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

During the COVID-19 pandemic, multiple observational studies reported a counterintuitive epidemiological observation: active smokers appeared less frequently infected or seropositive for SARS-CoV-2 compared with never-smokers, despite smoking being a risk factor for severe COVID-19 once infection occurs. This apparent paradox was rapidly marginalized due to public health concerns, leaving an informative biological observation largely unexplored. This Perspective proposes a mechanistic hypothesis to explain this paradox. We argue that much of this tension arises from a conceptual conflation between two distinct phases of the disease process: susceptibility to infection and progression to severe illness after infection has been established. Recent advances in virology and mucosal immunology make this question biologically plausible and experimentally tractable. These include: (i) evidence that plant viruses, including Tobacco Mosaic Virus (TMV), have been reported to be immunogenic in humans and capable of eliciting innate immune responses; (ii) direct documentation of mucosal exposure to TMV in smokers; and (iii) an improved understanding of viral interference, replication-independent RNA sensing, and interferon-lambda–mediated epithelial protection against SARS-CoV-2. This Perspective does not advocate smoking. Rather, it contends that if a specific biological component embedded within a harmful exposure were to modulate susceptibility to viral infection, scientific and ethical responsibility would require identifying that component, disentangling it from harm, rendering it safe, and evaluating its translational potential. We synthesize experimental evidence to propose interferon-mediated priming of innate mucosal immunity associated with Tobacco Mosaic Virus exposure as a testable mechanism underlying reduced SARS-CoV-2 attack rates in active smokers.