COVID-19: Elevated levels of autoantibodies against the testicular tissue specific protein SPANXN4 offer significant evidence of male reproductive complications

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A new study lead by researchers from the Proteomics Core Facility at Weill Cornell Medicine-Qatar has identified that the human host proteins SPANXN4, STK25, ATF4, PRKD2, and CHMP3 are targeted by the autoantibodies generated as a result of a SARS-CoV-2 infection.

As a result of these proteins being targeted, a variety of health and medical conditions arises in all those infected with the virus, many of which contribute to Long COVID.

Alarmingly, the SPANXN4 is essential for spermiogenesis and male fertility, which may imply that male fertility is greatly at risk.

The study team also comprised of experts from Hamad Bin Khalifa University-Qatar, Hamad General Hospital-Qatar, University College London-UK, University of Greifswald-Germany, University of Cape Town-South Africa, Sengenics Corporation-Malaysia and Weill Cornell Medicine-New York-USA.
 
To date, the detailed role of autoantibodies in COVID-19 complications is not yet fully understood.

The study findings were published on a preprint server and are current being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.09.479669v1

Autoantibodies have been identified in significant proportion of COVID-19 hospitalized patients with positive correlation with immune responses to SARS-CoV-2 proteins 5.

Several studies observed significant rise in a diverse range of autoantibodies against immunomodulatory proteins, a- and w-interferons, cardiolipin and prothrombin during antiviral responses in severely ill COVID-19 patients 6, 7, 8, 9, 10, 11.

Particularly, autoantibodies against immune-related signaling proteins were found to contribute to COVID-19 pathogenesis by antagonizing the function of the innate immune system 12. Although there have been some reports on disease-modifying autoantibody responses, the immunological and clinical consequences of autoantibodies in COVID-19 are yet to be fully understood.

Here, we therefore screened total IgG autoantibody responses against 1,318 human proteins in COVID-19 patients using KREX immunome protein-array technology. Sengenics KREX technology employs full-length, naturally folded proteins that allow maximum epitopes binding to discover autoantibody biomarker proteins 13.

The quantitative signal measured on the arrays for each autoantibody-autoantigen pair is directly proportional to the autoantibody concentration in the blood with higher autoantibody titres to these proteins simplistically implying higher autoantigen concentrations in COVID-19 patients compared to controls, albeit the correlation is non-linear.

Autoantibody-based precision immuno-profiling has previously been shown to aid discovery of biomarkers of immune-related adverse events, as well as therapeutic prediction of drug response 14.

In the present study, by utilizing a broad array-based immunoproteomics strategy that simultaneously quantifies autoantibody responses across multiple organ systems in ICU COVID-19 patients and post recovery cohort, we aimed to better identify novel markers of comorbidities in COVID-19 patients.

We identified a number of novel markers in COVID-19 patients that are also associated with male fertility, such as the sperm protein SPANXN4 15, the androgenic kinase STK25 16, 17, the apoptotic factor ATF4 18, the calcium channel regulator protein kinase PRKD2 19, and the multivesicular protein CHMP3 20.

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