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By combining bioinformatic analyses, serological studies, and experiments in mice, scientists show that antibodies mimicking those induced by the infection can recognize an essential testicular protein and impair male and female fertility in a murine model, raising questions about the long-term immunological consequences of COVID-19.
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Molecular mimicry and immune dysregulation induced by SARS-CoV-2
Molecular mimicry is a well-documented phenomenon in immunology. It is based on structural similarities between certain proteins of infectious agents and proteins of the organism. These similarities can induce cross-reactive immune responses: antibodies produced to neutralize the pathogen also mistakenly recognize self-proteins, which can disrupt immune system function and promote inflammatory reactions and the onset of autoimmune diseases.
In the context of the COVID-19 pandemic, several studies have highlighted persistent immune dysregulations following SARS-CoV-2 infection (long COVID). To systematically explore this phenomenon, scientists undertook a large-scale bioinformatic analysis aimed at identifying potential sequence similarities between SARS-CoV-2 proteins and human proteins.
Induced antibodies that can disrupt spermatogenesis
These in silico researches published in the journal Journal of Autoimmunity revealed that certain regions of the SARS-CoV-2 virus's Spike protein had sequences identical to those of human proteins expressed in very specific tissues. Unexpectedly, several of these proteins are involved in spermatogenesis, the biological process allowing the production of spermatozoa. These similarities led them to hypothesize that some antibodies produced during the infection could, through molecular mimicry, recognize proteins expressed in reproductive tissues.
Based on these analyses, several peptides were selected and tested with sera from patients with acute or long COVID, as well as from uninfected vaccinated individuals. The results show that certain peptides are specifically recognized by antibodies present in infected patients, whereas they are absent in vaccinated subjects. One of these peptides contains a sequence common with TSSK1, a protein expressed specifically in the testes and essential for spermatogenesis.
To assess the potential biological consequences of this cross-reactivity, an in vivo study was conducted on mice. Adult male mice in perfect health received purified antibodies directed against this peptide. These males were then mated with healthy and fertile females. This experimental model allows for the specific study of the effects of antibodies present in the male on fertility and the course of gestation, without directly exposing the females to the antibodies. The results show that the frequency of normal pregnancies decreases significantly when males have received these antibodies. In many cases, infertility or a delay in delivery is observed.
These data provide original experimental evidence showing that antibodies induced by molecular mimicry can have deleterious effects on reproduction, at least in a murine model. They suggest that, in humans, an immune response triggered by SARS-CoV-2 infection could, in some cases, interfere with essential reproductive functions. This study thus opens new research perspectives on the long-term immunological consequences of COVID-19 and underscores the importance of assessing the delayed effects of viral infections on fertility.
Effect of interaction between the SARS-CoV-2 Spike protein and proteins associated with spermatogenesis. The peptides are specifically recognized by antibodies from patients infected with COVID-19 and induce an impairment of fertility in a murine model.
© Laura Talamini