Key result
Blocking complement receptors CR2/CR1 with mAb 4B2 prior to FMDV infection significantly reduced viral localization on follicular dendritic cells and decreased neutralizing antibody titers.
Why the study?
The mechanisms associated with the establishment of persistent foot-and-mouth disease virus infections and long-lived neutralising antibody responses were poorly understood.
Does blocking CR2/CR1 with mAb 4B2 reduce FMDV localisation on FDCs and neutralising antibody responses in mice?
Does blocking CR2/CR1 with mAb 4B2 reduce FMDV localisation on FDCs and neutralising antibody responses in mice?
In a mouse model, FMDV binding to follicular dendritic cells and the sustained induction of neutralising antibodies are dependent on complement receptors CR2/CR1.
Animal data implicate complement in FDC Ab responses to FMDV; leaves open human relevance or vaccine implications.
Previous studies have shown after the resolution of acute infection and viraemia, foot- and-mouth disease virus (FMDV) capsid proteins and/or genome are localised in the light zone of germinal centres of lymphoid tissue in cattle and African buffalo. The pattern of staining for FMDV proteins was consistent with the virus binding to follicular dendritic cells (FDCs). We have now demonstrated a similar pattern of FMDV protein staining in mouse spleens after acute infection and showed FMDV proteins are colocalised with FDCs. Blocking antigen binding to complement receptor type 2 and 1 (CR2/CR1) prior to infection with FMDV significantly reduced the detection of viral proteins on FDCs and FMDV genomic RNA in spleen samples. Blocking the receptors prior to infection also significantly reduced neutralising antibody titres. Therefore, the binding of FMDV to FDCs and sustained induction of neutralising antibody responses are dependent on FMDV binding to CR2/CR1 in mice. Author Summary Foot and mouth disease virus causes a highly contagious acute vesicular disease, resulting in more than 50% of cattle, regardless of vaccination status, and almost 100% of African buffalo becoming persistently infected for long periods (months) of time. Yet, the mechanisms associated with establishment of persistent infections are still poorly understood. Infected animals are characterised by the presence of long-lived neutralising antibody titres, which contrast with the short-lived response induced by vaccination. We have used a mouse model to understand how foot and mouth disease virus is trapped and retained in the spleen for up to 28 days post infection and how the absence of antigen in the germinal centre prevents a sustainable neutralising antibody response, in the mouse. Our results highlight the importance of targeting antigen to FDCs to stimulate potent neutralising antibody responses after vaccination.
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Gordon et al. (2021) studied Foot-and-mouth disease virus (FMDV) infection. mAb 4B2 (anti-CR2/CR1) vs. IgG1 isotype control was evaluated on Percentage of germinal centres with FMDV fluorescent staining at 7 days post infection (p=≤0.001). Blocking complement receptors CR2/CR1 with mAb 4B2 prior to FMDV infection significantly reduced viral localization on follicular dendritic cells and decreased neutralizing antibody titers.
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