Recruitment of plasma cells to the bone marrow in primary and secondary immune reactions (preprint)

Bone marrow plasma cells (BMPC) emerge as a consequence of immune reactions and are considered the source of antibodies that protect against recurrent infectious diseases throughout life. Despite their importance, it remains unclear if these cells reflect different activation environments or the differentiation/maturation stages of their precursors. Here we track the recruitment of plasma cells, generated in primary and secondary immune reactions to SARS-CoV-2 spike protein vaccines, to the human bone marrow. Trajectories based on single cell transcriptomes and antigen-receptor clonotypes of antibody-secreting cells exiting the immune reaction and of those residing in the bone marrow, allow to follow the evolution of the immune response to these vaccines, leading to sequential colonization of these cells to different compartments (clans) of BMPC, and their establishment as long-lived (memory) plasma cells. In primary immune reactions, both CD19low (clans 1 and 4) and CD19high (clan 0) BMPC are generated. In secondary immune reactions, mostly CD19high BMPC of the largest compartment (clan 0) are generated, resulting from the reactivation of memory B lymphocytes. The latter is also observed in vaccinated convalescent individuals and upon recall vaccination against diphtheria/tetanus/pertussis (DTP). Thus, humoral immunological memory, i.e. serum antibodies secreted by long-lived memory BMPC, is generated already in the primary immune response, more so in the secondary, and it represents the evolution of the immune response.

Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota (preprint)

The commensal microflora is a source for multiple antigens that may induce cross-reactive antibodies against host proteins and pathogens. However, whether commensal bacteria can induce cross-reactive antibodies against SARS-CoV-2 remains unknown. Here we report that several commensal bacteria contribute to the generation of cross-reactive IgA antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. We identified SARS-CoV-2 unexposed individuals with RBD-binding IgA antibodies at their mucosal surfaces. Conversely, neutralising monoclonal anti-RBD antibodies recognised distinct commensal bacterial species. Some of these bacteria, such as Streptococcus salivarius, induced a cross-reactive anti-RBD antibodies upon supplementation in mice. Conversely, severely ill COVID-19 patients showed reduction of Streptococcus and Veillonella in their oropharynx and feces and a reduction of anti-RBD IgA at mucosal surfaces. Altogether, distinct microbial species of the human microbiota can induce secretory IgA antibodies cross-reactive for the RBD of SARS-CoV-2.

UVA radiation could be a significant contributor to sunlight inactivation of SARS-CoV-2 (preprint)

Past experiments demonstrated SARS-CoV-2 inactivation by simulated sunlight; models have considered exclusively mechanisms involving UVB acting directly on RNA. However, UVA inactivation has been demonstrated for other enveloped RNA viruses, through indirect mechanisms involving the suspension medium. We propose a model combining UVB and UVA inactivation for SARS-CoV-2, which improves predictions by accounting for effects associated with the medium. UVA sensitivities deduced for SARS-CoV-2 are consistent with data for SARS-CoV-1 under UVA only. This analysis calls for experiments to separately assess effects of UVA and UVB in different media, and for including UVA in inactivation models. Key words: SARS-CoV-2, COVID-19, environmental persistence, sunlight, UVA, UVB, modeling, inactivation methods, photobiology

Analysis of SARS-CoV-2 genomes from across Africa reveals potentially clinically relevant mutations. (preprint)

SARS-CoV-2 is a betacoronavirus, the etiologic agent of the novel Coronavirus disease 2019 (COVID-19). In December 2019, an outbreak of COVID-19 began in Wuhan province of the Hubei district in China and rapidly spread across the globe. On March 11th, 2020, the World Health Organization officially designated COVID-19 as a pandemic. Across the continents and specifically in Africa, all index cases were travel related. Thus, it is crucial to compare COVID-19 genome sequences from the African continent with sequences from COVID-19 hotspots (including China, Brazil, Italy, United State of America and the United Kingdom). To identify if there are distinguishing mutations in the African SARS-CoV-2 genomes compared to genomes from other countries, including disease hotspots, we conducted in silico analyses and comparisons. Complete African SARS-CoV-2 genomes deposited in GISAID and NCBI databases as of June 2020 were downloaded and aligned with genomes from Wuhan, China and other SARS-CoV-2 hotspots. Using phylogenetic analysis and amino acid sequence alignments of the spike and replicase (NSP12) proteins, we searched for possible targets for vaccine coverage or potential therapeutic agents. Our results showed a similarity between the African SARS-CoV-2 genomes and genomes in countries including China, Brazil, France, the United Kingdom, Italy, France and the United States of America. This study shows for the first time, an in-depth analysis of the SARS-CoV-2 landscape across Africa and will potentially provide insights into specific mutations to relevant proteins in the SARS-CoV-2 genomes in African populations.

In severe COVID-19, SARS-CoV-2 induces a chronic, TGF-β-dominated adaptive immune response (preprint)

The human immune response to SARS-CoV-2 infection is highly variable, with less than 10% of infections resulting in severe COVID-19 requiring intensive care unit (ICU) treatment. Here we have analyzed the dynamics of the adaptive immune response in COVID-19 ICU patients at the level of single cell transcriptomes and B cell and T cell receptor (BCR, TCR) repertoires. Early after ICU admission, before seroconversion in response to SARS-CoV-2 spike protein, patients generate activated peripheral B cells with a type 1 interferon-induced gene expression signature. After seroconversion, patients display circulating activated B cells expressing an IL-21-induced gene expression signature and mainly IgG1 and IgA1, two isotypes induced by IL-21 and TGF-{beta}, respectively. In sustained COVID-19, the persistent immune reaction is shifted to IgA2-expressing activated peripheral B cells, displaying somatic hypermutation, and expressing TGF-{beta}-induced signature genes, like IgA germline transcripts. The switch from an IgG1 to an IgA2-dominated B cell response correlates with the appearance of SARS-CoV-2 reactive follicular T helper cells expressing IL-21 and/or TGF-{beta} in the blood. Despite the continued presence of IgA2-expressing B cells and IgA antibodies in the blood of progressed COVID-19 patients, IgA2 secreting cells were scarce in the lungs of deceased COVID-19 patients. In summary, in severely affected COVID-19 patients SARS-CoV-2 triggers chronic immune reactions which are controlled by TGF-{beta}, with most of the activated B cells being no longer specific for the SARS-CoV-2 spike protein and its receptor binding domain, nor for nucleoprotein. TGF-{beta} may candidate as a target to ameliorate detrimental immunopathology in those patients.