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The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite,Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

Intestinal helminth infection promotes a Type 2 inflammatory response in resistant C57BL/6 mice that is essential for worm clearance. The study of inbred mouse strains has revealed factors that are critical for parasite resistance and delineated the role of Type 1 versus Type 2 immune responses in worm clearance. In C57BL/6 mice, basophils are key innate immune cells that promote Type 2 inflammation and are programmed via the Notch signaling pathway during infection with the helminth Trichuris muris. However, how the host genetic background influences basophil responses and basophil expression of Notch receptors remains unclear. Here we use genetically susceptible inbred AKR/J mice that have a Type 1-skewed immune response during T. muris infection to investigate basophil responses in a susceptible host. Basophil population expansion occurred in AKR/J mice even in the absence of fulminant Type 2 inflammation during T. muris infection. However, basophils in AKR/J mice did not robustly upregulate expression of the Notch2 receptor in response to infection as in C57BL/6 mice. Blockade of the Type 1 cytokine IFN-γ in infected AKR/J mice was not sufficient to elicit infection-induced basophil expression of the Notch2 receptor. These data suggest that the host genetic background, outside of the Type 1 skew, is important in regulating basophil responses during T. muris infection in susceptible AKR/J mice.

Given the pace of SARS-CoV-2 transmission and its relatively high mortality rate, COVID-19, has the potential to become the most severe pandemic in recent times. This virus’s spread across international borders has triggered different responses in countries around the globe with a spectrum of mild, moderate to severe outcomes. Nigeria, Africa’s most populous country with many densely populated cities, presents a unique situation for the explosive spread of SARS-CoV-2. However, at the point of this writing, the number of reported confirmed infection and mortality is comparatively lower to other countries with dense urban populations. The exact reasons for this are not clear but include societal, political and infrastructural factors that will influence the course of the outbreak in Nigeria. In this perspective, we have described the ongoing COVID-19 outbreak and its associated peculiarities. We identify critical steps that remain to be taken to contain and control the outbreak in Nigeria.

Type 2 inflammation is characterized by production of the cytokines IL-4, IL-5 and IL-13 and is required for clearance of gastrointestinal helminth parasites, which infect over 2 billion people worldwide. Basophils are innate immune cells that promote expulsion of the helminth Trichuris muris in mice. However, the molecular mechanisms that control basophil function and gene expression during helminth-induced Type 2 inflammation remain unclear. We show that during T. muris infection, basophils localized to the intestine and upregulated components of the Notch signaling pathway, which regulates inflammatory gene expression programs. In vitro, Notch inhibition abrogated IL-33-elicited IL-4 and IL-6 production from basophils by directly targeting Il4 and Il6. Transcriptional profiling of Notch-deficient basophils revealed that Notch directs basophil responsiveness to inflammatory cues and effector gene expression. Mice lacking basophil-intrinsic Notch signaling had impaired worm clearance and decreased intestinal Type 2 effector mechanisms following infection. These findings demonstrate that Notch regulates basophil gene expression and effector function during helminth-induced Type 2 inflammation. We are now actively investigating how basophils interact with other cells in the intestine to orchestrate optimal Type 2 immune activation, and the role Notch plays in this process. These findings increase our understanding of the molecular signals that control innate immunity during Type 2 inflammation and may have far-reaching impact on the development of therapeutics aimed at modulating Type 2 immune responses.