BREAKING! Study Identifies Human Proteins Targeted By COVID-19 Induced Autoantibodies And Also Alarmingly Discovers Male Fertility Is Greatly At Risk!
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 team screened two independent cohorts of 97 COVID-19 patients (Discovery (Disc) cohort from Qatar (n = 49) and Replication (Rep) cohort from New York (n = 48)) utilizing high-throughput KoRectly Expressed (KREX) immunome protein-array technology.
Autoantibodies, immune system proteins that mistakenly target the body’s own tissue, may be responsible for so many of the conditions in both a COVID-19 infection and also in long COVID. The study team screened total IgG autoantibody responses against 1,318 human proteins in the two COVID-19 patient cohorts.
Interestingly, autoantibody responses to 57 proteins were significantly altered in the COVID-19 Disc cohort compared to healthy controls (P ≤ 0.05). The Rep cohort had altered autoantibody responses against 26 proteins compared to non-COVID-19 ICU patients that served as controls.
However, both cohorts showed substantial similarities (r2 = 0.73) and exhibited higher autoantibodies responses to numerous transcription factors, immunomodulatory proteins, and human disease markers.
Detailed analysis of the combined cohorts revealed elevated autoantibody responses against SPANXN4, STK25, ATF4, PRKD2, and CHMP3 proteins in COVID-19 patients.
KREX analysis of the specific IgG autoantibody responses indicates that the targeted host proteins are supposedly increased in COVID-19 patients. The autoantigen-autoantibody response was cross-validated for SPANXN4 and STK25 proteins using Uniprot BLASTP and sequence alignment tools.
The study findings also showed that several proteins in COVID-19 patients that are associated with male fertility, such as sperm protein SPANXN4, STK25, and the apoptotic factor ATF4 were targeted. Particularly, elevated levels of autoantibodies against the testicular tissue-specific protein SPANXN4 offer significant evidence of anticipating the protein role in COVID-19 associated male reproductive complications.
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
The COVID-19 disease, caused by the SARS-CoV-2 virus, has emerged as a global pandemic w
ith a high morbidity rate and multiorgan complications. It is observed that the host immune system contributes to the varied responses to COVID-19 pathogenesis. Symptoms, from short-term flu-like effects with relatively little danger, to organ failure and severe lung damage, to long-term fatigue.
To date, some scientists have also suggested that there might be some risk to fertility, with angiotensin-converting enzyme 2 (ACE2) highly expressed in male reproductive cells.
The study team has been investigating auto-immune responses to natural human antigens in COVID-19 patients.
The study team identified the total IgG response of two sets of COVID-19 patients from different ethnic groups and their responses against 1,318 naturally folded human antigens.
One cohort was recruited at an ICU in Doha, Qatar, while the second was recruited from the ICU of a hospital in the United States (US).
The study team managed to gather a total of 97 cases (49 in Doha, 48 in the US), and 76 controls. The team began by using KREX high throughput autoantibody assay technology to discover IgG autoantibodies that could affect the outcome of COVID-19 infections.
The study team initially found 1,600 proteins, but reduced this to 1,318 in the replication cohort for increased stringency. The antibodies found varied in location, with most in the cytoplasm, nucleus or cell membrane. The KREX assay reported RFU values that correlate directly with antibody titers, with higher RFU values indicating higher titers or repeated exposure.
The general intensity distribution was initially calculated on the mean antibody-antigen titers across all samples. KEGG-Brite-based Voronai treemaps could be used to further examine the titers, and around 1,150 proteins were assigned to the annotation.
Interestingly, almost all showed strong IgG signals, with the highest autoantibodies found against mostly structure-related proteins, including RBPJ, TPM1, TACC1, KRT19, PTPN20, TBCB, KRT15, AFF4, HSPD1, and CBFA2T3. The lowest titers tended to be against cytoplasmic proteins involved in phosphorylation.
The study team performed a differential expression analysis between cases and controls using a T-test for the Doha cohort.
The team found that 57 proteins had significantly altered autoantibody responses, forty of which showed increased responses, and 17 decreased. They found the most elevated responses against ATF4 and the sperm protein associated with the X chromosome N4 nucleus.
Subsequently, a binarized autoimmune response analysis, assuming that all samples with a response exceeding standard deviation by one as positive and all others as negative, alongside a Fisher's exact test, showed 25 patients had higher RFU values for SPANXN4, compared to only five in the controls.
The findings also showed significantly higher autoantibodies against ATF4, recombining signal binding protein J (RBPJ) and programmed cell death 5 (PCD5), but only SPANXN4 showed the required significance.
While examining samples collected from patients six weeks after recovery, the study team also observed strong correlations between autoantibody responses for certain proteins that remained highly elevated in recovery, including SPANXN4, STK25, TRAF3IP1, AMOTL2, PSMD4, and PPP1R2P9.
A consequent repeat of these comparisons in the US patients showed much of the same results.
The stud team next performed principal components analysis (PCA) of RFU data from the two cohorts, which revealed a strong overlap between the two cohorts, which did not separate into discrete clusters. Pearson correlation analysis revealed a high correlation between the autoantibody responses of the two cohorts.
When the two cohorts were combined and compared to the controls, the study team discovered that 56 proteins showed a significantly altered response, with 35 increased antibody responses and 21 decreased.
Importantly the proteins that showed the highest effect size were SPANXN4, ATF4, STK25, and PRKD2. Sequence homology and antigen specificity analysis were used to check for cross-reactivities.
Although a few proteins did show significant sequence homology, many of these were included in the initial KREX analysis and showed no significant changes.
The study findings revealed several autoantibody responses that are significantly elevated during COVID-19 infection, with some, such as SPANXN4, remaining elevated for extended periods post-infection.
The study findings also suggest that this could have some association with the long-term chronic health issues some COVID-19 patients suffer, known as 'long-COVID
The findings also identified many of the physiological functions of the proteins, with structural proteins and reproductive proteins both present.
As well as this, they show there is little to no difference in the elevated proteins between the Doha and US cohorts.
The study findings highlight the importance of immune responses and could be used to help clarify the functions behind long-COVID
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