Correction: Re-opening the question of lower SARS-CoV-2 attack rates in active smokers: a perspective on viral interference and Tobacco Mosaic Virus

Hypothetical model of TMV-associated epithelial interferon priming and potential modulation of viral susceptibility. Repeated inhalation of aerosols containing Tobacco Mosaic Virus (TMV)-associated particles could, hypothetically, under certain exposure conditions, result in contact of the airway epithelium with non-replicating plant virus RNA. Following cellular uptake, TMV-associated RNA may be detected by epithelial pattern recognition receptors (PRRs). Endosomal sensors (e.g., TLR3/7) can recognize internalized viral RNA, whereas cytosolic sensors (RIG-I and MDA5) would require access of RNA to the cytoplasm. Engagement of these pathways may induce low-level baseline interferon signaling, with a prominent role for epithelial type III interferons (interferon-λ, IFN-λ). This signaling could promote upregulation of interferon-stimulated genes (ISGs), including antiviral effectors such as myxovirus resistance protein 1 (MX1), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), and interferon-stimulated gene 15 (ISG15), thereby establishing a transient, exposure-dependent antiviral state at the mucosal surface. In such a pre-activated state, the threshold for successful SARS-CoV-2 infection at the stage of viral entry or early replication may be increased. Importantly, this proposed mechanism is hypothesized to operate prior to viral establishment and does not imply protection once SARS-CoV-2 infection has occurred. The model illustrates a potential form of innate mucosal priming rather than durable adaptive immunity. Diagram illustrating a hypothesized mechanism in which inhalation of aerosols containing tobacco mosaic virus (TMV) RNA via cigarette smoke activates pattern recognition receptors in airway cells, leading to interferon signaling, upregulation of interferon-stimulated genes, and a primed antiviral state that may reduce the likelihood of SARS-CoV-2 infection. A flowchart summarizes the sequential steps from TMV particle inhalation to reduced SARS-CoV-2 infection likelihood.