A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome. (preprint)

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

Neutralising antibody activity against SARS-CoV-2 variants, including Omicron, in an elderly cohort vaccinated with BNT162b2 (preprint)

SARS-CoV-2 variants threaten the effectiveness of tools we have developed to mitigate against serious COVID-19. This is especially true in clinically vulnerable sections of society including the elderly. Using sera from BNT162b2 (Pfizer–BioNTech) vaccinated individuals aged between 70 and 89 (vaccinated with two doses 3-weeks apart) we examined the neutralising antibody (nAb) response to wildtype SARS-CoV-2. Between 3 and 20-weeks post 2 nd dose, nAb titres dropped 4.9-fold to a median titre of 21.3 (ND80) with 21.6% of individuals having no detectable nAbs at the later time point. Experiments examining the neutralisation of twenty-one different SARS-CoV-2 variant spike proteins confirmed a significant potential for antigenic escape, especially for the Omicron (BA.1), Beta (B.1.351), Delta (B.1.617.2), Theta (P.3), C.1.2 and B.1.638 variants. Interestingly, however, the recently-emerged sub-lineage AY.4.2 was more efficiently neutralised than parental Delta pseudotypes. Combining pseudotype neutralisation with specific receptor binding domain (RBD) ELISAs we confirmed that changes to position 484 in the spike RBD were predominantly responsible for SARS-CoV-2 nAb escape, although the effect of spike mutations is both combinatorial and additive. Lastly, using sera from the same individuals boosted with a 3 rd dose of BNT162b2 we showed that high overall levels of neutralising antibody titre can provide significant levels of cross-protection against Omicron. These data provide evidence that SARS-CoV-2 neutralising antibodies wane over time and that antigenically variable SARS-CoV-2 variants are circulating, highlighting the importance of ongoing surveillance and booster programmes. Furthermore, they provide important data to inform risk assessment of new SARS-CoV-2 variants, such as Omicron, as they emerge.

Potential of breadfruit cultivation to contribute to climate-resilient low latitude food systems (preprint)

The number of people in food crisis around the world is increasing, exacerbated by the challenges of COVID-19 and a rapidly changing climate. Major crop yields are projected to decrease in low-latitude regions due to anthropogenic climate change, making tropical and sub-tropical food systems particularly vulnerable to climate shocks. Increased cultivation of breadfruit ( Artocarpus altilis ), often categorized as a neglected and underutilized species (NUS), has been suggested as an agricultural adaptation pathway for food insecure tropical and subtropical regions, due to its potential to enhance climate resilience and overall sustainability of low-latitude agricultural systems. To better understand breadfruit’s cultivation suitability and geographic range in current and future climates, we employ a diverse set of observations and models to delineate the current climatically viable breadfruit range and assess the climatically viable breadfruit range in the future (2061-2080) under stabilization and high emission scenarios. We find that the area of suitable breadfruit range within the tropics and subtropics is projected to decrease ~4.4% in the stabilization scenario and ~4.5% in the high emission scenario. In Southeast Asia and the Pacific Islands, yield quality and consistency show minimal decreases under the high emission scenario, with increases in total suitable area under both scenarios. In contrast, in Latin America and the Caribbean, the current range of breadfruit suitability is projected to contract ~10.1-11.5% (stabilization-high emission). Present and future model suitability outputs suggest that opportunities to successfully expand breadfruit cultivation over the next several decades exist in sub-Saharan Africa, where food insecurity is coincidentally high. However, in all regions, high emission scenario conditions reduce the overall consistency and quality of breadfruit yields compared to the stabilization scenario. Our results have the potential to inform global food security adaptation planning and highlight breadfruit as an ideal NUS to incorporate in food security adaptation strategies in a changing climate.