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α-Dystroglycan (α-DG) is uniquely modified on O -mannose sites by a repeating disaccharide (-Xylα1,3-GlcAβ1,3-) n termed matriglycan, which is a receptor for laminin-G domain-containing proteins and employed by old-world arenaviruses for infection. Using chemoenzymatically synthesized matriglycans printed as a microarray, we demonstrate length-dependent binding to Laminin, Lassa virus GP1, and the clinically-important antibody IIH6. Utilizing an enzymatic engineering approach, an N -linked glycoprotein was converted into a IIH6-positive Laminin-binding glycoprotein. Engineering of the surface of cells deficient for either α-DG or O -mannosylation with matriglycans of sufficient length recovers infection with a Lassa-pseudovirus. Finally, free matriglycan in a dose and length dependent manner inhibits viral infection of wildtype cells. These results indicate that matriglycan alone is necessary and sufficient for IIH6 staining, Laminin and LASV GP1 binding, and Lassa-pseudovirus infection and support a model in which it is a tunable receptor for which increasing chain length enhances ligand-binding capacity. Matriglycan, a repeating disaccharide on α-dystroglycan, is the receptor for Lassa virus and specific extracellular matrix proteins. Here, the authors demonstrate that matriglycan, in a length-dependent tunable manner, is both necessary and sufficient for protein binding and viral infection.

Report of a human death and exposure of white-tailed deer to Heartland virus (HRTV) in Georgia, USA, prompted the sampling of questing ticks during 2018-2019 in 26 sites near where seropositive deer were captured and the residence of the human case-patient. We processed 9,294 Amblyomma americanum ticks in pools by virus isolation in Vero E6 cells and reverse transcription PCR. Positive pools underwent whole-genome sequencing. Three pools were positive for HRTV (minimum infection rate 0.46/1,000 ticks) and none for Bourbon virus. Cell cultures confirmed HRTV presence in 2 pools. Genome sequencing, achieved for the 3 HRTV isolates, showed high similarity among samples but marked differences with previously sequenced HRTV isolates. The isolation and genomic characterization of HRTV from A. americanum ticks in Georgia confirm virus presence in the state. Clinicians and public health professionals should be aware of this emerging tickborne pathogen.

The ruffed grouse ( Bonasa umbellus ) is a non-migratory upland game bird that inhabits young and mature forests in the USA and Canada. Population indices in some portions of its range, particularly the eastern USA, have been in decline since the arrival of West Nile virus (WNV), a mosquito-borne Flavivirus . Subsequent experimental research suggested that WNV may cause morbidity and/or mortality in up to 90% of grouse, which had similar clinicopathologic findings to naturally-infected grouse. Additionally, WNV serosurveys in Pennsylvania revealed low seroprevalence concurrent with elevated vector indices. To further elucidate aspects of WNV epidemiology in ruffed grouse, we tested hunter-collected filter paper strips for anti-WNV antibodies in 15 states during fall-winter, 2018–2022. Annual total seroprevalence ranged from 12.0% in 2019–2020 to 17.9% in 2021–2022. We assessed for associations between county-level WNV seroprevalence and large-scale climate, environmental, and landscape variables through Bayesian multilevel modeling, accounting for spatial autocorrelation. The top model suggested that WNV seroprevalence was positively correlated with summer precipitation; the second most supported model suggested similar findings of positive correlation between WNV seroprevalence and spring precipitation. Management strategies should prioritize understanding factors that influence mosquito-borne pathogen transmission in conjunction with providing more forested habitat of high quality for ruffed grouse to optimize survival in the face of WNV and other challenges.

Vector-borne parasites may be transmitted by multiple vector species, resulting in an increased risk of transmission, potentially at larger spatial scales compared to any single vector species. Additionally, the different abilities of patchily distributed vector species to acquire and transmit parasites will lead to varying degrees of transmission risk. Investigation of how vector community composition and parasite transmission change over space due to variation in environmental conditions may help to explain current patterns in diseases but also informs our understanding of how patterns will change under climate and land-use change. We developed a novel statistical approach using a multi-year, spatially extensive case study involving a vector-borne virus affecting white-tailed deer transmitted by Culicoides midges. We characterized the structure of vector communities, established the ecological gradient controlling change in structure, and related the ecology and structure to the amount of disease reporting observed in host populations. We found that vector species largely occur and replace each other as groups, rather than individual species. Moreover, community structure is primarily controlled by temperature ranges, with certain communities being consistently associated with high levels of disease reporting. These communities are essentially composed of species previously undocumented as potential vectors, whereas communities containing putative vector species were largely associated with low levels, or even absence, of disease reporting. We contend that the application of metacommunity ecology to vector-borne infectious disease ecology can greatly aid the identification of transmission hotspots and an understanding of the ecological drivers of parasite transmission risk both now and in the future.

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility. PU.1 is a master regulator of myeloid development but its role in disease-relevant neutrophils is not well known. Here, the authors look at primary neutrophils from a human population and find that genetic variants affecting binding of PU.1 are associated with cell count and disease susceptibility.

Theoretical models suggest that increased vector species participation in pathogen transmission significantly increases the prevalence of vector and host infections. However, there has been a lack of empirical evidence to support this. We linked transmission potential of multiple vector species to observed patterns of enzootic pathogen transmission by conducting longitudinal field surveillance of West Nile virus (WNv) infections in Culex spp. mosquitoes and avian host communities in the southeast U.S. We then used a temperature‐dependent vectorial capacity model as a predictor of WNv infections in mosquitoes and birds using general linear mixed effects models. Two WNv‐competent Culex spp. mosquitoes were present in our study sites, Culex restuans Theobald during the spring and Culex quinquefasciatus Say during the summer. Empirical evidence of WNv transmission was limited exclusively to time periods when night time temperatures were suitable for accelerated within‐vector viral replication, susceptible avian hosts (i.e. hatch year birds) were abundant and Cx. quinquefasciatus was the primary Culex spp. vector in the mosquito community. Contrary to theoretical predictions, increased presence of competent vector species through time did not significantly increase the prevalence of infections in the WNv enzootic system. Synthesis and applications. We extend a common theoretical model to both estimate the transmission potential of a mosquito community for West Nile virus (WNv) and quantify the relative contribution of two Culex mosquito species (Culex quinquefasciatus and Culex restuans) to observed patterns of WNv in the southeast U.S. Our findings suggest that to reduce the risk of human exposure to WNv in urban environments, vector control should focus on the primary WNv vector, Cx. quinquefasciatus. Additionally, vector control may be more effective if it coincides with the onset of the avian breeding season, when most WNv amplification occurs. Moreover, our results highlight relevant knowledge gaps pertaining to WNv transmission by secondary mosquito species that coexist either in time or space with Cx. quinquefasciatus. A better understanding of secondary WNv vector species is greatly needed in order to appropriately gauge their role in pathogen transmission dynamics. We extend a common theoretical model to both estimate the transmission potential of a mosquito community for West Nile virus (WNv) and quantify the relative contribution of two Culex mosquito species (Culex quinquefasciatus and Culex restuans) to observed patterns of WNv in the southeast U.S. Our findings suggest that to reduce the risk of human exposure to WNv in urban environments, vector control should focus on the primary WNv vector, Cx. quinquefasciatus. Additionally, vector control may be more effective if it coincides with the onset of the avian breeding season, when most WNv amplification occurs. Moreover, our results highlight relevant knowledge gaps pertaining to WNv transmission by secondary mosquito species that coexist either in time or space with Cx. quinquefasciatus. A better understanding of secondary WNv vector species is greatly needed in order to appropriately gauge their role in pathogen transmission dynamics.

West Nile virus (WNV) has been implicated in regional declines of numerous North American bird species, although its potential impact upon many species, including some game birds, remains unknown. Specifically, information about susceptibility to infection and infection outcome are crucial to assessing health risks. Northern bobwhite quail (Colinus virginianus) are a popular and common game bird across much of the United States, as well as in captive breeding programs and as backyard birds. Two age groups of bobwhites were subcutaneously inoculated with WNV and euthanatized on 15 days postinoculation (DPI). Three of 10 inoculated 5-wk-old and 4/10 inoculated 15-wk-old birds developed detectable viremia titers during 1–5 DPI, with low peak titers (101.7–103.0 plaque-forming units [PFU]/ml). Three of 10 inoculated 5-wk-old and 1/10 inoculated 15-wk-old birds shed low viral titers (peak 100.7–101.8 PFU/swab) either orally or cloacally or both for limited periods from 2 to 6 DPI. All inoculated birds (n = 20) remained apparently healthy and seroconverted by 15 DPI. No infectious virus was detected in select tissues: heart, kidney, brain, skeletal muscle, spleen (15-wk-old group only), and feathers from any of the bobwhites. No sham-inoculated, contact control birds (n = 8) became viremic or had virus isolated from tissues or swabs. The most consistent microscopic lesion was minimal to mild, lymphoplasmacytic myocarditis (6/10 in 5-wk-olds; 5/10 in 15-wk-olds). Immunohistochemical labeling was most often in macrophages in spleen and bone marrow, likely reflective of clearance of infection. There were no statistically significant differences in the peak viremia and shedding titers between age groups and no differences in the development of WNV-associated lesions between the two age groups. These results suggest that WNV is unlikely to pose a health risk to bobwhites and that bobwhites likely are an incompetent reservoir host species in WNV transmission.

Recent spillback events of SARS-CoV-2 from humans to animals has raised concerns about it becoming endemic in wildlife. A sylvatic cycle of SARS-CoV-2 could present multiple opportunities for repeated spillback into human populations and other susceptible wildlife. Based on their taxonomy and natural history, two native North American wildlife species —the striped skunk ( Mephitis mephitis ) and the raccoon ( Procyon lotor) —represent a high likelihood of susceptibility and ecological opportunity of becoming infected with SARS-CoV-2. Eight skunks and raccoons were each intranasally inoculated with one of two doses of the virus (10 3 PFU and 10 5 PFU) and housed in pairs. To evaluate direct transmission, a naïve animal was added to each inoculated pair 48 h post-inoculation. Four control animals of each species were handled like the experimental groups. At predetermined intervals, we collected nasal and rectal swabs to quantify virus shed via virus isolation and detect viral RNA via rRT-PCR and blood for serum neutralization. Lastly, animals were euthanized at staggered intervals to describe disease progression through histopathology and immunohistochemistry. No animals developed clinical disease. All intranasally inoculated animals seroconverted, suggesting both species are susceptible to SARS-CoV-2 infection. The highest titers in skunks and raccoons were 1:128 and 1:64, respectively. Low quantities of virus were isolated from 2/8 inoculated skunks for up to day 5 post-inoculation, however no virus was isolated from inoculated raccoons or direct contacts of either species. Neither species had gross lesions, but recovering mild chronic pneumonia consistent with viral insult was recorded histologically in 5/8 inoculated skunks. Unlike another SARS-CoV-2 infection trial in these species, we detected neutralizing antibodies in inoculated raccoons; thus, future wildlife serologic surveillance results must be interpreted with caution. Due to the inability to isolate virus from raccoons, the lack of evidence of direct transmission between both species, and low amount of virus shed by skunks, it seems unlikely for SARS-CoV-2 to become established in raccoon and skunk populations and for virus to spillback into humans. Continued outbreaks in non-domestic species, wild and captive, highlight that additional research on the susceptibility of SARS-CoV-2 in wildlife, especially musteloidea, and of conservation concern, is needed.

Burkholderia mallei is a host-adapted bacterium that does not persist outside of its equine reservoir. The organism causes the zoonosis glanders, which is endemic in Asia, Africa, the Middle East and South America. Infection by B. mallei typically occurs via the respiratory or percutaneous route, and the most common manifestations are life-threatening pneumonia and bacteremia. Glanders is difficult to diagnose and requires prolonged antibiotic therapy with low success rates. There is no vaccine to protect against B. mallei and there is concern regarding its use as a biothreat agent. Thus, experiments were performed to establish a non-human primate model of intranasal infection to study the organism and develop countermeasures. Groups of marmosets (Callithrix jacchus) were inoculated intranasally with B. mallei strain ATCC 23344 and monitored for clinical signs of illness for up to 13 days. We discovered that 83% of marmosets inoculated with doses of 2.5 X 10(4) to 2.5 X 10(5) bacteria developed acute lethal infection within 3-4 days. Signs of disease were severe and included lethargy, inappetence, conjunctivitis, mucopurulent and hemorrhagic nasal discharges, and increased respiratory effort with abdominal lifts. Burkholderia mallei was cultured from the lungs, spleen and liver of these animals, and pathologic examination of tissues revealed lesions characteristic of glanders. Challenge experiments also revealed that 91% of animals infected with doses ranging from 25 to 2.5 X 10(3) bacteria exhibited mild non-specific signs of illness and were culture negative. One marmoset inoculated with 2.5 X 10(3) organisms developed moderate signs of disease and reached humane end-points 8 days post-infection. The liver and spleen of this animal were colonized with the agent and pathological analysis of tissues showed nasal, splenic and hepatic lesions. Taken together, these data indicate that the marmoset is a suitable model to study respiratory infection by B. mallei.