It is well known that coronavirus (re)infections have a pathologic immune potential. Indeed:
Progressive immune-associated injury is a hallmark of SARS infection [1
] and, since 2003 [2
], the association with hyper-immune inflammation and systemic immunopathology in the SARS-CoV-infected host has been well illustrated [2
In 2008, it was reported [6
] that prior immunization with SARS-CoV nucleocapsid protein N causes severe pneumonia in mice infected with SARS-CoV;
In 2012, immunization with SARS coronavirus vaccines was found to lead to lung immunopathology on challenge with the SARS virus [7
In 2016, Agrawal et al. [8
] demonstrated that immunization with inactivated Middle East Respiratory Syndrome (MERS) coronavirus vaccine leads to lung immunopathology on challenge with live virus. Moreover, the Authors documented that immunopathology with SARS-CoV vaccines occurred for whole-virus vaccines, subunit vaccines, different inactivation methods, different preparation substrates, and with recombinant surface spike protein. Finally, the Authors also underscored that, even if studies with vector vaccines point to the nucleoprotein N as responsible for the immunopathological effects and indicate that the S protein might be free of risk, nonetheless, also recombinant spike protein induced the immunopathology [6
However, the molecular and cellular basis for how SARS-CoVs might impact on the host immune system resulting in dysfunctional immune responses, severe morbidity, and mortality remain obscure [1
Following the current SARS-CoV-2 pandemic, cross-reactivity was proposed as a mechanism that might explain the immunopathology associated with the coronavirus infection [11
]. The rationale is that the sharing of peptide motifs between SARS-CoV-2 and human proteins might evoke immune responses capable of hitting not only the virus but also the human proteins with consequent autoimmune pathologic sequelae in the human host. As a matter of fact, the study [11
] called attention to a vast and specific peptide sharing between SARS-CoV-2 spike glycoprotein and alveolar surfactant-related proteins, in this way addressing the issue of why SARS-CoV-2 so heavily attacks the respiratory system.
In the wake of such results, in order to validate (or, as well, invalidate) the cross-reactivity hypothesis, investigation was expanded here by analyzing the peptide sharing between the human host and immunoreactive epitopes that are also present in SARS-CoV-2. Actually, the mere sharing of peptide sequences between pathogens and human proteins might be of little significance whether it remained sterile of cross-reactive autoimmune reactions. On the contrary, a peptide sharing between immunoreactive pathogen-derived epitopes and human proteins would assume the value of a proof of concept of cross-reactivity as a mechanism contributing to the pathogen-induced diseases.
In this scientific framework, using the hexapeptide as an antigenic and immunogenic unit [12
], immunoreactive epitopes that are present in SARS-CoV-2 were analyzed for matches with the human proteome. The results confirm a vast peptide commonality that involves human proteins implied in pulmonary insufficiency, neurological disorders, cardiac and vascular alterations, pregnancy dysfunctions, multiple cancers and anosmia, among others.
This study shows that hexapeptides from immunoreactive epitopes present in SARS-CoV-2 are widespread among a high number of human proteins. Such a peptide sharing implies the possibility of cross-reactions and, consequently, as discussed in the Results (Section 3
), of a vast phenotypic constellation of diseases, from pneumonia and neurological disorders to cardio-vascular alterations and coagulopathies. Hence, this study appears to offer scientific hints to explain the clinical fact that SARS-CoV-2 infection is capable of triggering so many and so different pathologies in so many and so different organs of the human host [78
On the whole, the data indicate that—besides possible virus-induced multi-organ direct cytopathic effects and other possible pathogenic mechanisms—self-reactive antibodies may be at the root of the pathologic scenario that accompanies SARS-CoV-2 infection. In fact, previous research focusing on SARS-CoV, which similarly to SARS-CoV-2 causes a respiratory failure syndrome, showed that anti-spike protein IgGs can cause lung damage by directly affecting inflammatory mechanisms, promoting the release of pro-inflammatory cytokines, such as IL-8, as well as macrophagic tissue infiltration [79
]. A similar effect of SARS-CoV-2 on inflammatory response has already been proposed [80
]. Then it appears reasonable to hypothesize that autoantibody-mediated macrophagic and complement activation and autoantibody-dependent cell-mediated cytotoxicity mechanisms might be some of the mechanisms behind the well-documented multi-organ damage in COVID-19, thus representing one of many possible links between adaptive and innate immunity in the pathogenesis of the disease.
Moreover, as reviewed by Vabret et al. [81
], it has been shown that high antibody response can associate with more severe clinical cases. This had also been seen in the previous SARS-CoV-1 epidemic, where neutralizing antibody titers were found to be significantly higher in deceased patients compared to patients who had recovered [82
] and might lead to suspect antibody-dependent enhancement phenomena.
Of note, the present data also indicate that most possibly the damage caused by SARS-CoV-2 might not end with the end of the pandemic. Indeed, the peptide sharing between SARS-CoV-2 epitopes and specific tumor suppressor proteins, and, in general, many tumor-related proteins [26
], theoretically predicts, in the absence of current clinical data, that a morbidity/mortality increase in various cancers might follow the current SARS-CoV-2 pandemic.
As a conclusive note, it is mandatory also to observe that this study largely undervalues the potential risk of cross-reactivity between SARS-CoV-2 immunome and human proteins. Indeed, analyses were conducted on linear epitopes and used the hexapeptide as an immune unit probe. Then, if one considered conformational epitopes and used the pentapeptide as a minimal immune determinant [13
], the number of viral versus human commonalities would increase exponentially. Given this premise, the present results call researchers and clinicians for a common research effort to study the autoimmune pathogenicity connected to the anti-SARS-CoV-2 immune response and suggests, once more, that using entire antigens in anti-SARS-CoV-2 vaccine formulations might lead to autoimmune manifestations and adverse events [84
]. Actually, the present data further support the fundamental concept that only “non-self” peptides can lead to safe and efficacious immunotherapies [85