Publications by authors named "Stacey Schultz-Cherry"

147 Publications

Innate antiviral cytokine response to swine influenza virus by swine respiratory epithelial cells.

J Virol 2021 May 12. Epub 2021 May 12.

Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602

Swine influenza virus (SIV) can cause respiratory illness in swine. Swine contribute to influenza virus reassortment as avian, human, and/or SIV viruses can infect swine, reassort, and new viruses can emerge. Thus, it is important to determine the host antiviral responses that affect SIV replication. In this study, we examined the innate antiviral cytokine response to SIV by swine respiratory epithelial cells focusing on the expression of interferon (IFN) and interferon-stimulated genes (ISGs). Both primary and transformed swine nasal and tracheal respiratory epithelial cells were examined following infection with field isolates. The results show IFN and ISG expression is maximal at 12-hour post-infection (hpi) and is cell-type and virus genotype-dependent.Swine are considered intermediate hosts that have facilitated influenza virus reassortment events that have given rise pandemics or genetically related viruses have become established in swine. In this study, we examine the innate antiviral response to swine influenza virus in primary and immortalized swine nasal and tracheal epithelial cells, and show virus strain and host cell-type dependent differential expression of key interferons and interferon-stimulated genes.
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http://dx.doi.org/10.1128/JVI.00692-21DOI Listing
May 2021

Evidence of influenza infection in dogs and cats in central Chile.

Prev Vet Med 2021 Apr 16;191:105349. Epub 2021 Apr 16.

Department of Preventive Animal Medicine, Faculty of Veterinary Sciences, University of Chile, Santiago, Chile. Electronic address:

As companion animals, dogs and cats live in close contact with humans, generating the possibility of interspecies pathogen transmission events. Equine origin H3N8 and avian origin H5N1 influenza virus have been reported in dogs and cats respectively since 2004 with outbreaks associated with different strains recorded for both species in Asia and North America. To date, there have been no reports of influenza viruses from companion animals in South America. To fill this gap in knowledge, we performed active epidemiological surveillance in shelters that received abandoned animals, backyard production systems and veterinary clinics between May 2017 and January 2019 to estimate the burden of influenza infection in cats and dogs in the central region of Chile. Blood samples, oropharyngeal swabs or both were collected for influenza A virus detection by RT-qPCR, NP-ELISA, and hemagglutination inhibition assay. Logistic regression models were performed to assess the association between NP-ELISA-positivity and variables including sex and animal origin. The percentage of ELISA-positive samples was 43.5 % (95 % CI: 37.0-50.1) and 23.3 % (95 % CI: 10.6-42.7) for dogs and cats, respectively. No association was found between NP-ELISA results and sex or animal origin for either dogs or cats. Two ELISA positive samples showed hemagglutination inhibition titers against pandemic H1N1 influenza. One dog sample tested positive by RT-qPCR, indicating an overall RT-qPCR positivity in dogs of 1.1 % (95 % CI: 0.05-6.7). None of the tested cat samples were positive by this assay.
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http://dx.doi.org/10.1016/j.prevetmed.2021.105349DOI Listing
April 2021

Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract.

Nat Rev Microbiol 2021 Apr 6. Epub 2021 Apr 6.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

Influenza viruses cause annual epidemics and occasional pandemics of respiratory tract infections that produce a wide spectrum of clinical disease severity in humans. The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and has since caused a pandemic. Both viral and host factors determine the extent and severity of virus-induced lung damage. The host's response to viral infection is necessary for viral clearance but may be deleterious and contribute to severe disease phenotypes. Similarly, tissue repair mechanisms are required for recovery from infection across the spectrum of disease severity; however, dysregulated repair responses may lead to chronic lung dysfunction. Understanding of the mechanisms of immunopathology and tissue repair following viral lower respiratory tract infection may broaden treatment options. In this Review, we discuss the pathogenesis, the contribution of the host response to severe clinical phenotypes and highlight early and late epithelial repair mechanisms following influenza virus infection, each of which has been well characterized. Although we are still learning about SARS-CoV-2 and its disease manifestations in humans, throughout the Review we discuss what is known about SARS-CoV-2 in the context of this broad knowledge of influenza virus, highlighting the similarities and differences between the respiratory viruses.
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http://dx.doi.org/10.1038/s41579-021-00542-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023351PMC
April 2021

Obesity is associated with an altered baseline and post-vaccination influenza antibody repertoire.

medRxiv 2021 Mar 5. Epub 2021 Mar 5.

As highlighted by the ongoing COVID-19 pandemic, vaccination is critical for infectious disease prevention and control. Obesity is associated with increased morbidity and mortality from respiratory virus infections. While obese individuals respond to influenza vaccination, what is considered a seroprotective response may not fully protect the global obese population. In a cohort vaccinated with the 2010-2011 trivalent inactivated influenza vaccine, baseline immune history and vaccination responses were found to significantly differ in obese individuals compared to healthy controls, especially towards the 2009 pandemic strain of A/H1N1 influenza virus. Young, obese individuals displayed responses skewed towards linear peptides versus conformational antigens, suggesting aberrant obese immune response. Overall, these data have vital implications for the next generation of influenza vaccines, and towards the current SARS-CoV-2 vaccination campaign.

One Sentence Summary: Obese individuals have altered baseline and post-vaccination influenza antibody repertoires.
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http://dx.doi.org/10.1101/2021.03.02.21252785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941659PMC
March 2021

Human Astroviruses: A Tale of Two Strains.

Viruses 2021 02 27;13(3). Epub 2021 Feb 27.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Since the 1970s, eight closely related serotypes of classical human astroviruses (HAstV) have been associated with gastrointestinal illness worldwide. In the late 2000s, three genetically unique human astrovirus clades, VA1-VA3, VA2-VA4, and MLB, were described. While the exact disease associated with these clades remains to be defined, VA1 has been associated with central nervous system infections. The discovery that VA1 could be grown in cell culture, supports exciting new studies aimed at understanding viral pathogenesis. Given the association of VA1 with often lethal CNS infections, we tested its susceptibility to the antimicrobial drug, nitazoxanide (NTZ), which we showed could inhibit classical HAstV infections. Our studies demonstrate that NTZ inhibited VA1 replication in Caco2 cells even when added at 12 h post-infection, which is later than in HAstV-1 infection. These data led us to further probe VA1 replication kinetics and cellular responses to infection in Caco-2 cells in comparison to the well-studied HAstV-1 strain. Overall, our studies highlight that VA1 replicates more slowly than HAstV-1 and elicits significantly different cellular responses, including the inability to disrupt cellular junctions and barrier permeability.
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http://dx.doi.org/10.3390/v13030376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997325PMC
February 2021

Development and deployment of COVID-19 vaccines for those most vulnerable.

Sci Transl Med 2021 02;13(579)

Human Vaccines Project, New York, NY 10119, USA.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.
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http://dx.doi.org/10.1126/scitranslmed.abd1525DOI Listing
February 2021

The role of goblet cells in viral pathogenesis.

FEBS J 2021 Jan 28. Epub 2021 Jan 28.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

Goblet cells are specialized epithelial cells that are essential to the formation of the mucus barriers in the airways and intestines. Armed with an arsenal of defenses, goblet cells can rapidly respond to infection but must balance this response with maintaining homeostasis. Whereas goblet cell defenses against bacterial and parasitic infections have been characterized, we are just beginning to understand their responses to viral infections. Here, we outline what is known about the enteric and respiratory viruses that target goblet cells, the direct and bystander effects caused by viral infection and how viral interactions with the mucus barrier can alter the course of infection. Together, these factors can play a significant role in driving viral pathogenesis and disease outcomes.
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http://dx.doi.org/10.1111/febs.15731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013445PMC
January 2021

Tropism of SARS-CoV-2, SARS-CoV and influenza virus in canine tissue explants.

J Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Background: Human spillovers of SARS-CoV-2 to dogs and the emergence of a highly contagious avian-origin H3N2 canine influenza virus have raised concerns towards the role of dogs in the spread of SARS-CoV-2 and their susceptibility to existing human and avian influenza viruses which might result in further reassortment.

Methods: We systematically studied the replication kinetics of SARS-CoV-2, SARS-CoV, influenza A viruses of H1, H3, H5, H7 and H9 subtypes and influenza B viruses of Yamagata-like and Victoria-like lineages in ex-vivo canine nasal cavity (NC), soft palate (SP), trachea (T) and lung (L) tissue explant cultures and examined ACE2 and sialic acid (SA) receptor distribution in these tissues.

Results: There was limited productive replication of SARS-CoV-2 in canine NC and SARS-CoV in canine NC, SP and L with unexpectedly high ACE2 levels in canine NC and SP. Meanwhile, the canine tissues were susceptible to a wide range of human and avian influenza viruses, which matched with the abundance of both human and avian SA receptors.

Conclusions: Existence of suitable receptors and tropism for the same tissue foster virus adaptation and reassortment. Continuous surveillance in dog populations should be conducted given the plenty of chances for spillover during outbreaks.
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http://dx.doi.org/10.1093/infdis/jiab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799041PMC
January 2021

Transkingdom interactions important for the pathogenesis of human viruses.

J Infect Dis 2020 Dec 17. Epub 2020 Dec 17.

Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis TN USA.

The bacterial, fungal and helminthic species that comprise the microbiome of the mammalian host have profound effects on health and disease. Pathogenic viruses must contend with the microbiome during infection, and likely have evolved to exploit or evade the microbiome. Both direct interactions between the virions and the microbiota and immunomodulation and tissue remodeling caused by the microbiome alter viral pathogenesis in either host- or virus-beneficial ways. Recent insights from in vitro and murine models of viral pathogenesis have highlighted synergistic and antagonistic, direct and indirect interactions between the microbiome and pathogenic viruses. This review will focus on the transkingdom interactions between human gastrointestinal and respiratory viruses and the constituent microbiome of those tissues.
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http://dx.doi.org/10.1093/infdis/jiaa735DOI Listing
December 2020

Equine-Like H3 Avian Influenza Viruses in Wild Birds, Chile.

Emerg Infect Dis 2020 12;26(12):2887-2898

Since their discovery in the United States in 1963, outbreaks of infection with equine influenza virus (H3N8) have been associated with serious respiratory disease in horses worldwide. Genomic analysis suggests that equine H3 viruses are of an avian lineage, likely originating in wild birds. Equine-like internal genes have been identified in avian influenza viruses isolated from wild birds in the Southern Cone of South America. However, an equine-like H3 hemagglutinin has not been identified. We isolated 6 distinct H3 viruses from wild birds in Chile that have hemagglutinin, nucleoprotein, nonstructural protein 1, and polymerase acidic genes with high nucleotide homology to the 1963 H3N8 equine influenza virus lineage. Despite the nucleotide similarity, viruses from Chile were antigenically more closely related to avian viruses and transmitted effectively in chickens, suggesting adaptation to the avian host. These studies provide the initial demonstration that equine-like H3 hemagglutinin continues to circulate in a wild bird reservoir.
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http://dx.doi.org/10.3201/eid2612.202063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706983PMC
December 2020

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Nature 2020 11 28;587(7834):466-471. Epub 2020 Oct 28.

Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS). There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.
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http://dx.doi.org/10.1038/s41586-020-2877-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883627PMC
November 2020

Recipe for Zoonosis: How Influenza Virus Leaps into Human Circulation.

Cell Host Microbe 2020 10;28(4):506-508

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

The features that permit or prevent a virus from becoming a zoonotic threat is an ongoing area of investigation. In this issue of Cell Host & Microbe, Herfst et al. and Henritzi et al. help define the molecular and host determinants of influenza virus spillover from animal to human populations.
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http://dx.doi.org/10.1016/j.chom.2020.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539932PMC
October 2020

Primary Swine Respiratory Epithelial Cell Lines for the Efficient Isolation and Propagation of Influenza A Viruses.

J Virol 2020 11 23;94(24). Epub 2020 Nov 23.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Influenza virus isolation from clinical samples is critical for the identification and characterization of circulating and emerging viruses. Yet efficient isolation can be difficult. In these studies, we isolated primary swine nasal and tracheal respiratory epithelial cells and immortalized swine nasal epithelial cells (siNEC) and tracheal epithelial cells (siTEC) that retained the abilities to form tight junctions and cilia and to differentiate at the air-liquid interface like primary cells. Critically, both human and swine influenza viruses replicated in the immortalized cells, which generally yielded higher-titer viral isolates from human and swine nasal swabs, supported the replication of isolates that failed to grow in Madin-Darby canine kidney (MDCK) cells, and resulted in fewer dominating mutations during viral passaging than MDCK cells. Robust culture systems for influenza virus are critically needed. MDCK cells, the most widely used cell line for influenza isolation and propagation, do not adequately model the respiratory tract. Therefore, many clinical isolates, both animal and human, are unable to be isolated and characterized, limiting our understanding of currently circulating influenza viruses. We have developed immortalized swine respiratory epithelial cells that retain the ability to differentiate and can support influenza replication and isolation. These cell lines can be used as additional tools to enhance influenza research and vaccine development.
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http://dx.doi.org/10.1128/JVI.01091-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925196PMC
November 2020

Temporal dynamics and the influence of environmental variables on the prevalence of avian influenza virus in main wetlands in central Chile.

Transbound Emerg Dis 2021 May 26;68(3):1601-1614. Epub 2020 Sep 26.

Department of Preventive Veterinary Medicine, Faculty of Veterinary Science, Universidad de Chile, Santiago, Chile.

Although wild birds are considered the main reservoir of the influenza A virus (IAV) in nature, empirical investigations exploring the interaction between the IAV prevalence in these populations and environmental drivers remain scarce. Chile has a coastline of more than 4000 kilometres with hundreds of wetlands, which are important habitats for both resident and inter-hemispheric migratory species. The aim of this study was to characterize the temporal dynamics of IAV in main wetlands in central Chile and to assess the influence of environmental variables on AIV prevalence. For that purpose, four wetlands were studied from September 2015 to June 2018. Fresh faecal samples of wild birds were collected for IAV detection by real-time RT-PCR. Furthermore, a count of wild birds present at the site was performed and environmental variables, such as temperature, rainfall, vegetation coverage (Normalized Difference Vegetation Index (NDVI)) and water body size, were determined. A generalized linear mixed model was built to assess the association between IAV prevalence and explanatory variables. An overall prevalence of 4.28% ± 0.28% was detected with important fluctuations among seasons, being greater during summer (OR = 4.87, 95% CI 2.11 to 11.21) and fall (OR = 2.59, 95% CI 1.12 to 5.97). Prevalence was positively associated with minimum temperature for the month of sampling and negatively associated with water body size measured two months before sampling, and NDVI measured three months before sampling. These results contribute to the understanding of IAV ecological drivers in Chilean wetlands providing important considerations for the global surveillance of IAV.
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http://dx.doi.org/10.1111/tbed.13831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956909PMC
May 2021

Respiratory Bacteria Stabilize and Promote Airborne Transmission of Influenza A Virus.

mSystems 2020 Sep 1;5(5). Epub 2020 Sep 1.

Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA

Influenza A virus (IAV) is a major pathogen of the human respiratory tract, where the virus coexists and interacts with bacterial populations comprising the respiratory tract microbiome. Synergies between IAV and respiratory bacterial pathogens promote enhanced inflammation and disease burden that exacerbate morbidity and mortality. We demonstrate that direct interactions between IAV and encapsulated bacteria commonly found in the respiratory tract promote environmental stability and infectivity of IAV. Antibiotic-mediated depletion of the respiratory bacterial flora abrogated IAV transmission in ferret models, indicating that these virus-bacterium interactions are operative for airborne transmission of IAV. Restoring IAV airborne transmission in antibiotic-treated ferrets by coinfection with confirmed a role for specific members of the bacterial respiratory community in promoting IAV transmission. These results implicate a role for the bacterial respiratory flora in promoting airborne transmission of IAV. Infection with influenza A virus (IAV), especially when complicated with a secondary bacterial infection, is a leading cause of global mortality and morbidity. Gaining a greater understanding of the transmission dynamics of IAV is important during seasonal IAV epidemics and in the event of a pandemic. Direct bacterium-virus interactions are a recently appreciated aspect of infectious disease biology. Direct interactions between IAV and specific bacterial species of the human upper respiratory tract were found to promote the stability and infectivity of IAV during desiccation stress. Viral environmental stability is an important aspect during transmission, suggesting a potential role for bacterial respiratory communities in IAV transmission. Airborne transmission of IAV was abrogated upon depletion of nasal bacterial flora with topical antibiotics. This defect could be functionally complemented by coinfection. These data suggest that bacterial coinfection may be an underappreciated aspect of IAV transmission dynamics.
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http://dx.doi.org/10.1128/mSystems.00762-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470989PMC
September 2020

Movement Restriction and Increased Surveillance as Efficient Measures to Control the Spread of Highly Pathogenic Avian Influenza in Backyard Productive Systems in Central Chile.

Front Vet Sci 2020 24;7:424. Epub 2020 Jul 24.

Departamento de Medicina Preventiva, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile.

During the last 5 years there has been an alarming number of reports of highly pathogenic avian influenza worldwide. However, little is known about the status of this disease in South America. Chile has been the only country in South America where an HPAI outbreak was reported. This outbreak occurred in 2002 and was due to an H7N3 HPAI, where the most plausible hypothesis that explained the entrance of the disease to the country, had relation to migratory wild birds. Commercial poultry farms in Chile are highly integrated and have high biosecurity standards. Nevertheless, poultry backyard production systems lack biosecurity measures and are widely distributed. Since 2002 outbreak, avian influenza viruses have been identified in wild birds and different animal species kept in backyard productive systems (BPS) in Chile. The aim of this study was to simulate the possible natural history of HPAI after its introduction to BPS in central Chile and to simulate different intervention strategies. To do so, the North American Animal Disease Spread Model version 3.3 was used. The results showed that a median of 15,930 BPS would be affected if HPAI spread among BPS in central Chile, representing 97.8% of the current amount of BPS existing in study zone. Movement restrictions, pre-emptive destruction, passive surveillance, tracing of infected premises and combinations of the three, where the intervention strategies tested in the simulation model. From all the interventions simulated, movement restrictions together with increasing surveillance (through increasing passive surveillance and good tracing of infected premises) had the biggest effect, reducing the median number of infected BPS in 90.8%. However, more studies are needed to more accurately estimate local contact rates. These results can guide the official veterinary services to consider potential mechanisms to control or prevent an HPAI emergency situation.
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http://dx.doi.org/10.3389/fvets.2020.00424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393644PMC
July 2020

They are what you eat: Shaping of viral populations through nutrition and consequences for virulence.

PLoS Pathog 2020 08 13;16(8):e1008711. Epub 2020 Aug 13.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

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http://dx.doi.org/10.1371/journal.ppat.1008711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425860PMC
August 2020

Vitamin A Corrects Tissue Deficits in Diet-Induced Obese Mice and Reduces Influenza Infection After Vaccination and Challenge.

Obesity (Silver Spring) 2020 09 10;28(9):1631-1636. Epub 2020 Aug 10.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Objective: Individuals with obesity suffer from an increased susceptibility to severe respiratory viral infections and respond poorly to vaccinations, making it imperative to identify interventions. Recent evidence suggesting that obesity leads to tissue-specific vitamin A deficiency led to an investigation of whether high-dose oral vitamin A, a treatment used for remediating vitamin A deficiency in developing countries, could correct obesity-associated tissue deficits.

Methods: Adult C57BL/6 diet-induced obese mice were supplemented with vitamin A for 4 weeks. A subset of mice were then vaccinated with inactivated influenza virus and challenged. Following supplementation, tissue vitamin A levels, lung immune cell composition, blood inflammatory cytokines, antibody responses, and viral clearance were evaluated.

Results: Supplementation significantly improved vitamin A levels in lung and adipose tissues in diet-induced obese mice. Additionally, supplementation decreased inflammatory cytokines in the blood and altered the lung immune environment. Importantly, vaccinated, vitamin A-treated diet-induced obese mice exhibited improved antibody responses and significantly reduced viral loads post challenge compared with PBS-treated mice.

Conclusions: Results demonstrate a low-cost intervention that may correct vitamin A tissue deficits and help control respiratory viral infections in individuals with obesity.
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http://dx.doi.org/10.1002/oby.22929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483416PMC
September 2020

Metabolic Syndrome and Viral Pathogenesis: Lessons from Influenza and Coronaviruses.

J Virol 2020 08 31;94(18). Epub 2020 Aug 31.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Metabolic syndrome increases the risk of severe disease due to viral infection. Yet few studies have assessed the pathogenesis of respiratory viruses in high-risk populations. Here, we summarize how metabolic dysregulation impairs immune responses, and we define the role of metabolism during influenza virus and coronavirus infections. We also discuss the use of various , , and models to elucidate the contributions of host factors to viral susceptibility, immunity, and disease severity.
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http://dx.doi.org/10.1128/JVI.00665-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459568PMC
August 2020

A tale of two pandemics: obesity and COVID-19.

J Travel Med 2020 Aug;27(5)

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1093/jtm/taaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337738PMC
August 2020

Infectious Norovirus Is Chronically Shed by Immunocompromised Pediatric Hosts.

Viruses 2020 06 5;12(6). Epub 2020 Jun 5.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Noroviruses are a leading cause of gastroenteritis worldwide. Although infections in healthy individuals are self-resolving, immunocompromised individuals are at risk for chronic disease and severe complications. Chronic norovirus infections in immunocompromised hosts are often characterized by long-term virus shedding, but it is unclear whether this shed virus remains infectious. We investigated the prevalence, genetic heterogeneity, and temporal aspects of norovirus infections in 1140 patients treated during a 6-year period at a pediatric research hospital. Additionally, we identified 20 patients with chronic infections lasting 37 to >418 days. Using a new human norovirus in vitro assay, we confirmed the continuous shedding of infectious virus for the first time. Shedding lasted longer in male patients and those with diarrheal symptoms. Prolonged shedding of infectious norovirus in immunocompromised hosts can potentially increase the likelihood of transmission, highlighting the importance of isolation precautions to prevent nosocomial infections.
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http://dx.doi.org/10.3390/v12060619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354526PMC
June 2020

Astrovirus infects actively secreting goblet cells and alters the gut mucus barrier.

Nat Commun 2020 04 29;11(1):2097. Epub 2020 Apr 29.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

Astroviruses are a global cause of pediatric diarrhea, but they are largely understudied, and it is unclear how and where they replicate in the gut. Using an in vivo model, here we report that murine astrovirus preferentially infects actively secreting small intestinal goblet cells, specialized epithelial cells that maintain the mucus barrier. Consequently, virus infection alters mucus production, leading to an increase in mucus-associated bacteria and resistance to enteropathogenic E. coli colonization. These studies establish the main target cell type and region of the gut for productive murine astrovirus infection. They further define a mechanism by which an enteric virus can regulate the mucus barrier, induce functional changes to commensal microbial communities, and alter host susceptibility to pathogenic bacteria.
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http://dx.doi.org/10.1038/s41467-020-15999-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190700PMC
April 2020

Characterizing Emerging Canine H3 Influenza Viruses.

PLoS Pathog 2020 04 14;16(4):e1008409. Epub 2020 Apr 14.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.
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http://dx.doi.org/10.1371/journal.ppat.1008409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182277PMC
April 2020

Obesity-Related Microenvironment Promotes Emergence of Virulent Influenza Virus Strains.

mBio 2020 03 3;11(2). Epub 2020 Mar 3.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population. Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.
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http://dx.doi.org/10.1128/mBio.03341-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064783PMC
March 2020

Risk factors and spatial relative risk assessment for influenza A virus in poultry and swine in backyard production systems of central Chile.

Vet Med Sci 2020 08 21;6(3):518-526. Epub 2020 Feb 21.

Department of Preventive Veterinary Medicine, University of Chile, Santiago de Chile, Chile.

Backyard production systems (BPS) are a common form of poultry and swine production worldwide. The limited implementation of biosecurity standards in these operations makes BPS a potential source for the emergence of pathogens that have an impact on both animal and public health. Information regarding circulation of influenza A virus (IAV) in poultry and swine raised in BPS is scarce; particularly in South American countries. The objective of this study was to estimate prevalence and seroprevalence of IAV in BPS in central Chile, identify subtype diversity, evaluate risk factors and spatial relative risk for IAV. Samples were collected from 329 BPS from central Chile. Seroprevalence at BPS level was 34.7% (95% CI: 23.1%-46.2%), 19.7% (95% CI: 9.9%-30.6%) and 11.7% (95% CI: 7.2%-16.4%), whereas prevalence at BPS level was 4.2% (95% CI: 0.0%-8.8%), 8.2% (95% CI: 0.8%-14.0%) and 9.2% (95% CI: 4.8%-13.1%), for the Metropolitan, Valparaiso and LGB O'Higgins regions, respectively. Spatial analysis revealed that central-western area of Metropolitan region and the southern province of Valparaiso region could be considered as high-risk areas for IAV (spatial relative risk = 2.2, p < .05). Logistic regression models identified the practice of breeding both poultry and pigs at the BPS as a risk factor (95% CI 1.06-3.75). From 75 IAV ELISA-positive sera, 20 chicken sera had haemagglutination inhibition titres ranging from 20 to 160, and of these, 11 had microneutralization titres ranging from 40 to 960 for one or more IAV subtypes. Identified subtypes were H1, H3, H4, H9, H10 and H12. Results from this study highlight the need for further IAV surveillance programmes in BPS in Chile. Early detection of IAV strains circulating in backyard animals, especially in regions with large human populations, could have an enormous impact on animal and public health.
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http://dx.doi.org/10.1002/vms3.254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397882PMC
August 2020

Modified Sialic Acids on Mucus and Erythrocytes Inhibit Influenza A Virus Hemagglutinin and Neuraminidase Functions.

J Virol 2020 04 16;94(9). Epub 2020 Apr 16.

Baker Institute for Animal Health, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA

Sialic acids (Sia) are the primary receptors for influenza viruses and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include -acetyl modifications at C-4, C-7, C-8, and C-9 positions and -acetyl or -glycolyl at C-5. They can also vary in their linkages, including α2-3 or α2-6 linkages. Here, we analyze the distribution of modified Sia in cells and tissues of wild-type mice or in mice lacking CMP--acetylneuraminic acid hydroxylase (CMAH) enzyme, which synthesizes -glycolyl (Neu5Gc) modifications. We also examined the variation of Sia forms on erythrocytes and in saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9--acetyl, 7,9--acetyl, 4--acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal (GI) tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a high degree of variability in display of modified Sia between different species. IAV HAs from different virus strains showed consistently reduced binding to both Neu5Gc- and -acetyl-modified Sia; however, while IAV NAs were inhibited by Neu5Gc and -acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV and may affect both pathogens and the normal flora of different mucosal sites. Sialic acids (Sia) are involved in numerous different cellular functions and are receptors for many pathogens. Sia come in chemically modified forms, but we lack a clear understanding of how they alter interactions with microbes. Here, we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably among different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.
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http://dx.doi.org/10.1128/JVI.01567-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163148PMC
April 2020

Influenza in High-Risk Hosts-Lessons Learned from Animal Models.

Cold Spring Harb Perspect Med 2020 12 1;10(12). Epub 2020 Dec 1.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.

Factoring significantly into the global burden of influenza disease are high-risk populations that suffer the bulk of infections. Classically, the very young, very old, and pregnant women have been identified as high-risk populations; however, recent research has uncovered several other conditions that contribute to severe infection. By using varied animal models, researchers have identified molecular mechanisms underpinning the increased likelihood for infection due to obesity and malnourishment, as well as insight into the role sex hormones play in antiviral immunity in males, in females, and across the life span. Additionally, novel comorbidity models have helped elucidate the role of chronic infectious and genetic diseases in influenza virus pathogenesis. Animal models play a vital role in understanding the contribution of host factors to influenza severity and immunity. An in-depth understanding of these host factors represents an important step in reducing the burden of influenza among the growing number of people living with one or more chronic medical conditions.
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http://dx.doi.org/10.1101/cshperspect.a038604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706577PMC
December 2020

Astrovirus Replication Is Inhibited by Nitazoxanide and .

J Virol 2020 02 14;94(5). Epub 2020 Feb 14.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Astroviruses (AstV) are a leading cause of diarrhea, especially in the very young, the elderly, and immunocompromised populations. Despite their significant impact on public health, no drug therapies for astrovirus have been identified. In this study, we fill this gap in knowledge and demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication with a 50% effective concentration (EC) of approximately 1.47 μM. It can be administered up to 8 h postinfection and is effective against multiple human astrovirus serotypes, including clinical isolates. Most importantly, NTZ reduces viral shedding , exhibiting its potential as a future clinical therapeutic. Human astroviruses (HAstV) are thought to cause between 2 and 9% of acute, nonbacterial diarrhea cases in children worldwide. HAstV infection can be especially problematic in immunocompromised people and infants, where the virus has been associated with necrotizing enterocolitis and severe and persistent diarrhea, as well as rare instances of systemic and fatal disease. And yet, no antivirals have been identified to treat astrovirus infection. Our study provides the first evidence that nitazoxanide may be an effective therapeutic strategy against astrovirus disease.
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http://dx.doi.org/10.1128/JVI.01706-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022343PMC
February 2020