Development and significance of the plasma cell niche in the human infant thymus

SUMMARYWhile children can contract SARS-cov-2, they usually develop a milder form of the disease than adults. Acommon explanation is that their immune system is more robust than that of adults. Based on our previousresearch on B cell immunity in human neonates, we hypothesize that innate humoral immunity present at birth,and dwindling with age, confer a first line of defense against SARS-CoV-2, attenuating the severity of thedisease. Our studies will test for the presence of natural IgM, IgG and IgA reactive to major components of thevirus (spike, nucleocapsid...) in neonates and adults. Moreover, we have already generated >300 recombinantmonoclonal antibodies (mabs) from plasma cells isolated from neonatal thymus specimens. We will test theantiviral activity of these mabs. If successful, our studies will uncover a critical immune component responsiblefor children's apparent resistance to SARS-cov-2. We will also identify specific mabs with therapeutic potential.Aim 1. To assess natural serological immunity to SARS-CoV-2Studies in aim 1 will test for the presence of IgM, IgG and IgA reactive to SARS-cov-2 proteins in the serum ofneonates and healthy adults as controls. Experimentally, we will use plasma and serum samples collected beforethe start of the COVID-19 pandemic. Our repository already includes 48 cord blood specimens and 35 healthyadult blood specimens as controls. As a source of antigens, we will first use commercially available recombinantviral proteins. We will also test the reactivity of cord blood antibodies to viral proteins expressed in primary humanairway epithelial cells.Aim 2. To identify recombinant monoclonal antibodies with therapeutic potentialAs part of our ongoing study on the development of humoral immunity in human neonates (U01-AI-131339), wehave generated 362 recombinant monoclonal antibodies (mabs) from plasma cells isolated from 5 neonatalthymus specimens. These mabs are a representative sample of the natural antibody repertoire of neonates.Experiments in aim 2 will assess the reactivity of these mabs to SARS-CoV-2 antigens. All reactive mabs will befurther characterized for their reactivity profile, sequence and capacity to neutralize SARS-CoV-2 infectivity.