A substantial comorbidity between atherosclerotic cardiovascular diseases and coronavirus infections has been consistently reported [1, 2]. The underlying mechanisms of this association remain the subject of active investigation and scientific debate.

Coronaviruses are a large family of viruses that cause respiratory diseases of varying severity, from the common cold to lethal pneumonia. These viruses infect both humans and animals and can induce diseases affecting the respiratory, enteric, hepatobiliary, neuroendocrine, and other physiological systems [3, 4]. To date, seven human coronaviruses have been identified, including the seasonal strains human coronavirus 229E (HCoV-229E), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), and human coronavirus HKU1 (HCoV-HKU1), as well as the highly pathogenic viruses severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

A typical coronavirus virion contains several structurally and functionally significant antigens, including the spike protein (SP), envelope protein (EP), membrane protein (MP), and nucleocapsid protein (NP) [5, 6]. The SP of SARS-CoV-2 and other human coronaviruses plays a key role in mediating viral entry into host cells [7] and represents one of the principal immunodominant viral antigens [8]. It is also a central component of SARS-CoV-2 vaccines. The EP, MP, and NP proteins are likewise mechanistically important and immunogenic molecular targets.

In response to SARS-CoV-2 infection or vaccination, an increase in the intensity of autoimmune processes may occasionally occur. This phenomenon appears to arise in individuals whose immune systems are robust yet somewhat “short-sighted”, relying on mimicking peptides during the immune response. Accordingly, identifying molecular mimicry between coronavirus proteins and human autoantigens may contribute to a deeper understanding of disease pathogenesis, facilitate the development of improved therapeutic approaches, and enhance vaccine safety.

In recent years, a growing body of evidence has documented the promotion, exacerbation, or complication of atherosclerotic cardiovascular disease and/or vasculitides in individuals who have experienced coronavirus disease 2019 (COVID-19) [9–12].

Atherosclerosis may be broadly defined as a chronic, progressive inflammatory condition affecting large and medium-sized elastic and muscular-elastic arteries. It is characterized by a proliferative response of the vascular wall and blood cells to atherogenic lipoproteins, resulting in the formation of atheromas [13–15].

The diversity of existing atherogenesis theories reflects the multifactorial nature of the condition. Among the most influential theories are the response-to-injury hypothesis, the endothelial dysfunction theory, the monoclonal theory, and several infectious theories implicating viruses, Mycoplasma, or Chlamydia. A mosaic of genetic, endocrine, and autoimmune factors is likewise implicated, as these represent critical predispositions and mechanistic contributors to atherogenesis. In addition to classical concepts, an emerging microangiopathic paradigm proposes that atherogenesis may be initiated by vasculitis or ischemia of the vasa vasorum, leading to impaired blood supply and drainage of major arteries [15].

Regarding the proposed mechanisms linking COVID-19 to alterations in the cardiovascular system, several key pathways have been highlighted: the direct cytopathic effect of SARS-CoV-2 on cardiomyocytes, endothelial dysfunction and coagulopathy, an imbalance between myocardial oxygen supply and demand due to compensatory cardiac overstrain in hypoxic conditions, excessive systemic activity of inflammatory mediators, and dysregulation of the renin-angiotensin-aldosterone system [2]. However, the observation that hyperlipidemia in immunodeficient nude mice does not induce atherosclerosis [16] underscores the importance of autoimmune components in atherogenesis [17, 18]. The presumption: “Everything is autoimmune and infectious until proven otherwise”, once coined by Shoenfeld et al. [19], is still valid. The principal concepts of autoimmunity that implicate viral agents as causal factors include epitope spreading [20], cryptic epitope exposure [21], bystander activation [22], and molecular mimicry [23, 24]. Molecular mimicry is defined as the possibility that sequence similarities between foreign and self-peptides may lead to cross-activation of autoreactive T or B cells by pathogen-derived peptides [25].

This phenomenon has been described as “the most suspicious culprit incriminated in the pathophysiology of autoimmunity in the time of COVID-19” [26].

Previously, we demonstrated peptide sharing between immunogenic epitopes of the SARS-CoV-2 SP and several autoantigens of human endocrine cells, accompanied by pathomorphological evidence of autoimmune inflammation in the corresponding endocrine glands in victims of COVID-19 [27, 28].

In the present study, we report new data indicating molecular mimicry between human coronavirus antigens and proteins implicated in atherogenesis and vasculitides. In our view, these findings contribute to a better understanding of the autoimmune component underlying the comorbidity between atherosclerotic cardiovascular complications and coronavirus infection.

Several general considerations regarding antigenic mimicry merit emphasis. Beyond the direct pathological effects of coronavirus infection on cardiovascular tissues, indirect immune-mediated mechanisms are plausible. Previously, we documented molecular mimicry between SARS-CoV-2 antigens and host autoantigens implicated in autoimmune endocrinopathies [28], with accompanying lymphocytic inflammation of multiple endocrine glands in fatal COVID-19 cases. Such lymphoid infiltration reflects cell-mediated immunopathology.

In the context of post-COVID cardiovascular disease, endocrine involvement—particularly thyroid dysfunction—may be relevant. Hypothyroidism is strongly associated with atherogenesis, owing to alterations in lipid metabolism [67] and the frequent presence of secondary arterial hypertension [68], both of which are established risk factors of atherosclerosis. Autoantibody formation after infection is widely attributed to molecular mimicry between pathogen antigens and self-antigens [69].

Our bioinformatic and serological findings support a potential role for mimicry in atherogenesis. The study demonstrates sequence homology and correlational findings, such as the presence of antibodies and inflammation; however, it lacks functional validation to confirm that the shared peptides can trigger cross-reactive immune responses leading to functional pathology. Therefore, the Discussion emphasizes that the proposed mechanism of molecular mimicry is supported by circumstantial evidence but not definitively proven.

The human immune system exhibits differential responses to various microorganisms, primarily attributable to human leukocyte antigen (HLA) haplotypes. It is posited that the development of autoimmunity is associated with human HLA. When shared peptides bind to human HLA and are presented on the surface of antigen-presenting cells, the potential for autoimmune reactions may arise within the human body.

Antigenic mimicry constitutes a prerequisite rather than a guarantee of post-infectious autoimmunity. Antigen-presenting cells may present different protein fragments depending on individual HLA haplotypes, as demonstrated for infectious triggers of autoimmune encephalitides [70]. Nevertheless, in post-COVID atherothrombosis, we observed productive inflammation with lymphoid infiltrates surrounding the vasa vasorum in regions of unstable plaques. Such changes are characteristic of autoimmune vascular inflammation, as described in various vasculitides and in atherosclerotic aneurysms [71, 72]. Our findings of both T- and B-cell infiltration align with the concept that molecular mimicry may mislead both T-cell receptors and B-cell immunoglobulins. Involvement of the vasa vasorum (“vasa-vasoritis”) is typical of infection-triggered aortitis [73] and has long been considered a contributing factor in atherogenesis [74]. Cases of COVID-19-associated arteritis, aortitis, and systemic vasculitides have also been reported [75].

All shared pentapeptides identified in this study were predicted to induce IFN-γ, but not IL-10, and 45 shared pentapeptides across various coronaviruses were predicted to be potentially allergenic.

Innate immunity—particularly natural killer (NK) cell activation in response to reduced HLA class I expression on metabolically impaired or virus-infected cells—is a key early component of antiviral defense. Activated NK cells release perforin, granzyme B, and IFN-γ [76, 77]. IFN-γ upregulates transcription of numerous immune-related genes [78] and enhances antigen presentation by shifting proteasome activity toward immunoproteasomes [79]. Excessive immune stimulation is a hallmark of autoimmune pathology, including autoimmune aspects of atherogenesis. The predicted allergenicity of 45 shared pentapeptides is noteworthy, as IgE-mediated allergies represent hyperreactive immune states and have been linked to an increased risk of atherosclerotic cardiovascular disease [80] as well as to COVID-19 pathogenesis [81].

In the absence of control groups, the proposed causal link between coronavirus infection, molecular mimicry, and the observed pathology remains speculative. While our observations suggest an association, we cannot confirm causation. Therefore, our conclusions should be approached with caution, highlighting the need for further research with appropriate controls to validate these findings and elucidate the underlying mechanisms.

In conclusion, despite extensive research, no unified theory of atherogenesis currently exists. Infectious and autoimmune mechanisms remain central components of its etiopathogenesis. As Khan et al. [82] (2024) observed, “atherosclerosis triggers the breakdown of tolerance to self-components” [82]. Bioinformatic analysis represents an important step toward elucidating the potential molecular mimicry between exogenous pathogens and human proteins. Our findings of sequence similarity between human coronavirus proteins and autoantigens associated with atherogenesis and arteritides—supported by the corresponding pathomorphological and serological evidence—suggest that COVID-19 may represent a novel factor contributing to the immunopathological mechanisms underlying atherosclerotic cardiovascular disease.

The study provides hypothesis-generating evidence for a potential role of COVID-19 via molecular mimicry in atherosclerotic disease, which requires validation through controlled, functional studies.

It is essential to emphasize the importance of further morphometric research to gain a deeper understanding of the obtained results on lymphocytic infiltration around the vasa vasorum. We also recommend conducting serological studies with case controls to validate our findings, as well as utilizing in vitro analysis of T-cell and B-cell cross-reactivity with peptide-stimulated T-cell proliferation assays or immunization models. Additionally, it would be beneficial to consider conducting studies in animal models for a functional test of the mimicry hypothesis, which could provide further insights into the mechanisms underlying our observations.

In our view, further laboratory experiments verifying antigenic cross-talk and its functional consequences could be organized in the same way as previously used in our study of the molecular mimicry of coronavirus proteins with antigens involved in spermatogenesis [83]. Proteins could be synthesized from mimicking peptides, followed by testing for the presence of autoantibodies to them in patients and controls, and then the immunogenicity and pathogenicity studies can be performed by immunizing mice with selected peptides and testing the antigenicity of induced antibodies. The influence of such immunization on the course and severity of experimental atherosclerosis can also be checked.

The study limitations are:

One of the primary limitations of this study is the relatively small sample size. A limited number of participants may affect the generalizability of the findings and reduce the statistical power of the analyses. Future research should aim to include a larger and more diverse sample to enhance the robustness of the results and ensure that they are representative of the broader population.