Association between COVID-19 Severity and Expression of Viral Nucleic Acid Sensor Genes in Peripheral Blood Mononuclear Cells and Nasopharyngeal Epithelial Cells

Zohreh-Al-Sadat Ghoreshi School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran;

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Emad Behboudi Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran;

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Hedyeh Askarpour School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran;

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Fatemeh Raesi Nejad Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran;

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Nasir Arefinia Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran

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This study examined expression of key viral nucleic acid sensor genes MDA5, ZBP1, and AIM2 in nasopharyngeal epithelial cells and peripheral blood mononuclear cells (PBMCs) obtained from 153 COVID-19 patients across a spectrum of disease severity (mild, severe, and critical) and 42 healthy controls. Quantitative reverse transcription polymerase chain reaction was used to quantify and compare sensor transcript levels. The COVID-19 cohort had a mean age of 53.6 years. All three sensor genes including MDA5 (3.2-fold), ZBP1 (5.1-fold), and AIM2 (4.7-fold) exhibited significantly higher messenger RNA expression in both nasopharyngeal and PBMC samples from infected patients compared with healthy controls. Furthermore, sensor transcript upregulation positively correlated with escalating disease severity. During early stages, ZBP1 and AIM2 transcripts were selectively elevated within the nasopharyngeal compartment, suggesting a localized antiviral response. Whereas later during critical disease stages, ZBP1 and AIM2 levels became preferentially heightened within circulating PBMCs, indicating systemic immune cell activation. By comparison, MDA5 elevation manifested within nasopharyngeal epithelial cells during both early- and late-phase infection. Intriguingly, males displayed higher ZBP1 and AIM2 expression compared with females, whereas MDA5 transcript levels were conversely higher among females. Overall, escalation of these key viral sensor genes appears closely linked to COVID-19 progression, with initial nasal mucosal upregulation transitioning to widespread blood cell activation in severe systemic disease. These patterns of sensor expression suggest frontline immunological efforts to constrain early viral invasion and combat severe late-stage COVID-19 illness through innate detection of replicating SARS-CoV-2.

Author Notes

Authors’ addresses: Zohreh-Al-Sadat Ghoreshi and Hedyeh Askarpour, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran, E-mails: zs.ghoreshi@gmail.com and Hedyehaskarpour94@gmail.com. Emad Behboudi, Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran, E-mail: emadbehboudi69@gmail.com. Fatemeh Raesi Nejad, Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran, E-mail: fa_raesi80@gmail.com. Nasir Arefinia, Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran, E-mail: n.arefinia@gmail.com.

Address correspondence to Nasir Arefinia, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran. E-mail: N.arefinia@jmu.ac.ir or N.arefinia@gmail.com
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