The protective effect of SARS-CoV-2 antibodies in Scottish healthcare workers.

BACKGROUND: Healthcare workers (HCWs) are believed to be at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection. METHODS: A prospective observational study of HCWs in Scotland (UK) from May to September 2020 was performed. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general local population, were studied for comparison. New infections (up to 2 December 2020) post antibody testing were recorded to determine whether the presence of SARS-CoV-2 antibodies protects against re-infection. RESULTS: A total of 2063 health and social care workers were recruited for this study. At enrolment, 300 HCWs had a positive antibody test (14.5%). 11 out of 231 control sera tested positive (4.8%). HCWs therefore had an increased likelihood of a positive test (OR 3.4, 95% CI 1.85-6.16; p<0.0001). Dentists were most likely to test positive. 97.3% of patients who had previously tested positive for SARS-CoV-2 by reverse transcriptase (RT)-PCR had positive antibodies. 18.7% had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCWs who were previously antibody negative, and one symptomatic RT-PCR-positive re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (hazard ratio 0.15, 95% CI 0.06-0.35; p=0.026). CONCLUSION: HCWs were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all infected individuals developed an antibody response, which was 85% effective in protecting against re-infection with SARS-CoV-2.

Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.

The anthelmintic drug praziquantel promotes human Tr1 differentiation.

Praziquantel (PZQ) is an anthelminthic human and veterinary drug used to treat trematode and cestode worms. Changes in immune responses have been demonstrated in humans following curative PZQ treatment of schistosome infections. These changes have been attributed to the removal of immunosupressive worms and immune responses to parasite antigens exposed from dying worms. To date, there has been no study investigating the potential direct effect of PZQ on the host immune cells. Herein, we analyzed the effect of PZQ on human CD4+ T cells classically costimulated by CD3/CD28 or costimulated by the complement regulator CD46 to induce Type 1 regulatory T cells (Tr1). Our results show that PZQ enhanced T-cell proliferation, increased secretion of IL-17 and IL-10 but had no effect on secretion of GM-CSF or IFNγ. Moreover, PZQ increased the coexpression of CD49b and LAG-3, a hallmark of Tr1 cells, suggesting increased Tr1 differentiation. Indeed, supernatants from PZQ-treated cells were able to decrease bystander T-cell activation, and this was partly reduced when blocking IL-10. Hence, our study demonstrates that PZQ directly modulates human T-cell activation and promotes Tr1 differentiation, suggesting that PZQ may have immunomodulatory functions in parasite-unrelated human inflammatory diseases.

Complement as a regulator of adaptive immunity.

The complement system is an ancient and evolutionarily conserved effector system comprising in mammals over 50 circulating and membrane bound proteins. Complement has long been described as belonging to the innate immune system; however, a number of recent studies have demonstrated its key role in the modulation of the adaptive immune response. This review does not set out to be an exhaustive list of the numerous interactions of the many complement components with adaptive immunity; rather, we will focus more precisely on the role of some complement molecules in the regulation of antigen presenting cells, as well as on their direct effect on the activation of the core adaptive immune cells, B and T lymphocytes. Recent reports on the local production and activation of complement proteins also suggest a major role in the control of effector responses. The crucial role of complement in adaptive immunity is further highlighted by several examples of dysregulation of these pathways in human diseases.