Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 55 Records) |
Query Trace: Shane H [original query] |
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Systemic and immunotoxicity induced by topical application of perfluorohexane sulfonic acid (PFHxS) in a murine model
Weatherly LM , Shane HL , Jackson LG , Lukomska E , Baur R , Cooper MP , Anderson SE . Food Chem Toxicol 2024 186 114578 Per- and polyfluoroalkyl substances (PFAS) are a large group of stable synthetic surfactants that are incorporated into numerous products for their water and oil resistance and have been associated with adverse health effects. The present study evaluated the systemic and immunotoxicity of sub-chronic 28- or 10-day dermal exposure of PFHxS (0.625-5% or 15.63-125 mg/kg/dose) in a murine model. Elevated levels of PFHxS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. Liver weight (% body) significantly increased and spleen weight (% body) significantly decreased with PFHxS exposure, which was supported by histopathological changes. Additionally, PFHxS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen with genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells, NK cells, and CD11b(+) monocyte/macrophages in the spleen along with increases in CD4(+) and CD8(+) T-cells, NK cells, and neutrophils in the skin. These findings support dermal PFHxS-induced liver damage and immune suppression. Overall, data support PFHxS absorption through the skin and demonstrate immunotoxicity via this exposure route, suggesting the need for further examination. |
Effects of inhaled tier-2 diesel engine exhaust on immunotoxicity in a rat model: A hazard identification study. Part II. Immunotoxicology
Weatherly LM , Shane HL , Baur R , Lukomska E , McKinney W , Roberts JR , Fedan JS , Anderson SE . Toxicol Rep 2024 12 135-147 Diesel exhaust (DE) is an air pollutant containing gaseous compounds and particulate matter. Diesel engines are common on gas extraction and oil sites, leading to complex DE exposure to a broad range of compounds through occupational settings. The US EPA concluded that short-term exposure to DE leads to allergic inflammatory disorders of the airways. To further evaluate the immunotoxicity of DE, the effects of whole-body inhalation of 0.2 and 1 mg/m(3) DE (total carbon; 6 h/d for 4 days) were investigated 1-, 7-, and 27-days post exposure in Sprague-Dawley rats using an occupationally relevant exposure system. DE exposure of 1 mg/m(3) increased total cellularity, number of CD4+ and CD8+ T-cells, and B-cells at 1 d post-exposure in the lung lymph nodes. At 7 d post-exposure to 1 mg/m(3), cellularity and the number of CD4+ and CD8+ T-cells decreased in the LLNs. In the bronchoalveolar lavage, B-cell number and frequency increased at 1 d post-exposure, Natural Killer cell number and frequency decreased at 7 d post-exposure, and at 27 d post-exposure CD8+ T-cell and CD11b+ cell number and frequency decreased with 0.2 mg/m(3) exposure. In the spleen, 0.2 mg/m(3) increased CD4+ T-cell frequency at 1 and 7 d post-exposure and at 27 d post-exposure increased CD4+ and CD8+ T-cell number and CD8+ T-cell frequency. B-cells were the only immune cell subset altered in the three tissues (spleen, LLNs, and BALF), suggesting the induction of the adaptive immune response. The increase in lymphocytes in several different organ types also suggests an induction of a systemic inflammatory response occurring following DE exposure. These results show that DE exposure induced modifications of cellularity of phenotypic subsets that may impair immune function and contribute to airway inflammation induced by DE exposure in rats. |
Postvaccination SARS-CoV-2 infections among skilled nursing facility residents and staff members - Chicago, Illinois, December 2020-March 2021.
Teran RA , Walblay KA , Shane EL , Xydis S , Gretsch S , Gagner A , Samala U , Choi H , Zelinski C , Black SR . Am J Transplant 2021 21 (6) 2290-2297 This article describes 22 cases of breakthrough SARS-CoV-2 infection among over 14,000 fully vaccinated skilled nursing facility residents and staff. The majority of such infections were asymptomatic or were associated with mild symptoms, and there was no intra- facility spread related to these cases. This report suggests that postvaccination breakthrough infections are rare, but also confirms that vaccines do not offer 100% protection even in nonimmunosuppressed hosts, thus underscoring the need for studies of vaccine efficacy in immunosuppressed transplant recipients. |
Emerging issues in probiotic safety: 2023 perspectives.
Merenstein D , Pot B , Leyer G , Ouwehand AC , Preidis GA , Elkins CA , Hill C , Lewis ZT , Shane AL , Zmora N , Petrova MI , Collado MC , Morelli L , Montoya GA , Szajewska H , Tancredi DJ , Sanders ME . Gut Microbes 2023 15 (1) 2185034 Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety. | What is the context? Probiotics, available to healthy consumers as both dietary supplements and foods, are also used by some patient populations. The goal of this paper is to determine if any new factors have emerged that would impact current views about probiotic safety for both these populations.What is new? The authors conclude that established practices are sensibly addressing factors important to the safety of traditional probiotics used by the general population. They also make recommendations regarding emerging safety considerations. Probiotics targeted for patient populations should undergo stringent testing to meet quality standards appropriate for that population, preferably verified by an independent third party. The safety of probiotics derived from species without a history of safe use must be considered on a case-by-case basis. Research is needed to address some gaps, for example which best animal models to use for safety assessment of live microbes, the possibility of antibiotic resistance gene transfer via transformation, and potential impact of probiotic-induced changes in microbiomes, interactions with drugs, and probiotic colonization.What is the impact? Probiotics of sufficient quality for patient populations are being developed and should be used accordingly. Long-term safety assessments for probiotics should be consistent with, and not more stringent than, current regulatory requirements for biologic drugs, including fecal microbial transplants. Rigor in collecting and reporting data on adverse events is needed. The authors confirm the need for understanding the entire genetic makeup of a probiotic as a cornerstone for assessing its safety. | eng |
Exposure to the anti-microbial chemical triclosan disrupts keratinocyte function and skin integrity in a model of reconstructed human epidermis
Baur R , Kashon M , Lukomska E , Weatherly LM , Shane HL , Anderson SE . J Immunotoxicol 2023 20 (1) 1-11 Triclosan is an anti-microbial chemical incorporated into products that are applied to the skin of healthcare workers. Exposure to triclosan has previously been shown to be associated with allergic disease in humans and impact the immune responses in animal models. Additionally, studies have shown that exposure to triclosan dermally activates the NLRP3 inflammasome and disrupts the skin barrier integrity in mice. The skin is the largest organ of the body and plays an important role as a physical barrier and regulator of the immune system. Alterations in the barrier and immune regulatory functions of the skin have been demonstrated to increase the risk of sensitization and development of allergic disease. In this study, the impact of triclosan exposure on the skin barrier and keratinocyte function was investigated using a model of reconstructed human epidermis. The apical surface of reconstructed human epidermis was exposed to triclosan (0.05-0.2%) once for 6, 24, or 48 h or daily for 5 consecutive days. Exposure to triclosan increased epidermal permeability and altered the expression of genes involved in formation of the skin barrier. Additionally, exposure to triclosan altered the expression patterns of several cytokines and growth factors. Together, these results suggest that exposure to triclosan impacts skin barrier integrity and function of human keratinocytes and suggests that these alterations may impact immune regulation. |
Systemic toxicity induced by topical application of perfluoroheptanoic acid (PFHpA), perfluorohexanoic acid (PFHxA), and perfluoropentanoic acid (PFPeA) in a murine model.
Weatherly LM , Shane HL , Lukomska E , Baur R , Anderson SE . Food Chem Toxicol 2022 171 113515 Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic structurally diverse chemicals incorporated into industrial and consumer products. PFHpA, PFHxA, and PFPeA are carboxylic PFAS (C7, C6, C5, respectively) labeled as a safer alternative to legacy carboxylic PFAS due to their shorter half-life in animals. Although there is a high potential for dermal exposure, these studies are lacking. The present study conducted analyses of serum chemistries, immune phenotyping, gene expression, and histology to evaluate the systemic toxicity of a sub-chronic 28-day dermal exposure of alternative PFAS (1.25-5% or 31.25-125 mg/kg/dose) in a murine model. Liver weight (% body) significantly increased with PFHpA, PFHxA, and PFPeA exposure and histopathological changes were observed in both the liver and skin. Gene expression changes were observed with PPAR isoforms in the liver and skin along with changes in genes involved in steatosis, fatty acid metabolism, necrosis, and inflammation. These findings, along with significant detection levels in serum and urine, support PFAS-induced liver damage and PPARα, δ, and γ involvement in alternative PFAS systemic toxicity and immunological disruption. This demonstrates that these compounds can be absorbed through the skin and brings into question whether these PFAS are a suitable alternative to legacy PFAS. |
Exposure to the immunomodulatory chemical triclosan differentially impacts immune cell populations in the skin of haired (BALB/c) and hairless (SKH1) mice
Baur R , Shane HL , Weatherly LM , Lukomska E , Kashon M , Anderson SE . Tox Report 2022 9 1766-1776 Workers across every occupational sector have the potential to be exposed to a wide variety of chemicals, and the skin is a primary route of exposure. Furthermore, exposure to certain chemicals has been linked to inflammatory and allergic diseases. Thus, understanding the immune responses to chemical exposures on the skin and the potential for inflammation and sensitization is needed to improve worker safety and health. Responses in the skin microenvironment impact the potential for sensitization; these responses may include proinflammatory cytokines, inflammasome activation, barrier integrity, skin microbiota, and the presence of immune cells. Selection of specific mouse strains to evaluate skin effects, such as haired (BALB/c) or hairless (SKH1) mice, varies dependent on experimental design and needs of a study. However, dermal chemical exposure may impact reactions in the skin differently depending on the strain of mouse. Additionally, there is a need for established methods to evaluate immune responses in the skin. In this study, exposure to the immunomodulatory chemical triclosan was evaluated in two mouse models using immunophenotyping by flow cytometry and gene expression analysis. BALB/c mice exposed to triclosan (2%) had a higher number and frequency of neutrophils and lower number and frequency of dendritic cells in the skin compared to controls. Although these changes were not observed in SKH1 mice, SKH1 mice exposed to triclosan had a higher number and frequency of type 2 innate lymphoid cells in the skin. Taken together, these results demonstrate that exposure to an immunomodulatory chemical, triclosan, differentially impacts immune cell populations in the skin of haired and hairless mice. Additionally, the flow cytometry panel reported in this manuscript, in combination with gene expression analysis, may be useful in future studies to better evaluate the effect of chemical exposures on the skin immune response. These findings may be important to consider during strain selection, experimental design, and result interpretation of chemical exposures on the skin. Copyright © 2022 |
Biological effects of inhaled crude oil. VI. Immunotoxicity
Weatherly LM , Shane HL , Baur R , Lukomska E , Roberts JR , Fedan JS , Anderson SE . Toxicol Appl Pharmacol 2022 449 116100 Crude oil is an unrefined petroleum product that is a mixture of hydrocarbons and other organic material. Studies on the individual components of crude oil and crude oil exposure itself suggest it has immunomodulatory potential. As investigations of the immunotoxicity of crude oil focus mainly on ingestion and dermal exposure, the effects of whole-body inhalation of 300ppm crude oil vapor [COV; acute inhalation exposure: (6h1 d); or a 28 d sub-chronic exposure (6h/d4 d/wk.4 wks)] was investigated 1, 28, and 90 d post-exposure in Sprague-Dawley rats. Acute exposure increased bronchoalveolar lavage (BAL) fluid cellularity, CD4+ and CD8+ cells, and absolute and percent CDllb+ cells only at 1 d post-exposure; additionally, NK cell activity was suppressed. Sub-chronic exposure resulted in a decreased frequency of CD4+ T-cells at 1 d post-exposure and an increased number and frequency of B-cells at 28 d post-exposure in the lung-associated lymph nodes. A significant increase in the number and frequency of B-cells was observed in the spleen at 1 d post-exposure; however, NK cell activity was suppressed at this time point. No effect on cellularity was identified in the BALF. No change in the IgM response to sheep red blood cells was observed. The findings indicate that crude oil inhalation exposure resulted in alterations in cellularity of phenotypic subsets that may impair immune function in rats. |
Development and evaluation of a structured guide to assess the preventability of hospital-onset bacteremia and fungemia
Schrank GM , Sick-Samuels A , Bleasdale SC , Jacob JT , Dantes R , Gokhale RH , Mayer J , Mehrotra P , Mehta SA , MenaLora AJ , Ray SM , Rhee C , Salinas JL , Seo SK , Shane AL , Nadimpalli G , Milstone AM , Robinson G , Brown CH , Harris AD , Leekha S . Infect Control Hosp Epidemiol 2022 43 (10) 1-7 OBJECTIVE: To assess preventability of hospital-onset bacteremia and fungemia (HOB), we developed and evaluated a structured rating guide accounting for intrinsic patient and extrinsic healthcare-related risks. DESIGN: HOB preventability rating guide was compared against a reference standard expert panel. PARTICIPANTS: A 10-member panel of clinical experts was assembled as the standard of preventability assessment, and 2 physician reviewers applied the rating guide for comparison. METHODS: The expert panel independently rated 82 hypothetical HOB scenarios using a 6-point Likert scale collapsed into 3 categories: preventable, uncertain, or not preventable. Consensus was defined as concurrence on the same category among 70% experts. Scenarios without consensus were deliberated and followed by a second round of rating.Two reviewers independently applied the rating guide to adjudicate the same 82 scenarios in 2 rounds, with interim revisions. Interrater reliability was evaluated using the (kappa) statistic. RESULTS: Expert panel consensus criteria were met for 52 scenarios (63%) after 2 rounds.After 2 rounds, guide-based rating matched expert panel consensus in 40 of 52 (77%) and 39 of 52 (75%) cases for reviewers 1 and 2, respectively. Agreement rates between the 2 reviewers were 84% overall (, 0.76; 95% confidence interval [CI], 0.64-0.88]) and 87% (, 0.79; 95% CI, 0.65-0.94) for the 52 scenarios with expert consensus. CONCLUSIONS: Preventability ratings of HOB scenarios by 2 reviewers using a rating guide matched expert consensus in most cases with moderately high interreviewer reliability. Although diversity of expert opinions and uncertainty of preventability merit further exploration, this is a step toward standardized assessment of HOB preventability. |
Dermal exposure to the immunomodulatory antimicrobial chemical triclosan alters the skin barrier integrity and microbiome in mice
Baur R , Gandhi J , Marshall NB , Lukomska E , Weatherly LM , Shane HL , Hu G , Anderson SE . Toxicol Sci 2021 184 (2) 223-235 Triclosan is an antimicrobial chemical used in healthcare settings that can be absorbed through the skin. Exposure to triclosan has been positively associated with food and aeroallergy and asthma exacerbation in humans and, although not directly sensitizing, has been demonstrated to augment the allergic response in a mouse model of asthma. The skin barrier and microbiome are thought to play important roles in regulating inflammation and allergy and disruptions may contribute to development of allergic disease. To investigate potential connections of the skin barrier and microbiome with immune responses to triclosan, SKH1 mice were exposed dermally to triclosan (0.5-2%) or vehicle for up to 7 consecutive days. Exposure to 2% triclosan for 5-7 days on the skin was shown to increase trans-epidermal water loss levels. Seven days of dermal exposure to triclosan decreased filaggrin 2 and keratin 10 expression, but increased filaggrin and keratin 14 protein along with the danger signal S100a8 and interleukin-4. Dermal exposure to triclosan for 7 days also altered the alpha and beta diversity of the skin and gut microbiome. Specifically, dermal triclosan exposure increased the relative abundance of the Firmicutes family, Lachnospiraceae on the skin but decreased the abundance of Firmicutes family, Ruminococcaceae in the gut. Collectively, these results demonstrate that repeated dermal exposure to the antimicrobial chemical triclosan alters the skin barrier integrity and microbiome in mice, suggesting that these changes may contribute to the increase in allergic immune responses following dermal exposure to triclosan. |
Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model.
Weatherly LM , Shane HL , Lukomska E , Baur R , Anderson SE . Food Chem Toxicol 2021 156 112528 Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative to legacy PFAS which have been linked to numerous health effects. Despite the high potential for dermal exposure, occupationally and environmentally, dermal exposure studies are lacking. Using a murine model, this study analyzed serum chemistries, histology, immune phenotyping, and gene expression to evaluate the systemic toxicity of sub-chronic dermal PFBA 15-day (15% v/v or 375 mg/kg/dose) or 28-day (3.75-7.5% v/v or 93.8-187.5 mg/kg/dose) exposures. PFBA exposure produced significant increases in liver and kidney weights and altered serum chemistries (all exposure levels). Immune-cell phenotyping identified significant increases in draining lymph node B-cells (15%) and CD11b + cells (3.75-15%) and skin T-cells (3.75-15%) and neutrophils (7.5-15%). Histopathological and gene expression changes were observed in both the liver and skin after dermal PFBA exposure. The findings indicate PFBA induces liver toxicity and alterations of PPAR target genes, suggesting a role of a PPAR pathway. These results demonstrate that sustained dermal exposure to PFBA induces systemic effects and raise concerns of short-chain PFAS being promoted as safer alternatives. |
Outbreak of Acute Respiratory Illness Associated with Human Adenovirus Type 4 at the U.S. Coast Guard Academy, 2019.
Chu VT , Simon E , Lu X , Rockwell P , Abedi GR , Gardner C , Kujawski SA , Schneider E , Gentile M , Ramsey LA , Liu R , Jones S , Janik C , Siniscalchi A , Landry ML , Christopher J , Lindstrom S , Steiner S , Thomas D , Gerber SI , Biggs HM . J Infect Dis 2021 225 (1) 55-64 BACKGROUND: Although a human adenovirus (HAdV) vaccine is available for military use, officers-in-training are not routinely vaccinated. We describe an HAdV-associated respiratory outbreak among unvaccinated cadets at the U.S. Coast Guard Academy and its impact on cadet training. METHODS: We defined a case as a cadet with new onset cough or sore throat during August 1-October 4, 2019. We reviewed medical records and distributed a questionnaire to identify cases and to estimate impact on cadet training. We performed real-time PCR testing on patient and environmental samples and whole genome sequencing on a subset of positive patient samples. RESULTS: Among the 1,072 cadets, 378 (35%) cases were identified by medical records (n=230) or additionally by the questionnaire (n=148). Of the 230 cases identified from medical records, 138 (60%) were male and 226 (98%) had no underlying conditions. From questionnaire responses, 113/228 (50%) cases reported duty restrictions. Of cases with respiratory specimens, 36/50 (72%) were HAdV positive; all 14 sequenced specimens were HAdV-4a1. Sixteen (89%) of 18 environmental specimens from the cadet dormitory were HAdV-positive. CONCLUSIONS: The HAdV-4-associated outbreak infected a substantial number of cadets and significantly impacted cadet training. Routine vaccination could prevent HAdV respiratory outbreaks in this population. |
Administration of Bamlanivimab to Skilled Nursing Facility Residents During a COVID-19 Outbreak, January-February 2021, Arizona.
Dale AP , Hudson M , Cullen T , Ellingson K , Davis K , Armenta D , Friebus H , Currie C , Bhattarai R , Brady S , Komatsu K , Stone N , Uyeki T , Slifka KJ , Perez-Velez C , Keaton A . J Am Med Dir Assoc 2021 22 (7) 1357-1358 In November 2020, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for bamlanivimab, a monoclonal antibody (mAb), for treatment of mild to moderate COVID-19 in nonhospitalized individuals at high risk for severe disease.1 Since that time, several other mAb therapies, either alone or in combination, have also been issued EUA for use in the treatment of mild-to-moderate COVID-19.2 Although COVID-19 poses a high morbidity and mortality risk among older adult residents of long-term care facilities, reports on mAb use in the management of COVID-19 in skilled nursing facilities (SNFs) are limited, and perceived logistical barriers to on-site infusion of the mAb therapy may reduce their use in these settings.3 , 4 This letter describes the use of bamlanivimab during a large SARS-CoV-2 outbreak at a 270-bed SNF (Facility A). |
Postvaccination SARS-CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members - Chicago, Illinois, December 2020-March 2021.
Teran RA , Walblay KA , Shane EL , Xydis S , Gretsch S , Gagner A , Samala U , Choi H , Zelinski C , Black SR . MMWR Morb Mortal Wkly Rep 2021 70 (17) 632-638 Early studies suggest that COVID-19 vaccines protect against severe illness (1); however, postvaccination SARS-CoV-2 infections (i.e., breakthrough infections) can occur because COVID-19 vaccines do not offer 100% protection (2,3). Data evaluating the occurrence of breakthrough infections and impact of vaccination in decreasing transmission in congregate settings are limited. Skilled nursing facility (SNF) residents and staff members have been disproportionately affected by SARS-CoV-2, the virus that causes COVID-19 (4,5), and were prioritized for COVID-19 vaccination (6,7). Starting December 28, 2020, all 78 Chicago-based SNFs began COVID-19 vaccination clinics over several weeks through the federal Pharmacy Partnership for Long-Term Care Program (PPP).(†) In February 2021, through routine screening, the Chicago Department of Public Health (CDPH) identified a SARS-CoV-2 infection in a SNF resident >14 days after receipt of the second dose of a two-dose COVID-19 vaccination series. SARS-CoV-2 cases, vaccination status, and possible vaccine breakthrough infections were identified by matching facility reports with state case and vaccination registries. Among 627 persons with SARS-CoV-2 infection across 75 SNFs since vaccination clinics began, 22 SARS-CoV-2 infections were identified among 12 residents and 10 staff members across 15 facilities ≥14 days after receiving their second vaccine dose (i.e., breakthrough infections in fully vaccinated persons). Nearly two thirds (14 of 22; 64%) of persons with breakthrough infections were asymptomatic; two residents were hospitalized because of COVID-19, and one died. No facility-associated secondary transmission occurred. Although few SARS-CoV-2 infections in fully vaccinated persons were observed, these cases demonstrate the need for SNFs to follow recommended routine infection prevention and control practices and promote high vaccination coverage among SNF residents and staff members. |
Reactive astrocyte nomenclature, definitions, and future directions.
Escartin C , Galea E , Lakatos A , O'Callaghan JP , Petzold GC , Serrano-Pozo A , Steinhäuser C , Volterra A , Carmignoto G , Agarwal A , Allen NJ , Araque A , Barbeito L , Barzilai A , Bergles DE , Bonvento G , Butt AM , Chen WT , Cohen-Salmon M , Cunningham C , Deneen B , De Strooper B , Díaz-Castro B , Farina C , Freeman M , Gallo V , Goldman JE , Goldman SA , Götz M , Gutiérrez A , Haydon PG , Heiland DH , Hol EM , Holt MG , Iino M , Kastanenka KV , Kettenmann H , Khakh BS , Koizumi S , Lee CJ , Liddelow SA , MacVicar BA , Magistretti P , Messing A , Mishra A , Molofsky AV , Murai KK , Norris CM , Okada S , Oliet SHR , Oliveira JF , Panatier A , Parpura V , Pekna M , Pekny M , Pellerin L , Perea G , Pérez-Nievas BG , Pfrieger FW , Poskanzer KE , Quintana FJ , Ransohoff RM , Riquelme-Perez M , Robel S , Rose CR , Rothstein JD , Rouach N , Rowitch DH , Semyanov A , Sirko S , Sontheimer H , Swanson RA , Vitorica J , Wanner IB , Wood LB , Wu J , Zheng B , Zimmer ER , Zorec R , Sofroniew MV , Verkhratsky A . Nat Neurosci 2021 24 (3) 312-325 Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. |
Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization.
Konopka-Anstadt Jennifer L, Campagnoli Ray, Vincent Annelet, Shaw Jing, Wei Ling, Wynn Nhien T, Smithee Shane E, Bujaki Erika, Te Yeh Ming, Laassri Majid, Zagorodnyaya Tatiana, Weiner Amy J, Chumakov Konstantin, Andino Raul, Macadam Andrew, Kew Olen, Burns Cara C. NPJ vaccines 2020 Mar 5(1) 26 . NPJ vaccines 2020 Mar 5(1) 26 Konopka-Anstadt Jennifer L, Campagnoli Ray, Vincent Annelet, Shaw Jing, Wei Ling, Wynn Nhien T, Smithee Shane E, Bujaki Erika, Te Yeh Ming, Laassri Majid, Zagorodnyaya Tatiana, Weiner Amy J, Chumakov Konstantin, Andino Raul, Macadam Andrew, Kew Olen, Burns Cara C. NPJ vaccines 2020 Mar 5(1) 26 |
Topical exposure to triclosan inhibits Th1 immune responses and reduces T cells responding to influenza infection in mice
Shane HL , Othumpangat S , Marshall NB , Blachere F , Lukomska E , Weatherly LM , Baur R , Noti JD , Anderson SE . PLoS One 2020 15 (12) e0244436 Healthcare workers concurrently may be at a higher risk of developing respiratory infections and allergic disease, such as asthma, than the general public. Increased incidence of allergic diseases is thought to be caused, in part, due to occupational exposure to chemicals that induce or augment Th2 immune responses. However, whether exposure to these chemical antimicrobials can influence immune responses to respiratory pathogens is unknown. Here, we use a BALB/c murine model to test if the Th2-promoting antimicrobial chemical triclosan influences immune responses to influenza A virus. Mice were dermally exposed to 2% triclosan for 7 days prior to infection with a sub-lethal dose of mouse adapted PR8 A(H1N1) virus (50 pfu); triclosan exposure continued until 10 days post infection (dpi). Infected mice exposed to triclosan did not show an increase in morbidity or mortality, and viral titers were unchanged. Assessment of T cell responses at 10 dpi showed a decrease in the number of total and activated (CD44hi) CD4+ and CD8+ T cells at the site of infection (BAL and lung) in triclosan exposed mice compared to controls. Influenza-specific CD4+ and CD8+ T cells were assessed using MHCI and MHCII tetramers, with reduced populations, although not reaching statistical significance at these sites following triclosan exposure. Reductions in the Th1 transcription factor T-bet were seen in both activated and tetramer+ CD4+ and CD8+ T cells in the lungs of triclosan exposed infected mice, indicating reduced Th1 polarization and providing a potential mechanism for numerical reduction in T cells. Overall, these results indicate that the immune environment induced by triclosan exposure has the potential to influence the developing immune response to a respiratory viral infection and may have implications for healthcare workers who may be at an increased risk for developing infectious diseases. |
Pediatric research priorities in healthcare-associated infections and antimicrobial stewardship
Coffin SE , Abanyie F , Bryant K , Cantey J , Fiore A , Fritz S , Guzman-Cottrill J , Hersh AL , Huskins WC , Kociolek LK , Kronman M , Lautenbach E , Lee G , Linam M , Logan LK , Milstone A , Newland J , Nyquist AC , Palazzi DL , Patel S , Puopolo K , Reddy SC , Saiman L , Sandora T , Shane AL , Smith M , Tamma PD , Zaoutis T , Zerr D , Gerber JS . Infect Control Hosp Epidemiol 2020 42 (5) 1-4 OBJECTIVE: To develop a pediatric research agenda focused on pediatric healthcare-associated infections and antimicrobial stewardship topics that will yield the highest impact on child health. PARTICIPANTS: The study included 26 geographically diverse adult and pediatric infectious diseases clinicians with expertise in healthcare-associated infection prevention and/or antimicrobial stewardship (topic identification and ranking of priorities), as well as members of the Division of Healthcare Quality and Promotion at the Centers for Disease Control and Prevention (topic identification). METHODS: Using a modified Delphi approach, expert recommendations were generated through an iterative process for identifying pediatric research priorities in healthcare associated infection prevention and antimicrobial stewardship. The multistep, 7-month process included a literature review, interactive teleconferences, web-based surveys, and 2 in-person meetings. RESULTS: A final list of 12 high-priority research topics were generated in the 2 domains. High-priority healthcare-associated infection topics included judicious testing for Clostridioides difficile infection, chlorhexidine (CHG) bathing, measuring and preventing hospital-onset bloodstream infection rates, surgical site infection prevention, surveillance and prevention of multidrug resistant gram-negative rod infections. Antimicrobial stewardship topics included β-lactam allergy de-labeling, judicious use of perioperative antibiotics, intravenous to oral conversion of antimicrobial therapy, developing a patient-level "harm index" for antibiotic exposure, and benchmarking and or peer comparison of antibiotic use for common inpatient conditions. CONCLUSIONS: We identified 6 healthcare-associated infection topics and 6 antimicrobial stewardship topics as potentially high-impact targets for pediatric research. |
Biological effects of inhaled hydraulic fracturing sand dust. IX. Summary and significance
Anderson SE , Barger M , Batchelor TP , Bowers LN , Coyle J , Cumpston A , Cumpston JL , Cumpston JB , Dey RD , Dozier AK , Fedan JS , Friend S , Hubbs AF , Jackson M , Jefferson A , Joseph P , Kan H , Kashon ML , Knepp AK , Kodali V , Krajnak K , Leonard SS , Lin G , Long C , Lukomska E , Marrocco A , Marshall N , Mc Kinney W , Morris AM , Olgun NS , Park JH , Reynolds JS , Roberts JR , Russ KA , Sager TM , Shane H , Snawder JE , Sriram K , Thompson JA , Umbright CM , Waugh S , Zheng W . Toxicol Appl Pharmacol 2020 409 115330 An investigation into the potential toxicological effects of fracking sand dust (FSD), collected from unconventional gas drilling sites, has been undertaken, along with characterization of their chemical and biophysical properties. Using intratracheal instillation of nine FSDs in rats and a whole body 4-d inhalation model for one of the FSDs, i.e., FSD 8, and related in vivo and in vitro experiments, the effects of nine FSDs on the respiratory, cardiovascular and immune systems, brain and blood were reported in the preceding eight tandem papers. Here, a summary is given of the key observations made in the organ systems reported in the individual studies. The major finding that inhaled FSD 8 elicits responses in extra-pulmonary organ systems is unexpected, as is the observation that the pulmonary effects of inhaled FSD 8 are attenuated relative to forms of crystalline silica more frequently used in animal studies, i.e., MIN-U-SIL®. An attempt is made to understand the basis for the extra-pulmonary toxicity and comparatively attenuated pulmonary toxicity of FSD 8. |
Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop
Maruvada P , Stover PJ , Mason JB , Bailey RL , Davis CD , Field MS , Finnell RH , Garza C , Green R , Gueant JL , Jacques PF , Klurfeld DM , Lamers Y , MacFarlane AJ , Miller JW , Molloy AM , O'Connor DL , Pfeiffer CM , Potischman NA , Rodricks JV , Rosenberg IH , Ross SA , Shane B , Selhub J , Stabler SP , Trasler J , Yamini S , Zappalà G . Am J Clin Nutr 2020 112 (5) 1390-1403 Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas. |
Biological effects of inhaled hydraulic fracturing sand dust. VIII. Immunotoxicity
Anderson SE , Shane H , Long C , Marrocco A , Lukomska E , Roberts JR , Marshall N , Fedan JS . Toxicol Appl Pharmacol 2020 408 115256 Hydraulic fracturing ("fracking") is a process used to enhance retrieval of gas from subterranean natural gas-laden rock by fracturing it under pressure. Sand used to stabilize fissures and facilitate gas flow creates a potential occupational hazard from respirable fracking sand dust (FSD). As studies of the immunotoxicity of FSD are lacking, the effects of whole-body inhalation (6 h/d for 4 d) of a FSD, i.e., FSD 8, was investigated at 1, 7, and 27 d post-exposure in rats. Exposure to 10 mg/m(3) FSD 8 resulted in decreased lung-associated lymph node (LLN) cellularity, total B-cells, CD4+ T-cells, CD8+ T-cells and total natural killer (NK) cells at 7-d post exposure. The frequency of CD4+ T-cells decreased while the frequency of B-cells increased (7 and 27 d) in the LLN. In contrast, increases in LLN cellularity and increases in total CD4+ and CD8+ T-cells were observed in rats following 30 mg/m(3) FSD 8 at 1 d post-exposure. Increases in the frequency and number of CD4+ T-cells and NK cells were observed in bronchial alveolar lavage fluid at 7-d post-exposure (10 mg/m(3)) along with an increase in total CD4+ T-cells, CD11b + cells, and NK cells at 1-day post-exposure (30 mg/m(3)). Increases in the numbers of B-cells and CD8+ T-cells were observed in the spleen at 1-day post 30 mg/m(3) FSD 8 exposure. In addition, NK cell activity was suppressed at 1 d (30 mg/m(3)) and 27 d post-exposure (10 mg/m(3)). No change in the IgM response to sheep red blood cells was observed. The findings indicate that FSD 8 caused alterations in cellularity, phenotypic subsets, and impairment of immune function. |
Trends in COVID-19 Incidence After Implementation of Mitigation Measures - Arizona, January 22-August 7, 2020.
Gallaway MS , Rigler J , Robinson S , Herrick K , Livar E , Komatsu KK , Brady S , Cunico J , Christ CM . MMWR Morb Mortal Wkly Rep 2020 69 (40) 1460-1463 Mitigating the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), requires individual, community, and state public health actions to prevent person-to-person transmission. Community mitigation measures can help slow the spread of COVID-19; these measures include wearing masks, social distancing, reducing the number and size of large gatherings, pausing operation of businesses where maintaining social distancing is challenging, working from or staying at home, and implementing certain workplace and educational institution controls (1-4). The Arizona Department of Health Services' (ADHS) recommendations for mitigating exposure to SARS-CoV-2 were informed by continual monitoring of patient demographics, SARS-CoV-2 community spread, and the pandemic's impacts on hospitals. To assess the effect of mitigation strategies in Arizona, the numbers of daily COVID-19 cases and 7-day moving averages during January 22-August 7, 2020, relative to implementation of enhanced community mitigation measures, were examined. The average number of daily cases increased approximately 151%, from 808 on June 1, 2020 to 2,026 on June 15, 2020 (after stay-at-home order lifted), necessitating increased preventive measures. On June 17, local officials began implementing and enforcing mask wearing (via county and city mandates),* affecting approximately 85% of the state population. Statewide mitigation measures included limitation of public events; closures of bars, gyms, movie theaters, and water parks; reduced restaurant dine-in capacity; and voluntary resident action to stay at home and wear masks (when and where not mandated). The number of COVID-19 cases in Arizona peaked during June 29-July 2, stabilized during July 3-July 12, and further declined by approximately 75% during July 13-August 7. Widespread implementation and enforcement of sustained community mitigation measures informed by state and local officials' continual data monitoring and collaboration can help prevent transmission of SARS-CoV-2 and decrease the numbers of COVID-19 cases. |
Serial Testing for SARS-CoV-2 and Virus Whole Genome Sequencing Inform Infection Risk at Two Skilled Nursing Facilities with COVID-19 Outbreaks - Minnesota, April-June 2020.
Taylor J , Carter RJ , Lehnertz N , Kazazian L , Sullivan M , Wang X , Garfin J , Diekman S , Plumb M , Bennet ME , Hale T , Vallabhaneni S , Namugenyi S , Carpenter D , Turner-Harper D , Booth M , Coursey EJ , Martin K , McMahon M , Beaudoin A , Lifson A , Holzbauer S , Reddy SC , Jernigan JA , Lynfield R . MMWR Morb Mortal Wkly Rep 2020 69 (37) 1288-1295 SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), can spread rapidly in high-risk congregate settings such as skilled nursing facilities (SNFs) (1). In Minnesota, SNF-associated cases accounted for 3,950 (8%) of 48,711 COVID-19 cases reported through July 21, 2020; 35% of SNF-associated cases involved health care personnel (HCP*), including six deaths. Facility-wide, serial testing in SNFs has been used to identify residents with asymptomatic and presymptomatic SARS-CoV-2 infection to inform mitigation efforts, including cohorting of residents with positive test results and exclusion of infected HCP from the workplace (2,3). During April-June 2020, the Minnesota Department of Health (MDH), with CDC assistance, conducted weekly serial testing at two SNFs experiencing COVID-19 outbreaks. Among 259 tested residents, and 341 tested HCP, 64% and 33%, respectively, had positive reverse transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 test results. Continued SARS-CoV-2 transmission was potentially facilitated by lapses in infection prevention and control (IPC) practices, up to 12-day delays in receiving HCP test results (53%) at one facility, and incomplete HCP participation (71%). Genetic sequencing demonstrated that SARS-CoV-2 viral genomes from HCP and resident specimens were clustered by facility, suggesting facility-based transmission. Residents and HCP working in SNFs are at risk for infection with SARS-CoV-2. As part of comprehensive COVID-19 preparation and response, including early identification of cases, SNFs should conduct serial testing of residents and HCP, maximize HCP testing participation, ensure availability of personal protective equipment (PPE), and enhance IPC practices(†) (4-5). |
Evaluation of the skin-sensitizing potential of gold nanoparticles and the impact of established dermal sensitivity on the pulmonary immune response to various forms of gold
Roach KA , Anderson SE , Stefaniak AB , Shane HL , Boyce GR , Roberts JR . Nanotoxicology 2020 14 (8) 1-22 Gold nanoparticles (AuNP) are largely biocompatible; however, many studies have demonstrated their potential to modulate various immune cell functions. The potential allergenicity of AuNP remains unclear despite the recognition of gold as a common contact allergen. In these studies, AuNP (29 nm) dermal sensitization potential was assessed via Local Lymph Node Assay (LLNA). Soluble gold (III) chloride (AuCl(3)) caused lymph node (LN) expansion (SI 10.9), whereas bulk particles (Au, 942 nm) and AuNP did not. Next, the pulmonary immune effects of AuNP (10, 30, 90 µg) were assessed 1, 4, and 8 days post-aspiration. All markers of lung injury and inflammation remained unaltered, but a dose-responsive increase in LN size was observed. Finally, mice were dermally-sensitized to AuCl(3) then aspirated once, twice, or three times with Au or AuNP in doses normalized for mass or surface area (SA) to assess the impact of existing contact sensitivity to gold on lung immune responses. Sensitized animals exhibited enhanced responsivity to the metal, wherein subsequent immune alterations were largely conserved with respect to dose SA. The greatest increase in bronchoalveolar lavage (BAL) lymphocyte number was observed in the high dose group - simultaneous to preferential expansion of BAL/LN CD8+ T-cells. Comparatively, the lower SA-based doses of Au/AuNP caused more modest elevations in BAL lymphocyte influx (predominantly CD4+ phenotype), exposure-dependent increases in serum IgE, and selective expansion/activation of LN CD4+ T-cells and B-cells. Overall, these findings suggest that AuNP are unlikely to cause sensitization; however, established contact sensitivity to gold may increase immune responsivity following pulmonary AuNP exposure. |
Prior exposure to ortho-phthalaldehyde (OPA) augments IgE mediated immune responses to didecyldimethylammonium chloride (DDAC); potential for two commonly used antimicrobials to synergistically enhance allergic disease
Shane HL , Lukomska E , Weatherly L , Baur R , Anderson SE . Toxicol Sci 2020 178 (1) 127-137 Health care workers have an increased incidence of allergic disease compared to the general public and are exposed to a variety of high-level disinfectants. While exposure to these agents has been associated with allergic disease, findings between epidemiology and animal studies often conflict respecting immunological mechanisms. Therefore, we hypothesized that previous exposure to a representative IgE-mediated sensitizer, (Ortho-phthalaldehyde [OPA]) alters immune responses to a representative T-cell mediated sensitizer (didecyldimethlyammonium chloride [DDAC]). Here, BALB/c mice were topically exposed to OPA (0.5%) for 3-days, rested, then topically exposed to DDAC (0.0625, 0.125, 0.25%) for 14-days. Co-exposure resulted in phenotypic changes in draining lymph node (dLN) cells, including a decreased frequency of CD8+ T cells and increased frequency and number of B cells compared to DDAC-only treated mice. The co-exposed mice also had enhanced Th2 responses, including significant alterations in: dLN Il4 (increased), B-cell activation (increased), CD8 T-cell activation (decreased), and local and systemic IgE production (increased). These changes were not observed if mice were exposed to DDAC prior to OPA. Exposure to OPA alone shows Th2 skewing, indicated by increased activation of skin type 2 innate lymphoid cells, increased frequency and activation of draining lymph node B cells, and increased levels of type 2 cytokines. These findings suggest that the OPA-induced immune environment may alter the response to DDAC, resulting in increased IgE mediated immune responses. This data may partially explain the discordance between epidemiological and laboratory studies regarding disinfectants and provide insight into the potential immunological implications of mixed chemical exposures. |
Potential classification of chemical immunologic response based on gene expression profiles.
Anderson SE , Baur R , Kashon M , Lukomska E , Weatherly L , Shane HL . J Immunotoxicol 2020 17 (1) 122-134 Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases. |
Topical application of the antimicrobial agent triclosan induces NLRP3 inflammasome activation and mitochondrial dysfunction
Weatherly LM , Shane HL , Friend SA , Lukomska E , Baur R , Anderson SE . Toxicol Sci 2020 176 (1) 147-161 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In the present study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1beta secretion in the skin and draining lymph nodes (dLNs) after 1.5 and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial ROS, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan's effects on allergic disease and further support a connection between mitochondrial involvement in immunological responses. |
Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization.
Konopka-Anstadt JL , Campagnoli R , Vincent A , Shaw J , Wei L , Wynn NT , Smithee SE , Bujaki E , Te Yeh M , Laassri M , Zagorodnyaya T , Weiner AJ , Chumakov K , Andino R , Macadam A , Kew O , Burns CC . NPJ Vaccines 2020 5 (1) 26 Enormous progress has been made in global efforts to eradicate poliovirus, using live-attenuated Sabin oral poliovirus vaccine (OPV). However, as the incidence of disease due to wild poliovirus has declined, vaccine-derived poliovirus (VDPV) has emerged in areas of low-vaccine coverage. Coordinated global cessation of routine, type 2 Sabin OPV (OPV2) use has not resulted in fewer VDPV outbreaks, and continued OPV use in outbreak-response campaigns has seeded new emergences in low-coverage areas. The limitations of existing vaccines and current eradication challenges warranted development of more genetically stable OPV strains, most urgently for OPV2. Here, we report using codon deoptimization to further attenuate Sabin OPV2 by changing preferred codons across the capsid to non-preferred, synonymous codons. Additional modifications to the 5' untranslated region stabilized known virulence determinants. Testing of this codon-deoptimized new OPV2 candidate (nOPV2-CD) in cell and animal models demonstrated that nOPV2-CD is highly attenuated, grows sufficiently for vaccine manufacture, is antigenically indistinguishable from Sabin OPV2, induces neutralizing antibodies as effectively as Sabin OPV2, and unlike Sabin OPV2 is genetically stable and maintains an attenuation phenotype. In-human clinical trials of nOPV2-CD are ongoing, with potential for nOPV strains to serve as critical vaccine tools for achieving and maintaining polio eradication. |
Immunotoxicity and allergenic potential induced by topical application of perfluorooctanoic acid (PFOA) in a murine model
Shane HL , Baur R , Lukomska E , Weatherly L , Anderson SE . Food Chem Toxicol 2020 136 111114 Perfluorooctanoic acid (PFOA) is a per- and polyfluoroalkyl substance (PFAS) once used as a surfactant in the polymerization of chemicals. Because of its ubiquitous nature and long half-life, PFOA is commonly detected in the environment, wildlife, and humans. While skin exposure to PFOA is of concern, studies evaluating the immunotoxicity of dermal exposure are lacking. These studies evaluated the immunotoxicity of PFOA (0.5-2% w/v, or 12.5-50mg/kg/dose) following dermal exposure using a murine model. PFOA (0.5-2%) was not identified to be an irritant or sensitizer using the local lymph node assay. The IgM antibody response to sheep red blood cell. was significantly reduced in the spleen following 4-days of dermal exposure (2%). PFOA exposure produced a significant decrease in thymus (1 and 2%) and spleen (0.5-2%) weight along with an increase in liver weight (0.5-2%). Immune cell phenotyping identified a reduction in the frequency (1 and 2%) and number (0.5-2%) of splenic B-cells. To further define the mechanism of immunotoxicity, gene expression was also evaluated in the skin. The findings support a potential involvement of the nuclear receptor PPARalpha. These results demonstrate that dermal exposure to PFOA is immunotoxic and raise concern about potential adverse effects from dermal exposure. |
Surface area- and mass-based comparison of fine and ultrafine nickel oxide lung toxicity and augmentation of allergic response in an ovalbumin asthma model
Roach KA , Anderson SE , Stefaniak AB , Shane HL , Kodali V , Kashon M , Roberts JR . Inhal Toxicol 2019 31 (8) 1-26 Background: The correlation of physico-chemical properties with mechanisms of toxicity has been proposed as an approach to predict the toxic potential of the vast number of emerging nanomaterials. Although relationships have been established between properties and the acute pulmonary inflammation induced by nanomaterials, properties' effects on other responses, such as exacerbation of respiratory allergy, have been less frequently explored.Methods: In this study, the role of nickel oxide (NiO) physico-chemical properties in the modulation of ovalbumin (OVA) allergy was examined in a murine model. Results: 181 nm fine (NiO-F) and 42 nm ultrafine (NiO-UF) particles were characterized and incorporated into a time course study where measured markers of pulmonary injury and inflammation were associated with NiO particle surface area. In the OVA model, exposure to NiO, irrespective of any metric was associated with elevated circulating total IgE levels. Serum and lung cytokine levels were similar with respect to NiO surface area. The lower surface area was associated with an enhanced Th2 profile, whereas the higher surface area was associated with a Th1-dominant profile. Surface area-normalized groups also exhibited similar alterations in OVA-specific IgE levels and lung neutrophil number. However, lung eosinophil number and allergen challenge-induced alterations in lung function related more to particle size, wherein NiO-F was associated with an increased enhanced pause response and NiO-UF was associated with increased lung eosinophil burden.Conclusions: Collectively, these findings suggest that although NiO surface area correlates best with acute pulmonary injury and inflammation following respiratory exposure, other physico-chemical properties may contribute to the modulation of immune responses in the lung. |
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