Holmgren, J. | bioRxiv Science

bioRxiv2022

S100A4 exerts robust mucosal adjuvant activity for co-administered antigens in mice

The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than six months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel technique for measuring germinal center activity. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2.

immunology↗

bioRxiv2020

Serotype has a significant impact on the virulence of 7th pandemic Vibrio cholerae O1

Of over 200 different identified Vibrio cholerae serogroups only the O1 serogroup is consistently associated with endemic and epidemic cholera disease. The O1 serogroup has two serologically distinguishable variants, the Ogawa and Inaba serotypes, which differ only by a methyl group present on the terminal sugar of the Ogawa O-antigen but absent from Inaba strains. This methylation is catalyzed by a methyltransferase encoded by the wbeT gene, which in Inaba strains is disrupted by mutation. It is currently thought that there is little difference between the two serotypes. However, here we show, using isogenic pairs of O1 El Tor V. cholerae, that Inaba strains show significantly different patterns of gene expression and are significantly less able than the corresponding Ogawa strains to cause cholera in an infant mouse infection model. Our results suggest that changes in gene expression resulting from the loss of the wbeT gene lead to reduced virulence and possibly also reduced survival fitness outside the human host. Author SummaryThe bacterium Vibrio cholerae causes the pandemic diarrheal disease cholera. Despite many identified serotypes of V. cholerae only one, O1, causes pandemic cholera. The O1 serotype of pandemic V. cholerae has two distinguishable variants (called Ogawa and Inaba) long considered to be clinically and epidemiologically equivalent. Cholera outbreaks consist only of one the two variants at any time. In general, Ogawa strains cause the majority of outbreaks with relatively short-lived Inaba outbreaks occurring sporadically. We have suggested earlier that Inaba outbreaks occur during periods of environmental selective pressure against the Ogawa serotype. We demonstrate here that the two variants are not clinically equivalent. The Ogawa serotype is better able to respond to infection in an animal model by up regulating the expression of virulence genes essential for disease development. We suggest that this phenomenon is the result of wider ranging differences in gene expression resulting from the mutation that converts Ogawa into Inaba strains, and may help to explain the dominance of the Ogawa serotype in nature.

microbiology↗