Pierson, Mark

Abstract The objective of this study was to test the hypothesis that the increasing global incidence of allergy and atopy are due in part to improved hygiene and decreased microbial exposure. We have adopted a novel mouse model of normalized microbial exposure to test the impact of immune experience on subsequent responses to airway allergens. In this model, specific pathogen free (SPF) B6 mice are cohoused with mice from pet stores and become “dirty” – many commensals and pathogens are transmitted through cohousing and influence the immune cell populations systemically and in the lungs. We treated mice intranasally with a single dose of A. alternata fungal extract (Alt) and assessed production of type 2 cytokines. IL5 and IL13 levels in the lungs and bronchoalveolar lavage fluid were dramatically elevated by Alt in SPF mice but were not significantly increased by Alt in dirty mice. Type 2 innate lymphoid cells (ILC2) are the cells responsible for IL5 and IL13 after acute Alt treatment, and interestingly the number of lung ILC2 was unaltered by cohousing and their activation status appeared similar in both housing conditions. We treated mice with recombinant IL33, the alarmin released by lung epithelial cells in response to allergens, and the results suggest an impaired response to IL33 by dirty lung ILC2. In a repeated Alt exposure model, ILC2 cells expanded in SPF lungs and recruited eosinophils, neutrophils, and T cells. Most dirty mouse lungs contained these cell populations at steady state but were only modestly recruited with repeated Alt exposure. Lung function experiments are in progress. This study suggests that increased microbial exposure leads to more type-2 associated immune cells in the lungs, however responses to airway allergens are dampened.

Abstract The impact of microbes on restraining the immune response to allergens has been extensively studied and is a key element of the hygiene hypothesis. Lung type 2 innate lymphoid cell responses to airway allergens can be inhibited by administration of a number of microbial products; however, it is unclear whether such an effect would be observed with natural infections and how sustained any observed inhibitory effects would be. To answer these questions, we used a murine model of physiological microbial exposures through cohousing SPF laboratory mice with pet store mice and examined the acute type 2 response to intranasally delivered fungal allergen extract Alternaria alternata. We found laboratory mice cohoused with pet store mice for two weeks display a suppressed ILC2 response to A. alternata which resulted in reduced eosinophilia. By comparison, mice cohoused for at least two months had ILC2 and eosinophil responses similar to SPF mice despite dramatic changes to the composition of the immune cell populations in the lungs. Lung ILC2 in two-month cohoused mice were still sensitive to subsequent inflammatory cues, as administration of poly(I:C) was able to suppress ILC2 activation and eosinophilia equally well in SPF and two-month cohoused animals. These findings suggest ILC2 dynamically respond to their environment and are not easily desensitized long-term.

Senescent cells exacerbate COVID-19 Cellular senescence is a state elicited in response to stress signals and is associated with a damaging secretory phenotype. The number of senescent cells increases with advanced age and this in turn drives age-related diseases. Camell et al. show that senescent cells have an amplified inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see the Perspective by Cox and Lord). This response is communicated to nonsenescent cells, suppressing viral defense mechanisms and increasing the expression of viral entry proteins. In old mice infected with a SARS-CoV-2–related virus, treatment with senolytics to reduce the senolytic cell burden reduced mortality and increased antiviral antibodies. Science , abe4832, this issue p. eabe4832 ; see also abi4474, p. 281