Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 84 Records) |
Query Trace: Welch P [original query] |
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Effect of adopting a Timothy Hay-Based Diet at weaning or in adulthood on urinary tract parameters in strain 13/n guinea pigs (Cavia porcellus)
Wier RC , Flietstra TD , Coleman-McCray JD , Genzer SC , Brake ME , Velazquez EM , Forero C , Welch SR , Tansey CM , Condrey JA , Spengler JR . J Am Assoc Lab Anim Sci 2024 Type of feed is an important consideration in herbivore colony management, yet limited studies report on the effects of diet on common conditions such as urolithiasis in guinea pigs. Urolithiasis is a well-documented cause of lower urinary tract disease in guinea pigs, with calcium carbonate uroliths reported as the predominant calculi formed in the guinea pig urinary tract. A calcium-rich diet has been suggested as a risk factor for of urolithiasis, with numerous commercially available guinea pig diets formulated for adults avoiding ingredients that are higher in calcium. Due to the high incidence of urolithiasis in our strain 13/N guinea pig colony, we conducted a prospective control study following the implementation of dietary changes aimed at improving overall urinary tract health and reducing risk factors for urolithiasis, thus improving colony welfare. A control group was kept on the original ad libitum alfalfa hay-based pellet diet with restricted loose timothy hay (control diet, 14 juveniles and 24 adults). An experimental group was placed on a portioned, 1 oz daily, timothy hay-based pellet diet with ad libitum loose timothy hay (experimental diet, 21 juveniles and 23 adults). Juveniles and adults were followed for a total of 14 and 26 wk, respectively. Longitudinal blood and urine samples were collected to evaluate blood chemistry and urinary parameters, along with weight and body condition scores to assess general health. Overall, dietary changes did not improve parameters associated with improved urinary tract health or reduced risk of urolithiasis; feeding strategy was not found to meaningfully affect calcium crystalluria, urine protein, urine specific gravity, or renal values. These data support alfalfa hay-based pellet or timothy hay-based pellet, when fed with loose timothy hay, as viable options and suggest that practices aimed at reducing dietary calcium by reducing pelleted diet portions are insufficient to mitigate risk factors for urolithiasis in guinea pigs. |
Third International Conference on Crimean-Congo Hemorrhagic Fever in Thessaloniki, Greece, September 19-21, 2023
Welch SR , Garrison AR , Bente DA , Burt F , D'Addiego J , Devignot S , Dowall S , Fischer K , Hawman DW , Hewson R , Mirazimi A , Oestereich L , Vatansever Z , Spengler JR , Papa A . Antiviral Res 2024 225 105844 The Third International Conference on Crimean-Congo Hemorrhagic Fever (CCHF) was held in Thessaloniki, Greece, September 19-21, 2023, bringing together a diverse group of international partners, including public health professionals, clinicians, ecologists, epidemiologists, immunologists, and virologists. The conference was attended by 118 participants representing 24 countries and the World Health Organization (WHO). Meeting sessions covered the epidemiology of CCHF in humans; Crimean-Congo hemorrhagic fever virus (CCHFV) in ticks; wild and domestic animal hosts; molecular virology; pathogenesis and animal models; immune response related to therapeutics; and CCHF prevention in humans. The concluding session focused on recent WHO recommendations regarding disease prevention, control strategies, and innovations against CCHFV outbreaks. This meeting report summarizes lectures by the invited speakers and highlights advances in the field. |
Racial and ethnic disparities in phthalate exposure and preterm birth: A pooled study of sixteen U.S. Cohorts
Welch BM , Keil AP , Buckley JP , Engel SM , James-Todd T , Zota AR , Alshawabkeh AN , Barrett ES , Bloom MS , Bush NR , Cordero JF , Dabelea D , Eskenazi B , Lanphear BP , Padmanabhan V , Sathyanarayana S , Swan SH , Aalborg J , Baird DD , Binder AM , Bradman A , Braun JM , Calafat AM , Cantonwine DE , Christenbury KE , Factor-Litvak P , Harley KG , Hauser R , Herbstman JB , Hertz-Picciotto I , Holland N , Jukic AMZ , McElrath TF , Meeker JD , Messerlian C , Michels KB , Newman RB , Nguyen RHN , O'Brien KM , Rauh VA , Redmon B , Rich DQ , Rosen EM , Schmidt RJ , Sparks AE , Starling AP , Wang C , Watkins DJ , Weinberg CR , Weinberger B , Wenzel AG , Wilcox AJ , Yolton K , Zhang Y , Ferguson KK . Environ Health Perspect 2023 131 (12) 127015 BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): - 34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: - 19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831. |
Characterization of humoral responses to Nipah virus infection in the Syrian Hamster model of disease
Scholte FEM , Rodriguez SE , Welch SR , Davies KA , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Lo MK , Karaaslan E , Bergeron E , Montgomery JM , Spengler JR , Spiropoulou CF . J Infect Dis 2023 Nipah virus (NiV) is a highly pathogenic paramyxovirus. The Syrian hamster model recapitulates key features of human NiV disease and is a critical tool for evaluating antivirals and vaccines. Here we describe longitudinal humoral immune responses in NiV-infected Syrian hamsters. Samples were obtained 1-28 days after infection and analyzed by ELISA, neutralization, and Fc-mediated effector function assays. NiV infection elicited robust antibody responses against the nucleoprotein and attachment glycoprotein. Levels of neutralizing antibodies were modest and only detectable in surviving animals. Fc-mediated effector functions were mostly observed in nucleoprotein-targeting antibodies. Antibody levels and activities positively correlated with challenge dose. |
Author Correction: Multiplexed CRISPR-based microfluidic platform for clinical testing of respiratory viruses and identification of SARS-CoV-2 variants
Welch NL , Zhu M , Hua C , Weller J , Mirhashemi ME , Nguyen TG , Mantena S , Bauer MR , Shaw BM , Ackerman CM , Thakku SG , Tse MW , Kehe J , Uwera MM , Eversley JS , Bielwaski DA , McGrath G , Braidt J , Johnson J , Cerrato F , Moreno GK , Krasilnikova LA , Petros BA , Gionet GL , King E , Huard RC , Jalbert SK , Cleary ML , Fitzgerald NA , Gabriel SB , Gallagher GR , Smole SC , Madoff LC , Brown CM , Keller MW , Wilson MM , Kirby MK , Barnes JR , Park DJ , Siddle KJ , Happi CT , Hung DT , Springer M , MacInnis BL , Lemieux JE , Rosenberg E , Branda JA , Blainey PC , Sabeti PC , Myhrvold C . Nat Med 2023 In the version of the article originally published, some of the oligonucleotide sequences in Supplementary Table 4, on the “21 viruses” and “RVP” tabs, were mislabeled. The Supplementary Tables file has now been corrected. |
Optimal reference genes for RNA tissue analysis in small animal models of hemorrhagic fever viruses
Davies KA , Welch SR , Sorvillo TE , Coleman-McCray JD , Martin ML , Brignone JM , Montgomery JM , Spiropoulou CF , Spengler JR . Sci Rep 2023 13 (1) 19384 Reverse-transcription quantitative polymerase chain reaction assays are frequently used to evaluate gene expression in animal model studies. Data analyses depend on normalization using a suitable reference gene (RG) to minimize effects of variation due to sample collection, sample processing, or experimental set-up. Here, we investigated the suitability of nine potential RGs in laboratory animals commonly used to study viral hemorrhagic fever infection. Using tissues (liver, spleen, gonad [ovary or testis], kidney, heart, lung, eye, brain, and blood) collected from naïve animals and those infected with Crimean-Congo hemorrhagic fever (mice), Nipah (hamsters), or Lassa (guinea pigs) viruses, optimal species-specific RGs were identified based on five web-based algorithms to assess RG stability. Notably, the Ppia RG demonstrated stability across all rodent tissues tested. Optimal RG pairs that include Ppia were determined for each rodent species (Ppia and Gusb for mice; Ppia and Hrpt for hamsters; and Ppia and Gapdh for guinea pigs). These RG pair assays were multiplexed with viral targets to improve assay turnaround time and economize sample usage. Finally, a pan-rodent Ppia assay capable of detecting Ppia across multiple rodent species was developed and successfully used in ecological investigations of field-caught rodents, further supporting its pan-species utility. |
Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers
Bommarito PA , Friedman A , Welch BM , Cantonwine DE , Ospina M , Calafat AM , Meeker JD , McElrath TF , Ferguson KK . Environ Int 2023 180 108194 BACKGROUND: Organophosphate esters (OPEs), used as flame retardants and plasticizers, are chemicals of concern for maternal and infant health. Prior studies examining temporal trends and predictors of OPE exposure are primarily limited by small sample sizes. OBJECTIVES: Characterize temporal trends and predictors of OPE exposure biomarkers. METHODS: We determined urinary concentrations of eight biomarkers of OPE exposure at three timepoints during pregnancy for participants in the LIFECODES Fetal Growth Study (n = 900), a nested case-cohort recruited between 2007 and 2018. We examined biomarker concentrations, their variability during pregnancy, and temporal trends over the study period. In addition, we identified sociodemographic and pregnancy characteristics associated with biomarker concentrations. Analyses were conducted using both the within-subject pregnancy geometric means and biomarker concentrations measured at individual study visits. RESULTS: Five OPE biomarkers were detected in at least 60% of the study participants. Biomarkers were not strongly correlated with one another and intraclass correlation coefficients, measuring within-subject variability during pregnancy, ranged from 0.27 to 0.51. Biomarkers exhibited varying temporal trends across study years. For example, bis(1-chloro-2-propyl) phosphate (BCIPP) increased monotonically, whereas bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), displayed non-monotonic trends with concentrations that peaked between 2011 and 2014. We observed associations between sociodemographic characteristics and OPE biomarkers. In general, concentrations of most OPE biomarkers were higher among participants from racial and ethnic minority populations, participants who were younger, had higher pre-pregnancy body mass index (BMI), and less than a college degree. We observed consistent results using either averaged or visit-specific biomarker concentrations. SIGNIFICANCE: We observed widespread exposure to several OPEs and OPE biomarkers displayed varying temporal trends in pregnant people from 2007 to 2018. Concentrations of most OPE biomarkers varied according to sociodemographic factors, suggesting higher burdens of exposure among participants with higher pre-pregnancy BMI, those belonging to racial and ethnic minority populations, and lower educational attainment. |
Medicaid coverage of guidelines-based asthma care across 50 states, the District of Columbia, and Puerto Rico, 2021-2022
Link J , Green H , Kaplan B , Collins P , Welch P , Johnson C . Prev Chronic Dis 2023 20 E79 INTRODUCTION: Asthma affects more than 25 million Americans, including 4.2 million children. The burden of asthma disproportionately affects people enrolled in Medicaid, among other disparate groups. Improved availability and accessibility of guidelines-based treatments and services may ensure positive health outcomes for people with asthma. In this article, we provide an update to the American Lung Association's Asthma Guidelines-Based Care Coverage Project (the Project) to determine the extent of asthma care coverage and associated barriers in Medicaid programs for all 50 states, the District of Columbia, and Puerto Rico, and examine improvements in coverage since 2017. METHODS: Findings from the Project, representing coverage from 2016-2017, were first published in Preventing Chronic Disease in 2018. The Project was updated in 2021 to reflect the National Asthma Education and Prevention Program guidelines 2020 Expert Panel Report-3 updates, which were finalized in December 2020. It now tracks coverage for 8 areas of guidelines-based care and 7 barriers to care in Medicaid programs by reviewing publicly available plan documents and engaging with Medicaid programs to review and confirm findings. RESULTS: Results from the Project, which reflect coverage in 2021-2022, show an increase in comprehensive coverage in Medicaid programs over the last 5 years. However, coverage remains inconsistent across programs, and barriers to accessing asthma care still exist. CONCLUSION: Although substantial improvement has been made to coverage, certain gaps and barriers to care must be addressed for patients to fully benefit from guidelines-based care to manage their asthma and improve health outcomes. |
Vaccination with the Crimean-Congo hemorrhagic fever virus viral replicon vaccine induces NP-based T-cell activation and antibodies possessing Fc-mediated effector functions
Scholte FEM , Karaaslan E , O'Neal TJ , Sorvillo TE , Genzer SC , Welch SR , Coleman-McCray JD , Spengler JR , Kainulainen MH , Montgomery JM , Pegan SD , Bergeron E , Spiropoulou CF . Front Cell Infect Microbiol 2023 13 1233148 Crimean-Congo hemorrhagic fever virus (CCHFV; family Nairoviridae) is a tick-borne pathogen that frequently causes lethal disease in humans. CCHFV has a wide geographic distribution, and cases have been reported in Africa, Asia, the Middle East, and Europe. Availability of a safe and efficacious vaccine is critical for restricting outbreaks and preventing disease in endemic countries. We previously developed a virus-like replicon particle (VRP) vaccine that provides complete protection against homologous and heterologous lethal CCHFV challenge in mice after a single dose. However, the immune responses induced by this vaccine are not well characterized, and correlates of protection remain unknown. Here we comprehensively characterized the kinetics of cell-mediated and humoral immune responses in VRP-vaccinated mice, and demonstrate that they predominantly target the nucleoprotein (NP). NP antibodies are not associated with protection through neutralizing activity, but VRP vaccination results in NP antibodies possessing Fc-mediated antibody effector functions, such as complement activation (ADCD) and antibody-mediated cellular phagocytosis (ADCP). This suggests that Fc-mediated effector functions may contribute to this vaccine's efficacy. |
Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination
Welch SR , Spengler JR , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Scholte FEM , Rodriguez SE , O'Neal TJ , Ritter JM , Ficarra G , Davies KA , Kainulainen MH , Karaaslan E , Bergeron É , Goldsmith CS , Lo MK , Nichol ST , Montgomery JM , Spiropoulou CF . Sci Adv 2023 9 (31) eadh4057 Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease. |
Development of a neutralization assay using a vesicular stomatitis virus expressing Nipah virus glycoprotein and a fluorescent protein
Jain S , Lo MK , Kainulainen MH , Welch SR , Spengler JR , Satter SM , Rahman MZ , Hossain ME , Chiang CF , Klena JD , Bergeron É , Montgomery JM , Spiropoulou CF , Albariño CG . Virology 2023 587 109858 Nipah virus (NiV) is a highly pathogenic paramyxovirus with a high case fatality rate. Due to its high pathogenicity, pandemic potential, and lack of therapeutics or approved vaccines, its study requires biosafety level 4 (BSL4) containment. In this report, we developed a novel neutralization assay for use in biosafety level 2 laboratories. The assay uses a recombinant vesicular stomatitis virus expressing NiV glycoprotein and a fluorescent protein. The recombinant virus propagates as a replication-competent virus in a cell line constitutively expressing NiV fusion protein, but it is restricted to a single round of replication in wild-type cells. We used this system to evaluate the neutralization activity of monoclonal and polyclonal antibodies, plasma from NiV-infected hamsters, and serum from human patients. Therefore, this recombinant virus could be used as a surrogate for using pathogenic NiV and may constitute a powerful tool to develop therapeutics in low containment laboratories. |
Sustained replication of synthetic canine distemper virus defective genomes in vitro and in vivo (preprint)
Tilston-Lunel NL , Welch SR , Nambulli S , de Vries RD , Ho GW , Wentworth DE , Shabman R , Nichol ST , Spiropoulou CF , de Swart RL , Rennick LJ , Duprex WP . bioRxiv 2021 2021.06.11.448162 Defective interfering (DI) genomes restrict viral replication and induce type-I interferon. Since DI genomes have been proposed as vaccine adjuvants or therapeutic antiviral agents, it is important to understand their generation, delineate their mechanism of action, develop robust production capacities, assess their safety and in vivo longevity and determine their long-term effects. To address this, we generated a recombinant (r) canine distemper virus (CDV) from an entirely synthetic molecular clone designed using the genomic sequence from a clinical isolate obtained from a free-ranging raccoon with distemper. rCDV was serially passaged in vitro to identify DI genomes that naturally arise during rCDV replication. Defective genomes were identified by Sanger and next-generation sequencing techniques and predominant genomes were synthetically generated and cloned into T7-driven plasmids. Fully encapsidated DI particles (DIPs) were then generated using a rationally attenuated rCDV as a producer virus to drive DI genome replication. We demonstrate these DIPs interfere with rCDV replication in a dose-dependent manner in vitro. Finally, we show sustained replication of a fluorescent DIP in experimentally infected ferrets over a period of 14 days. Most importantly, DIPs were isolated from the lymphoid tissues which are a major site of CDV replication. Our established pipeline for detection, generation and assaying DIPs is transferable to highly pathogenic paramyxoviruses and will allow qualitative and quantitative assessment of the therapeutic effects of DIP administration on disease outcome.Importance Defective interfering (DI) genomes have long been considered inconvenient artifacts that suppressed viral replication in vitro. However, advances in sequencing technologies have led to DI genomes being identified in clinical samples, implicating them in disease progression and outcome. It has been suggested that DI genomes could be harnessed therapeutically. Negative strand RNA virus research has provided a rich pool of natural DI genomes over many years and they are probably the best understood in vitro. Here, we demonstrate identification, synthesis, production and experimental inoculation of novel CDV DI genomes in highly susceptible ferrets. These results provide important evidence that rationally designed and packaged DI genomes can survive the course of a wild-type virus infection. |
Equipment-free detection of SARS-CoV-2 and Variants of Concern using Cas13 (preprint)
Arizti-Sanz J , Bradley AD , Zhang YB , Boehm CK , Freije CA , Grunberg ME , Kosoko-Thoroddsen TSF , Welch NL , Pillai PP , Mantena S , Kim G , Uwanibe JN , John OG , Eromon PE , Kocher G , Gross R , Lee JS , Hensley LE , Happi CT , Johnson J , Sabeti PC , Myhrvold C . medRxiv 2021 02 The COVID-19 pandemic, and the recent rise and widespread transmission of SARS-CoV-2 Variants of Concern (VOCs), have demonstrated the need for ubiquitous nucleic acid testing outside of centralized clinical laboratories. Here, we develop SHINEv2, a Cas13-based nucleic acid diagnostic that combines quick and ambient temperature sample processing and lyophilized reagents to greatly simplify the test procedure and assay distribution. We benchmarked a SHINEv2 assay for SARS-CoV-2 detection against state-of-the-art antigen-capture tests using 96 patient samples, demonstrating 50-fold greater sensitivity and 100% specificity. We designed SHINEv2 assays for discriminating the Alpha, Beta, Gamma and Delta VOCs, which can be read out visually using lateral flow technology. We further demonstrate that our assays can be performed without any equipment in less than 90 minutes. SHINEv2 represents an important advance towards rapid nucleic acid tests that can be performed in any location. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. |
Meeting report: 36th international conference on antiviral research in Lyon, France, March 13-17, 2023
Spengler JR , Carter K , Delang L , Durantel D , Gowen BB , Herrero LJ , Hurst B , Janeba Z , Jordan R , Luo D , Meier C , Moffat J , Rocha-Pereira J , Seley-Radtke KL , Welch SR , Schang LM . Antiviral Res 2023 217 105678 The 36th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held March 13-17, 2023, in Lyon, France, and concurrently through an interactive remote meeting platform. Here we provide a report summarizing the presentations at the 36th ICAR, including the ISAR speaker awards. We also detail special events, sessions, and additional awards conferred at the meeting. ICAR returned to in-person meetings in 2022, convening in Seattle, WA, USA. The 36th ICAR is the first in-person meeting of the society in Europe since the beginning of the COVID-19 pandemic, which restricted most events to virtual attendance to help mitigate the spread and subsequent public health impact of SARS-CoV-2. An exceptionally high number of registrants and record attendance at this year's ICAR, along with a vast array of demonstrable expertise in a variety of antiviral research-related fields, reflected a strong and growing antiviral research community committed to improving health outcomes from viral diseases, including SARS-CoV-2, and to future pandemic preparedness. This report highlights the breadth of expertise, quality of research, and notable advancements that were contributed by members of ISAR and other participants at the meeting. ICAR aims to continue to provide a platform for sharing information, fostering collaborations, and supporting trainees in the field of antiviral research. The 37th ICAR will be held in Gold Coast, Australia, May 20-24, 2024. |
Fluorescent and bioluminescent reporter mouse-adapted Ebola viruses maintain pathogenicity and can be visualized in vivo
Davies KA , Welch SR , Jain S , Sorvillo TE , Coleman-McCray JD , Montgomery JM , Spiropoulou CF , Albariño C , Spengler JR . J Infect Dis 2023 228 S536-S547 Ebola virus (EBOV) causes lethal disease in humans but not in mice. Here, we generated recombinant mouse-adapted (MA)-EBOVs, including one based on the previously reported serially adapted strain (rMA-EBOV), along with single-reporter rMA-EBOVs expressing either fluorescent (ZsGreen1 [ZsG]) or bioluminescent (nano-luciferase [nLuc]) reporters, and dual-reporter rMA-EBOVs expressing both ZsG and nLuc. No detriment to viral growth in vitro was seen with inclusion of MA-associated mutations or reporter proteins. In CD-1 mice, infection with MA-EBOV, rMA-EBOV, and single-reporter rMA-EBOVs conferred 100% lethality; infection with dual-reporter rMA-EBOV resulted in 80% lethality. Bioluminescent signal from rMA-EBOV expressing nLuc was detected in vivo and ex vivo using the IVIS Spectrum CT. Fluorescent signal from rMA-EBOV expressing ZsG was detected in situ using hand-held blue-light transillumination and ex vivo through epi-illumination with the IVIS Spectrum CT. These data support the use of reporter MA-EBOV for studies of Ebola virus in animal disease models. |
Assessment of neurodevelopment in infants with and without exposure to asymptomatic or mild maternal SARS-CoV-2 infection during pregnancy
Firestein MR , Shuffrey LC , Hu Y , Kyle M , Hussain M , Bianco C , Hott V , Hyman SP , Kyler M , Rodriguez C , Tejeda Romero M , Tzul Lopez H , Alcántara C , Amso D , Austin J , Bain JM , Barbosa J , Battarbee AN , Bruno A , Ettinger S , Factor-Litvak P , Gilboa S , Goldman S , Gyamfi-Bannerman C , Maniatis P , Marsh R , Morrill T , Mourad M , Muhle R , Newes-Adeyi G , Noble KG , O'Reilly KC , Penn AA , Reichle L , Sania A , Semenova V , Silver WG , Smotrich G , Tita AT , Tottenham N , Varner M , Welch MG , Zork N , Garey D , Fifer WP , Stockwell MS , Monk C , Dawood F , Dumitriu D . JAMA Netw Open 2023 6 (4) e237396 IMPORTANCE: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. OBJECTIVE: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. EXPOSURES: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. RESULTS: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (β = 0.31; 95% CI, -2.97 to 3.58), gross motor (β = 0.82; 95% CI, -1.34 to 2.99), fine motor (β = 0.36; 95% CI, -0.74 to 1.47), expressive language (β = -1.00; 95% CI, -4.02 to 2.02), or receptive language (β = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. CONCLUSIONS AND RELEVANCE: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections. |
Effect of parental age, parity, and pairing approach on reproduction in strain 13/N guinea pigs (Cavia porcellus)
Genzer SC , Flietstra T , Coleman-McCray JD , Tansey C , Welch SR , Spengler JR . Animals 2023 13 (5) Guinea pigs are important animal models for human disease, and both outbred and inbred lines are utilized in biomedical research. The optimal maintenance of guinea pig colonies, commercially and in research settings, relies on robust informed breeding programs, however, breeding data on specialized inbred strains are limited. Here, we investigated the effects of parental age, parity, and pairing approaches on mean total fetus count, percentage of female pups in the litter, and pup survival rate after 10 days in strain 13/N guinea pigs. Our analysis of colony breeding data indicates that the average litter size is 3.3 pups, with a 25.2% stillbirth rate, a failure-to-thrive outcome in 5.1% of pups, and a 10 day survival rate of 69.7%. The only variable to significantly affect the reproductive outcomes examined was parental age (p < 0.05). In comparison to adults, both juvenile and geriatric sows had lower total fetus counts; juvenile boars had a higher percentage of females in litters, and geriatric boars had a lower 10 day survival rate of pups. These studies provide valuable information regarding the reproductive characteristics of strain 13/N guinea pigs, and support a variety of breeding approaches without significant effects on breeding success. |
Meeting report: 35th international conference on antiviral research in Seattle, WA, USA - March 21-25, 2022.
Spengler JR , Welch SR , Deval J , Gentry BG , Brancale A , Carter K , Moffat J , Meier C , Seley-Radtke KL , Schang LM . Antiviral Res 2022 211 105521 The 35th International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held in Seattle, Washington, USA, on March 21-25, 2022 and concurrently through an interactive remote meeting platform. This report gives an overview of the conference on behalf of the society. It provides a general review of the meeting and awardees, summarizing the presentations and their main conclusions from the perspective of researchers active in many different areas of antiviral research and development. Through ICAR, leaders in the field of antiviral research were able to showcase their efforts, as participants learned about key advances in the field. The impact of these efforts was exemplified by many presentations on SARS-CoV-2 demonstrating the remarkable response to the ongoing pandemic, as well as future pandemic preparedness, by members of the antiviral research community. As we address ongoing outbreaks and seek to mitigate those in the future, this meeting continues to support outstanding opportunities for the exchange of knowledge and expertise while fostering cross-disciplinary collaborations in therapeutic and vaccine development. The 36th ICAR will be held in Lyon, France, March 13-17, 2023. |
Mouse models of Ebola virus tolerance and lethality: Characterization of CD-1 mice infected with wild-type, guinea pig-adapted, or mouse-adapted variants
Spengler JR , Welch SR , Ritter JM , Harmon JR , Coleman-McCray JD , Genzer SC , Nascimento Seixas J , Scholte FEM , Davies KA , Bradfute SB , Montgomery JM , Spiropoulou CF . Antiviral Res 2022 210 105496 Development of lethal models of Ebola virus disease has been achieved by the serial passage of virus isolates from human cases in mice and guinea pigs. Use of mice infected with non-adapted virus has been limited due to the absence of overt clinical disease. In recent years, newly recognized sequelae identified in human cases has highlighted the importance of continued investigations of non-lethal infection both in humans and animal models. Here, we revisit the use of rodent-adapted and non-adapted Ebola virus (EBOV) variants in mice to investigate infection tolerance and future utility of these models in pathogenesis and therapeutic intervention studies. We found that like non-adapted wild-type EBOV, guinea pig-adapted EBOV results in widespread tissue infection, variably associated with tissue pathology, and alterations in clinical and immunological analytes in the absence of overt disease. Notably, infection with either non-lethal variant does not greatly differ from lethal mouse-adapted EBOV until near the time end-point criteria are reached in these mice, supporting use of these models of virus tolerance for continued investigations of non-lethal infection and sequelae. |
Tissue replication and mucosal swab detection of Sosuga virus in Syrian hamsters in the absence of overt tissue pathology and clinical disease
Welch SR , Ritter JM , Schuh AJ , Genzer SC , Sorvillo TE , Harmon JR , Coleman-McCray JD , Jain S , Shrivastava-Ranjan P , Seixas JN , Estetter LB , Fair PS , Towner JS , Montgomery JM , Albariño CG , Spiropoulou CF , Spengler JR . Antiviral Res 2022 209 105490 Human infection with Sosuga virus (SOSV), a recently discovered pathogenic paramyxovirus, has been reported in one individual to date. No animal models of disease are currently available for SOSV. Here, we describe initial characterization of experimental infection in Syrian hamsters, including kinetics of virus dissemination and replication, and the corresponding clinical parameters, immunological responses, and histopathology. We demonstrate susceptibility of hamsters to infection in the absence of clinical signs or significant histopathologic findings in tissues. |
Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus
Durie IA , Tehrani ZR , Karaaslan E , Sorvillo TE , McGuire J , Golden JW , Welch SR , Kainulainen MH , Harmon JR , Mousa JJ , Gonzalez D , Enos S , Koksal I , Yilmaz G , Karakoc HN , Hamidi S , Albay C , Spengler JR , Spiropoulou CF , Garrison AR , Sajadi MM , Bergeron É , Pegan SD . Nat Commun 2022 13 (1) 7298 Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective against a wide swath of CCHFV strains. |
Using the food and drug administrations sentinel system for surveillance of TB infection
Walker WL , Schmit KM , Welch EC , Vonnahme LA , Talwar A , Nguyen M , Stojanovic D , Langer AJ , Cocoros NM . Int J Tuberc Lung Dis 2022 26 (12) 1170-1176 BACKGROUND: We examined patterns in care for individuals treated for latent TB infection (LTBI) in the US Food and Drug Administration´s Sentinel System.METHODS: Using administrative claims data, we identified patients who filled standard LTBI treatment prescriptions during 2008-2019. In these cohorts, we assessed LTBI testing, clinical management, and treatment duration.RESULTS: Among 113,338 patients who filled LTBI prescriptions, 80% (90,377) received isoniazid (INH) only, 19% (21,235) rifampin (RIF) only, and 2% (1,726) INH + rifapentine (RPT). By regimen, the proportion of patients with documented prior testing for TBI was 79%, 54%, and 91%, respectively. Median therapy duration was 84 days (IQR 35-84) for the 3-month once-weekly INH + RPT regimen, 60 days (IQR 30-100) for the 6- to 9-month INH regimen, and 30 days (IQR 2-60) for the 4-month RIF regimen.CONCLUSIONS: Among the cohorts, INH-only was the most commonly prescribed LTBI treatment. Most persons who filled a prescription for LTBI treatment did not have evidence of completing recommended treatment duration. These data further support preferential use of shorter-course regimens such as INH + RPT. |
Associations between prenatal urinary biomarkers of phthalate exposure and preterm birth: A pooled study of 16 US cohorts
Welch BM , Keil AP , Buckley JP , Calafat AM , Christenbury KE , Engel SM , O'Brien KM , Rosen EM , James-Todd T , Zota AR , Ferguson KK , Alshawabkeh AN , Cordero JF , Meeker JD , Barrett ES , Bush NR , Nguyen RHN , Sathyanarayana S , Swan SH , Cantonwine DE , McElrath TF , Aalborg J , Dabelea D , Starling AP , Hauser R , Messerlian C , Zhang Y , Bradman A , Eskenazi B , Harley KG , Holland N , Bloom MS , Newman RB , Wenzel AG , Braun JM , Lanphear BP , Yolton K , Factor-Litvak P , Herbstman JB , Rauh VA , Drobnis EZ , Sparks AE , Redmon JB , Wang C , Binder AM , Michels KB , Baird DD , Jukic AMZ , Weinberg CR , Wilcox AJ , Rich DQ , Weinberger B , Padmanabhan V , Watkins DJ , Hertz-Picciotto I , Schmidt RJ . JAMA Pediatr 2022 176 (9) 895-905 IMPORTANCE: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. OBJECTIVE: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. DESIGN, SETTING, AND PARTICIPANTS: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. EXPOSURES: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. MAIN OUTCOMES AND MEASURES: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n=539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. RESULTS: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. CONCLUSIONS AND RELEVANCE: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery. |
Design and evaluation of neutralizing and fusion inhibitory peptides to Crimean-Congo hemorrhagic fever virus
Mears MC , Rodriguez SE , Schmitz KS , Padilla A , Biswas S , Cajimat MNB , Mire CE , Welch SR , Bergeron , Alabi CA , Porotto M , Bente DA . Antiviral Res 2022 207 105401 Crimean-Congo hemorrhagic fever (CCHF) is a medically relevant tick-borne viral disease caused by the Bunyavirus, Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is endemic to Asia, the Middle East, South-eastern Europe, and Africa and is transmitted in enzootic cycles among ticks, mammals, and birds. Human infections are mostly subclinical or limited to mild febrile illness. Severe disease may develop, resulting in multi-organ failure, hemorrhagic manifestations, and case-fatality rates up to 30%. Despite the widespread distribution and life-threatening potential, no treatments have been approved for CCHF. Antiviral inhibitory peptides, which antagonize viral entry, are licensed for clinical use in certain viral infections and have been experimentally designed against human pathogenic bunyaviruses, with in vitro and in vivo efficacies. We designed inhibitory peptides against CCHFV with and without conjugation to various polyethylene glycol and sterol groups. These additions have been shown to enhance both cellular uptake and antiviral activity. Peptides were evaluated against pseudotyped and wild-type CCHFV via neutralization tests, Nairovirus fusion assays, and cytotoxicity profiling. Four peptides neutralized CCHFV with two of these peptides shown to inhibit viral fusion. This work represents the development of experimental countermeasures for CCHF, describes a nairovirus immunofluorescence fusion assay, and illustrates the utility of pseudotyped CCHFV for the screening of entry antagonists at low containment settings for CCHF. |
Volume-Associated Clinical and Histopathological Effects of Intranasal Instillation in Syrian Hamsters: Considerations for Infection and Therapeutic Studies.
Forero C , Ritter JM , Seixas JN , Coleman-McCray JD , Brake M , Condrey JA , Tansey C , Welch SR , Genzer SC , Spengler JR . Pathogens 2022 11 (8) Syrian hamsters are a key animal model of SARS-CoV-2 and other respiratory viruses and are useful for the evaluation of associated medical countermeasures. Delivery of an infectious agent or intervention to the respiratory tract mirrors natural routes of exposure and allows for the evaluation of clinically relevant therapeutic administration. The data to support instillation or inoculation volumes are important both for optimal experimental design and to minimize or avoid effects of diluent alone, which may compromise both data interpretation and animal welfare. Here we investigate four intranasal (IN) instillation volumes in hamsters (50, 100, 200, or 400 µL). The animals were monitored daily, and a subset were serially euthanized at one of four pre-determined time-points (1, 3, 7, and 14 days post-instillation). Weight, temperature, oxygen saturation, CBC, radiographs, and respiratory tissue histopathology were assessed to determine changes associated with instillation volume alone. With all the delivery volumes, we found no notable differences between instilled and non-instilled controls in all of the parameters assessed, except for histopathology. In the animals instilled with 200 or 400 µL, inflammation associated with foreign material was detected in the lower respiratory tract indicating that higher volumes may result in aspiration of nasal and/or oropharyngeal material in a subset of animals, resulting in IN instillation-associated histopathology. |
Partnership Between a Federal Agency and 4 Tribal Nations to Improve COVID-19 Response Capacities.
Kaur H , Welch S , Bhairavabhotla R , Weidle PJ , Santibanez S , Haberling DL , Smith EM , Ferris-George W , Hayashi K , Hostler A , Ao T , Dieke A , Boyer D , King E , Teton R , Williams-Singleton N , Flying EM , Hladik W , Marshall KJ , Pourier D , Ruiz Z , Yatabe G , Abe K , Parise M , Anderson M , Evans ME , Hunt H , Balajee SA . Public Health Rep 2022 137 (5) 333549221099239 Upon request from tribal nations, and as part of the Centers for Disease Control and Prevention's (CDC's) emergency response, CDC staff provided both remote and on-site assistance to tribes to plan, prepare, and respond to the COVID-19 pandemic. From April 2, 2020, through June 11, 2021, CDC deployed a total of 275 staff to assist 29 tribal nations. CDC staff typically collaborated in multiple work areas including epidemiology and surveillance (86%), contact tracing (76%), infection prevention control (72%), community mitigation (72%), health communication (66%), incident command structure (55%), emergency preparedness (38%), and worker safety (31%). We describe the activities of CDC staff in collaboration with 4 tribal nations, Northern Cheyenne, Hoopa Valley, Shoshone-Bannock, and Oglala Sioux Tribe, to combat COVID-19 and lessons learned from the engagement. |
Simplified Cas13-based assays for the fast identification of SARS-CoV-2 and its variants.
Arizti-Sanz J , Bradley A , Zhang YB , Boehm CK , Freije CA , Grunberg ME , Kosoko-Thoroddsen TF , Welch NL , Pillai PP , Mantena S , Kim G , Uwanibe JN , John OG , Eromon PE , Kocher G , Gross R , Lee JS , Hensley LE , MacInnis BL , Johnson J , Springer M , Happi CT , Sabeti PC , Myhrvold C . Nat Biomed Eng 2022 6 (8) 932-943 The widespread transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for rapid nucleic acid diagnostics that are easy to use outside of centralized clinical laboratories. Here we report the development and performance benchmarking of Cas13-based nucleic acid assays leveraging lyophilised reagents and fast sample inactivation at ambient temperature. The assays, which we named SHINEv.2 (for 'streamlined highlighting of infections to navigate epidemics, version 2'), simplify the previously reported RNA-extraction-free SHINEv.1 technology by eliminating heating steps and the need for cold storage of the reagents. SHINEv.2 detected SARS-CoV-2 in nasopharyngeal samples with 90.5% sensitivity and 100% specificity (benchmarked against the reverse transcription quantitative polymerase chain reaction) in less than 90 min, using lateral-flow technology and incubation in a heat block at 37 °C. SHINEv.2 also allows for the visual discrimination of the Alpha, Beta, Gamma, Delta and Omicron SARS-CoV-2 variants, and can be run without performance losses by using body heat. Accurate, easy-to-use and equipment-free nucleic acid assays could facilitate wider testing for SARS-CoV-2 and other pathogens in point-of-care and at-home settings. |
Validation and comparison of fall screening tools for predicting future falls among older adults
Burns ER , Lee R , Hodge SE , Pineau VJ , Welch B , Zhu M . Arch Gerontol Geriatr 2022 101 104713 BACKGROUND: Falls are the leading cause of injuries among older adults in the United States (US). Falls are preventable and clinicians are advised to screen for fall risk yearly. There are many falls screening tools and not all have been validated for their ability to predict future falls. METHODS: We enrolled 1905 community-dwelling older adults into a 13-month study using a probability-based representative panel of the US population recruited from NORC at the University of Chicago's National Frame. Respondents completed a baseline survey, 11 monthly fall calendars, and a final survey. The baseline survey included six falls screening tools (the Stay Independent, Three Key Questions (3KQ), a modified American Geriatric/British Geriatric tool, the short Falls Efficacy-1[FES-I]) and two single screening questions ("I have fallen in the past year" and "How many times did you fall in the past 12 months?"). The baseline and final survey collected demographic and health information, including falls. Sensitivity, specificity, positive and negative likelihood ratios, and corresponding 95% confidence intervals were calculated in SAS using weighted proportions. RESULTS: There were 1563 respondents who completed the final survey (completion rate 82%). Sensitivity estimates ranged from 22.5% for the short FES-I to 68.7% for the 3KQ. Specificity estimates ranged from 57.9% for the 3KQ to 89.4% for the short FES-I. CONCLUSIONS: Falls screening tools have varying sensitivity and specificity for predicting the occurrence of a fall in the following 12 months. |
Viral RNA and infectious virus in mucosal specimens from guinea pigs modeling early phases of lethal and non-lethal Lassa fever
Welch SR , Genzer SC , Coleman-McCray JD , Harmon JR , Scholte FEM , Montgomery JM , Spiropoulou CF , Spengler JR . Emerg Microbes Infect 2022 11 (1) 1-17 ABSTRACTLassa fever (LF) is endemic to broad regions of West Africa. Infection with Lassa virus (LASV), the etiologic agent of LF, results in a spectrum of clinical signs in humans, including severe and lethal hemorrhagic disease. Person-to-person transmission occurs through direct contact with body fluids or contaminated bedding and clothing. To investigate transmission risk in acute LASV infection, we evaluated viral RNA and infectious virus obtained from conjunctival, nasal, oral, genital, and rectal swab specimens from guinea pigs modeling lethal and non-lethal LF. Viral RNA and infectious virus were detected in all specimen types beginning 8 days post infection, prior to onset of fever. In the pre-clinical and clinical period, virus was isolated from a subset of nasal, oral, genital, and rectal swabs, and from all conjunctival swabs. Overall, conjunctival and nasal specimens most frequently yielded infectious virus. These findings indicate mucosal transmission risk based on virus isolation from various sites early in infection and support potential utility of minimally invasive specimen evaluation by RT-qPCR for LASV diagnostics. |
Defective Interfering Viral Particle Treatment Reduces Clinical Signs and Protects Hamsters from Lethal Nipah Virus Disease.
Welch SR , Spengler JR , Harmon JR , Coleman-McCray JD , Scholte FEM , Genzer SC , Lo MK , Montgomery JM , Nichol ST , Spiropoulou CF . mBio 2022 13 (2) e0329421 Defective interfering particles (DIs) contain a considerably smaller genome than the parental virus but retain replication competency. As DIs can directly or indirectly alter propagation kinetics of the parental virus, they offer a novel approach to antiviral therapy, capitalizing on knowledge from natural infection. However, efforts to translate in vitro inhibition to in vivo screening models remain limited. We investigated the efficacy of virus-like particles containing DI genomes (therapeutic infectious particles [TIPs]) in the Syrian hamster model of lethal Nipah virus (NiV) disease. We found that coadministering a high dose of TIPs intraperitoneally with virus challenge improved clinical course and reduced lethality. To mimic natural exposure, we also evaluated lower-dose TIP delivery and virus challenge intranasally, finding equally efficacious reduction in disease severity and overall lethality. Eliminating TIP replicative capacity decreased efficacy, suggesting protection via direct inhibition. These data provide evidence that TIP-mediated treatment can confer protection against disease and lethal outcome in a robust animal NiV model, supporting further development of TIP treatment for NiV and other high-consequence pathogens. IMPORTANCE Here, we demonstrate that treatment with defective interfering particles (DIs), a natural by-product of viral infection, can significantly improve the clinical course and outcome of viral disease. When present with their parental virus, DIs can directly or indirectly alter viral propagation kinetics and exert potent inhibitory properties in cell culture. We evaluated the efficacy of a selection of virus-like particles containing DI genomes (TIPs) delivered intranasally in a lethal hamster model of Nipah virus disease. We demonstrate significantly improved clinical outcomes, including reduction in both lethality and the appearance of clinical signs. This work provides key efficacy data in a robust model of Nipah virus disease to support further development of TIP-mediated treatment against high-consequence viral pathogens. |
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