NIEHS and partners harmonize environmental health language

Researchers from NIEHS and the international environmental health sciences community have proposed the creation of the Environmental Health Language Collaborative, an effort to develop and promote harmonized language in the field.

Through a community model, the collaborative seeks to standardize vocabulary, terminologies, and statistical and modeling approaches to enhance findability, shareability, and interoperability of data. The group supports increased use of artificial intelligence and machine learning to parse the enormous quantities of data and metadata produced through research.

The collaborative includes a community of practice as a hub of information and exchange of ideas, a forum for coordination and collaboration, and the development of a platform to address needs identified in use cases. To aid the sharing and integration of environmental health sciences data across platforms, the group will take advantage of communication structures in the Research Data Alliance model. NIEHS recently hosted a workshop to help advance this initiative. (KC)

Citation: Holmgren SD, Boyles RR, Cronk RD, Duncan CG, Kwok RK, Lunn RM, Osborn KC, Thessen AE, Schmitt CP. 2021. Catalyzing knowledge-driven discovery in environmental health sciences through a community-driven harmonized language. Int J Environ Res Public Health 18(17):8985.

Several types of lung dendritic cells involved in neutrophilic asthma

NIEHS scientists have identified five clusters of conventional dendritic cells (cDC2s) in the lungs of mice following their inhalation of house dust extract. As a result, the team is closer to understanding the cellular and molecular mechanisms involved in pulmonary diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.

The researchers used mass cytometry, single cell RNA sequencing, and a mouse model of asthma to assess how the developmental progression of cDC2s affects their ability to promote differentiation of the distinct T-helper (Th) cell lineages, Th2 and Th17. The researchers found that Ly6C, a cell-surface marker of immature dendritic cells, is associated with those cells’ ability to promote the differentiation of Th17 cells.

This finding is important because cDC2s in the lung direct immune responses to inhaled agents in the environmental bioaerosol. People with asthma who are resistant to steroids often present with neutrophilic inflammation of the airway. Th17 cells likely contribute to this form of asthma, so understanding how these cells develop may lead to improved strategies to reduce the incidence of neutrophilic asthma and other Th17-dependent pulmonary diseases, such as cystic fibrosis or COPD. (JH)

Citation: Izumi G, Nakano H, Nakano K, Whitehead GS, Grimm SA, Fessler MB, Karmaus PW, Cook DN. 2021. CD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation. Nat Commun 12(1):5029.

GLIS1 protein regulates pressure in eye, linked to human glaucoma risk

The gene regulatory protein GLIS1 is associated with glaucoma in humans and the regulation of intraocular pressure inside the eyes of mice, according to NIEHS researchers and their collaborators. This study sheds light on the cellular and molecular causes of the second most common cause of blindness in the U.S. and may lead to the development of new therapies.

In most cases, glaucoma is caused by an increase in intraocular pressure, which is largely regulated by an eye tissue known as the trabecular meshwork. The researchers found that mice lacking GLIS1 developed enlarged eyes and a long-lasting increase in intraocular pressure, hinting at the potential role of this regulatory protein in glaucoma.

The study revealed that low levels of GLIS1 induce the degeneration of the trabecular meshwork, leading to inefficient drainage of the ocular fluid called the aqueous humor. In addition, they showed that GLIS1 regulates the expression of several glaucoma-associated genes in trabecular meshwork cells.

In addition, the researchers discovered that common variants in the GLIS1 gene in humans are linked to primary open-angle glaucoma, the most common type of glaucoma in the U.S. This result suggests that GLIS1 is a glaucoma risk gene. Thus, targeting GLIS1 may increase trabecular meshwork functions and drainage of the aqueous humor, and ultimately slow the progression of glaucoma. (JW)

Citation: Nair KS, Srivastava C, Brown RV, Koli S, Choquet H, Kang HS, Kuo YM, Grimm SA, Sutherland C, Badea A, Johnson GA, Zhao Y, Yin J, Okamoto K, Clark G, Borras T, Zode G, Kizhatil K, Chakrabarti S, John SWM, Jorgenson E, Jetten AM. 2021. GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans. Nat Commun 12(1):4877.

SARS-CoV-2 nonstructural proteins a target for antiviral measures

NIEHS scientists determined that the SARS-CoV-2 nonstructural protein 15 (Nsp15) relies on recognition of the nucleoside uridine to cleave viral RNA and evade detection by the host immune system. Because of Nsp15’s involvement in helping SARS-CoV-2 spread undetected throughout the body, the work will help scientists develop new antiviral therapeutics to treat COVID-19, the disease caused by SARS-CoV-2.

Previous research using Nsp15s from several members of the Coronaviridae family found that Nsp15 forms a homo-hexamer, or a six-subunit structure, and has an active site that is similar to another RNA-degrading enzyme called RNase A. The scientists used cryo-electron microscopy to characterize the hexamer crystal structures of Nsp15 bound to RNA in both pre- and post-cleavage states. They also conducted molecular dynamics — computer simulations used to analyze the behavior of nucleotides at the substrate site — to determine where the virus cuts RNA strands. Finally, in vitro biochemical assays revealed that at the cleavage site, Nsp15 prefers a purine to follow the position of the uridine.

The researchers suggest Nsp15 could be inhibited by disrupting the substrate binding site or destabilizing the hexamer. Once Nsp15 is inactivated, the host’s immune system sensors will react to attack the viral invader. (KC)

Citation: Frazier MN, Dillard LB, Krahn JM, Perera L, Williams JG, Wilson IM, Stewart ZD, Pillon MC, Deterding LJ, Borgnia MJ, Stanley RE. 2021. Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U. Nucleic Acids Res; doi: 10.1093/nar/gkab719 [Online 17 August 2021].

When DNA repair goes awry

A molecule called polymerase (pol) mu may be a previously underappreciated and ironic source of mutations during DNA repair, according to NIEHS researchers and their collaborators.

Environmental and metabolic endogenous insults often trigger DNA damage, including double-strand breaks, which in turn may cause cancer or cell death. Double-strand breaks can be repaired with the aid of polymerases, which are proteins that synthesize DNA from building blocks called nucleotides. As with DNA, nucleotides are also damaged by environmental toxicants and when used during the repair process, can result in more harm than good. For example, polymerases can cause DNA defects by inserting certain types of damaged nucleotides into the genome, potentially leading to deleterious biological effects.

To understand the structural basis of this phenomenon, the researchers combined an imaging technique called time-lapse crystallography with computational simulations. The findings suggested that pol mu may cause mutations by incorporating a nucleotide called 8-oxo-rGTP into the genome during double-strand break repair.

Unfortunately, this process poses a persistent threat to genomic stability because it circumvents the intricate cellular defense network that typically protects against DNA damage. According to the authors, future research could uncover strategies to implement effective safeguards and thereby prevent disease. (JW)

Citation: Jamsen JA, Sassa A, Perera L, Shock DD, Beard WA, Wilson SH. 2021. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair. Nat Commun 12(1):5055.