Woodsmoke particle exposure prior to SARS-CoV-2 infection alters antiviral response gene expression in human nasal epithelial cells in a sex-dependent manner

Abstract

Inhalational exposure to particulate matter (PM) derived from natural or anthropogenic sources alters gene expression in the airways and increases susceptibility to respiratory viral infection. Woodsmoke-derived ambient PM from wildfire events during 2020 was associated with higher COVID-19 case rates in the western US. We hypothesized that exposure to suspensions of woodsmoke particles (WSP) or diesel exhaust particles (DEP) prior to SARS-CoV-2 infection would alter host immune gene expression at the transcript level. Primary human nasal epithelial cells (hNECs) from both sexes were exposed to WSP or DEP (22 μg/cm2) for 2 h, followed by infection with SARS-CoV-2 at a multiplicity of infection of 0.5. Forty-six genes related to SARS-CoV-2 entry and host response were assessed. Particle exposure alone minimally affected gene expression, while SARS-CoV-2 infection alone induced a robust transcriptional response in hNECs, upregulating type I and III interferons, interferon-stimulated genes, and chemokines by 72 h p.i. This upregulation was higher overall in cells from male donors. However, exposure to WSP prior to infection dampened expression of antiviral, interferon, and chemokine mRNAs. Sex-stratification of these results revealed that WSP exposure downregulated gene expression in cells from females more so than males. We next hypothesized that hNECs exposed to particles would have increased apical viral loads compared to unexposed cells. While apical viral load was correlated to expression of host response genes, viral titer did not differ between groups. These data indicate that WSP alter epithelial immune responses in a sex-dependent manner, potentially suppressing host defense to SARS-CoV-2 infection.

Wildfire Variable Toxicity: Identifying Biomass Smoke Exposure Groupings through Transcriptomic Similarity Scoring

“…In addition, a cohort of rhesus macaque monkeys that experienced early life exposure to wildfire smoke in California showed an impairment in interleukin expression within cultures of peripheral blood mononuclear cell samples . In terms of immune function and pathogen signaling, primary nasal epithelial cell cultures were recently shown to have altered host immune gene expression profiles that potentially influence defense mechanisms against SARS-CoV-2 infection . Molecular signaling involved in inflammation and immune pathways are notably linked to oxidative stress and tissue damage processes, , representing additional pathways identified here as altered in association with biomass smoke exposures.…”

“…47 In terms of immune function and pathogen signaling, primary nasal epithelial cell cultures were recently shown to have altered host immune gene expression profiles that potentially influence defense mechanisms against SARS-CoV-2 infection. 48 Molecular signaling involved in inflammation and immune pathways are notably linked to oxidative stress and tissue damage processes, 49,50 representing additional pathways identified here as altered in association with biomass smoke exposures. The long-term implications of such molecular alterations remain understudied in relation to wildfire-associated exposures, though recent studies surrounding the health of firefighters support chronic exposures influencing immune signaling and associated function through observed increases in respiratory infection severity.…”

Wildfires and extracellular vesicles: Exosomal MicroRNAs as mediators of cross-tissue cardiopulmonary responses to biomass smoke

“…Future efforts could also leverage in vitro -based designs to more efficiently evaluate the wide variety of exposure scenarios relevant to wildfires ( Zavala et al 2020 ). Sex-specific responses are also important to evaluate, as we have identified sex-dependent differential molecular response patterns to biomass smoke exposures ( Brocke et al 2022 ; Rebuli et al 2019 ) that could be further evaluated through controlled animal experimentation. Further molecular characterization of EVs isolated from plasma samples of exposed mice will also enhance this growing area of research, including additional markers that inform EV origins in terms of biogenesis and host tissue (e.g., additional tetraspanins and tissue-specific markers) ( Carberry et al 2022 ).…”

“…We have also used female CD-1 mice previously, which allows for direct comparisons between studies ( Cho et al 2009 ; Kim et al 2014 ; Kim et al 2015 ; Tong et al 2010 ). Use of female mice further increased study feasibility by adding increased power to detect differences in expression between exposure groups using fewer mice, though we recognize that inclusion of both sexes in future studies will further enhance this research topic, as we have identified sex-dependent responses to biomass smoke exposures through in vitro models using human donor cells ( Brocke et al 2022 ; Rebuli et al 2019 ). Mice were weighed and weight-randomized into groups of six for each exposure.…”

Wildfires and the COVID-19 pandemic: a systematized literature review of converging health crises

“…These concerns included limited availability of N95 respiratory masks for both wildfire smoke and frontline healthcare workers, conflicting ventilation priorities, and tradeoffs between social distancing and clean air shelters [19]. This respiratory concern was reinforced by an in vitro study demonstrating a potential biological mechanism of action for wildfire smoke exposure to facilitate or exacerbate SARS-CoV-2 infection: exposure of human nasal epithelial cells to particulate matter (PM) from woodsmoke reduced expression of antiviral, interferon, and chemokine genes, suppressing respiratory cells' immune response [22]. General disaster response concerns were also raised regarding hospital capacity [23,24]; burnout of the disaster response workforce [25]; and risks to housing, employment, mental wellbeing, and access to healthcare [23].…”