Cross-Reactivity of SARS-CoV-2 Antibodies With Typhoid Flagellar-H Protein.
Aneela Pasha, Mohammad Saeed
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Figure 2A of the article (Copyright with TMIH Journal) and depicts the molecular overlap between Salmonella typhi Flagellar-H antigen and SARS-CoV-2 RBM antigen. This overlap was eliminated due to the Delta mutation (Figure 2B). This, we hypothesize underlies the antibody cross-reactivity between the two organisms.
COVID-19 affected different regions of the world with varying intensity leading to high mortality in some regions and low in others. This proof-of-concept study presents evidence that one potential infection that may have provided natural herd immunity against COVID-19, due to adaptive heterologous immunity, is Typhoid fever.
During the COVID-19 pandemic several patients presented to ImmunoCure from interior Sindh with COVID-19 symptoms and a positive Typhidot test. They had been treated with antibiotics for Typhoid fever. However, their symptoms and clinical exam was suggestive of mild to moderate COVID-19. After informed consents patients were tested for both SARS-COV-2 antibodies and Typhidot (without charge). We found high correlation between the two tests (~72%).
Dr. Mohammad Saeed suspected antibody cross-reactivity, which occurs when antibody against one antigen (usually a protein) reacts against a different antigen / protein. Usual matching analysis (using the BLAST software) did not show any overlap. However, with specialized analysis involving cutting the protein sequences into small pieces and matching them (k-mer analysis) showed that a 5-amino acid sequence overlapped between SARS-CoV-2 (that causes COVID-19) and Salmonella typhi (that causes Typhoid fever).
This 5-amino acid sequence, NGVEG, was found in the Flagellar-H protein of Salmonella typhi and very interestingly in the critical region of SARS-CoV-2 called the Spike protein. The Spike protein is responsible for the entry of the SARS-CoV-2 virus in the cells and vaccines are also made against it to protect from COVID-19. Moreover, NGVEG was found in the special region of the Spike protein called the Receptor Binding Motif (RBM) which is the critical most region of SARS-CoV-2. The Delta variant of SARS-CoV-2 emerged in India after a super-spreader event and the mortality rate in South Asia and around the world from COVID-19 skyrocketed. This Delta variant contained a mutation E484Q. This mutation targeted the very sequence that overlapped between Salmonella typhi and SARS-CoV-2 i.e. NGVEG, turning it into NGVQG. This single amino acid change, completely altered the 3-dimensional structure of the SARS-CoV-2 RBM as shown in the Figure 2 of the article (above).
We next looked at whether COVID-19 mortality was impacted by Typhoid prevalence. Epidemiological data showed that Typhoid endemic regions, such as Pakistan, Bangladesh and others, had lower COVID-19 mortality than Typhoid non-endemic regions such as Europe and United States.
After the COVID-19 pandemic, the Government of Pakistan permanently banned the use of the Typhidot test due to widespread concerns over false-positive results. This policy action, while driven by diagnostic concerns indirectly supports the idea that cross-reactivity between SARS-CoV-2 and Salmonella typhi was of real-world relevance. Our study brings to light this possibility and attempts to highlight the science-policy interface and the public health implications of diagnostic cross-reactivity in endemic settings.