Cross-Reactivity of SARS-CoV-2 Antibodies With Typhoid Flagellar-H Protein

Antigen cross-reactivity in infections may induce heterologous immunity, leading to immunological protection against widely divergent organisms. We hypothesised that this may be a factor in the varying intensity of COVID-19 infection globally.

During the COVID-19 pandemic, we tested 46 symptomatic patients for both COVID-19 antibodies and the Typhidot test. The kappa statistic in STATA 16.0 was used to analyse agreement between the two tests. Python-based k-mer analysis was used to identify overlapping fragments between SARS-CoV-2 and Salmonella typhi proteins. PEP-Fold3, TM-align and RasMol software were used to evaluate the 3D-structural changes. World COVID-19 and Typhoid mortality and infection statistics were obtained from published data. Line graphs were used to assess correlations between Typhoid cases and COVID-19 mortality.

There was a high degree of agreement between Typhidot and COVID-19 antibody tests (Cohen's kappa = 0.43, p = 0.0016). A 5-amino-acid peptide, NGVEG, located in the receptor binding motif (RBM) of the SARS-CoV-2 Spike protein matched with the Typhoid flagellar-H protein on k-mer analysis. SARS-CoV-2 Delta (B.1.617.2) variant 3D structure displayed marked changes that may have altered this cross-reactivity. COVID-19 mortality between Pre-Delta (2020) and Post-Delta (2021) periods showed a negative correlation in Typhoid endemic regions and a reverse trend in non-endemic regions.

Cross-reactivity of Typhoid flagellar-H protein antibodies with SARS-CoV-2, mediated by a peptide in the RBM, may have provided partial heterologous immunity to COVID-19 in Typhoid endemic regions and this was eliminated by the Delta variant.