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Environmental arsenic, immunoregulation, and viral disease risk

Award Number: R21ES033303
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/11/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Environmental arsenic, immunoregulation, and viral disease risk - PROJECT SUMMARY / ABSTRACT Arsenic exposure from well water and food is a major public health concern and is associated with increased morbidity and mortality from viral infections. Influenza A virus (IAV) annually infects ~5 million people causing acute respiratory symptoms and up to 646,000 deaths. The severity of viral disease varies between individuals and is likely to involve both genetic and environmental effects on immunoregulation. Epidemiological and animal model studies suggest that early life exposure to arsenic alters the immune response to pathogens, resulting in prolonged or excessive inflammation. Furthermore, available evidence indicates that arsenic is an endocrine disruptor that interferes with the glucocorticoid receptor (GR) signaling pathway, a critical regulator of inflammation, possibly with intergenerational epigenetic effects. However, significant gaps remain in our understanding of how arsenic disrupts GR signaling and promotes inflammation. This exploratory/ developmental research project will use zebrafish as a model system to test the novel hypothesis that arsenic exacerbates viral disease by downregulating the klf9-dependent anti-inflammatory GR signaling pathway. Preliminary studies indicate that Klf9 is a GR-responsive negative regulator of proinflammatory genes, and that basal and cortisol- induced klf9 activity is suppressed in zebrafish embryos exposed to very low levels of arsenic. Zebrafish larvae have a functional innate immune system and are a powerful model to study host-pathogen interactions during systemic or localized influenza (IAV) infection, as trafficking of macrophages and neutrophils to the site of IAV infection can be visualized using live imaging with transgenic lines with fluorescently labeled leukocytes as well as fluorescently labeled viruses. The proposed research will use those tools, as well as GR amd klf9 knockout lines that we recently created using CRISPR, to accomplish two specific aims. The first is to determine if arsenic dysregulates the inflammatory response to IAV infection by suppressing the anti-inflammatory GR-Klf9 signaling pathway, leading to excessive an/or prolonged pro-inflammatory gene expression and failure to resolve the response. This will be accomplished by asking how treatment of zebrafish larvae with arsenic affects expression of klf9 and downstream proinflammatory genes that we have identified as putative targets of Klf9-mediated repression, and assessing the effects of arsenic and klf9 dosage on the response dynamics of inflammatory cells (neutrophils and macrophages) and NF-kB activity following IAV infection. The second specific aim is to determine if arsenic exposure has intergenerational effects on the innate immune response to IAV infection that correlate with aberrant activity of the GR-Klf9 immunoregulatory pathway. To accomplish this, F0 arsenic- or vehicle-exposed wild-type larvae will be raised to adulthood and inbred through 2 generations without further exposure. In larvae from each generation (F1 and F2) we will assess immunoregulatory gene expression and larval survival after IAV infection. The project will elucidate a novel anti-viral immunoregulatory pathway impacted by arsenic, opening an avenue for future research focused on further elucidating the underlying mechanisms.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$15,820 )
2025	2023	THE MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Environmental Health	000	2	2/20/2025	NON-COMPETING CONTINUATION	-$15,820
														Subtotal = -$15,820

Issue Date FY: 2023 ( Subtotal = $194,809 )
2023	2023	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Environmental Health	000	2	2/28/2023	NON-COMPETING CONTINUATION	$194,809
														Subtotal = $194,809

Issue Date FY: 2022 ( Subtotal = $255,479 )
2022	2022	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Environmental Health	000	1	3/10/2022	NEW	$255,479
														Subtotal = $255,479

Grand Total All Awards = $434,468

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Environmental arsenic, immunoregulation, and viral disease risk

Award Number: R21ES033303

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/11/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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