforts to improve nature-relatedness are crucial for restoring symbiosis, balance, and mutualism in every sense, recognizing that both personal lifestyle choices and collective structural actions are needed in tandem. Ultimately, meaningful ecological approaches will depend on placing greater emphasis on psychological and cultural dimensions such as mindfulness, values, and moral wisdom to ensure a sustainable and resilient future.Peer reviewe

Anticytomegalovirus Peptides Point to New Insights for CMV Entry Mechanisms and the Limitations of In Vitro Screenings

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease following in utero exposure, during primary infection, or la- tent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation. These treatments have unwanted side effects, and HCMV is be- coming resistant to them. Therefore, we sought to develop an alternative treatment that targets a different stage in viral infection. Currently, small antiviral peptides are being investigated as anti-influenza and anti-HIV treatments. We have developed heparan sulfate-binding peptides as tools for preventing CMV infections. These pep- tides are highly effective at stopping infection of fibroblasts with in vitro-derived HCMV and murine cytomegalovirus (MCMV). However, they do not prevent MCMV infection in vivo. Interestingly, these peptides inhibit infectivity of in vivo-derived CMVs, albeit not as well as tissue culture-grown CMVs. We further demonstrate that this class of heparan sulfate-binding peptides is incapable of inhibiting MCMV cell- to-cell spread, which is independent of heparan sulfate usage. These data indicate that inhibition of CMV infection can be achieved using synthetic polybasic peptides, but cell-to-cell spread and in vivo-grown CMVs require further investigation to de- sign appropriate anti-CMV peptides

The Human Cytomegalovirus Chemokine vCXCL-1 Modulates Normal Dissemination Kinetics of Murine Cytomegalovirus In Vivo

Human cytomegalovirus (HCMV) is a betaherpesvirus that is a significant pathogen within newborn and immunocompromised populations. Morbidity associated with HCMV infection is the consequence of viral dissemination. HCMV has evolved to manipulate the host immune system to enhance viral dissemination and ensure long-term survival within the host. The immunomodulatory protein vCXCL-1, a viral chemokine functioning primarily through the CXCR2 chemokine receptor, is hypothesized to attract CXCR2+ neutrophils to infection sites, aiding viral dissemination. Neutrophils harbor HCMV in vivo; however, the interaction between vCXCL-1 and the neutrophil has not been evaluated in vivo. Using the mouse model and mouse cytomegalovirus (MCMV) infection, we show that murine neutrophils harbor and transfer infectious MCMV and that virus replication initiates within this cell type. Utilizing recombinant MCMVs expressing vCXCL-1 from the HCMV strain (Toledo), we demonstrated that vCXCL-1 significantly enhances MCMV dissemination kinetics. Through cellular depletion experiments, we observe that neutrophils impact dissemination but that overall dissemination is largely neutrophil independent. This work adds neutrophils to the list of innate cells (i.e., dendritic and macrophages/monocytes) that contribute to MCMV dissemination but refutes the hypothesis that neutrophils are the primary cell responding to vCXCL-1

Circumpolar Diversity and Geographic Differentiation of mtDNA in the Critically Endangered Antarctic Blue Whale (Balaenoptera musculus intermedia)

The Antarctic blue whale (Balaenoptera musculus intermedia) was hunted to near extinction between 1904 and 1972, declining from an estimated initial abundance of more than 250,000 to fewer than 400. Here, we describe mtDNA control region diversity and geographic differentiation in the surviving population of the Antarctic blue whale, using 218 biopsy samples collected under the auspices of the International Whaling Commission (IWC) during research cruises from 1990-2009. Microsatellite genotypes and mtDNA sequences identified 166 individuals among the 218 samples and documented movement of a small number of individuals, including a female that traveled at least 6,650 km or 131 degrees longitude over four years. mtDNA sequences from the 166 individuals were aligned with published sequences from 17 additional individuals, resolving 52 unique haplotypes from a consensus length of 410 bp. From this minimum census, a rarefaction analysis predicted that only 72 haplotypes (95% CL, 64, 86) have survived in the contemporary population of Antarctic blue whales. However, haplotype diversity was relatively high (0.968 +/- 0.004), perhaps as a result of the longevity of blue whales and the relatively recent timing of the bottleneck. Despite the potential for circumpolar dispersal, we found significant differentiation in mtDNA diversity (F-ST = 0.032, p<0.005) and microsatellite alleles (F-ST = 0.005, p<0.05) among the six Antarctic Areas historically used by the IWC for management of blue whales

Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells.

Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection