Influenza A virus directly modulates mouse eosinophil responses

Abstract

Allergic asthma and influenza are common respiratory diseases with a high probability of co‐occurrence. During the 2009 influenza pandemic, hospitalized patients with influenza experienced lower morbidity if asthma was an underlying condition. We have previously demonstrated that acute allergic asthma protects mice from severe influenza and have implicated eosinophils in the airways of mice with allergic asthma as participants in the antiviral response. However, very little is known about how eosinophils respond to direct exposure to influenza A virus (IAV) or the microenvironment in which the viral burden is high. We hypothesized that eosinophils would dynamically respond to the presence of IAV through phenotypic, transcriptomic, and physiologic changes. Using our mouse model of acute fungal asthma and influenza, we showed that eosinophils in lymphoid tissues were responsive to IAV infection in the lungs and altered surface expression of various markers necessary for cell activation in a niche‐specific manner. Siglec‐F expression was altered in a subset of eosinophils after virus exposure, and those expressing high Siglec‐F were more active (IL‐5RαhiCD62Llo). While eosinophils exposed to IAV decreased their overall transcriptional activity and mitochondrial oxygen consumption, transcription of genes encoding viral recognition proteins, Ddx58 (RIG‐I), Tlr3, and Ifih1 (MDA5), were up‐regulated. CD8+ T cells from IAV‐infected mice expanded in response to IAV PB1 peptide‐pulsed eosinophils, and CpG methylation in the Tbx21 promoter was reduced in these T cells. These data offer insight into how eosinophils respond to IAV and help elucidate alternative mechanisms by which they regulate antiviral immune responses during IAV infection.

Insights Into Type I and III Interferons in Asthma and Exacerbations

“…It was observed that increased viral control correlated with higher numbers of eosinophils arriving earlier to the lung during influenza (96). More recent findings show that influenza exposure causes murine eosinophils to up-regulate the expression of genes encoding viral sensors (105), and that these eosinophils can become infected by influenza virus and degranulate in response to influenza (106). Strikingly, adoptive transfer of eosinophils into the airways of A. fumigatus-sensitized mice reduced influenza viral burden and weight loss in response to influenza infection, suggesting these cells are actively beneficial during influenza infection in mice with AAD.…”

Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies

“…Likewise, intestinal eosinophils are phenotypically distinguishable from autologous blood eosinophils and express antigen presentation markers not seen on blood eosinophils (46). In addition to type 2 responses, eosinophils exposed to viral (47)(48)(49)(50)(51), bacterial, or fungal pathogens (52)(53)(54) and eosinophils involved in cancer or autoimmunity (reviewed in 9, 55, 56) undergo unique phenotypic changes associated with their ability to differentially regulate activation or suppression of the in ammatory process. Taken together, the emerging evidence indicates that eosinophils are pleiotropic cells, capable of dramatically and dynamically modifying their transcriptomic content in response to microenvironment and in ammatory signals.…”

“…Eosinophils have the capacity to release IL-6 or type 17 mediators that occur in certain patients with exacerbation-prone asthma (144). Moreover, eosinophils have unique functions in viral infections (47)(48)(49)51), when they may produce inducible nitric oxide synthase, take up viral particles, and activate CD8 T cells to kill viruses. In these nuanced disease processes, eosinophils may be contributory cells rather than primary mediators.…”

Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

“…Several immune cell populations in the lungs have been found to play vital roles in the response to respiratory virus infection (Channappanavar et al, 2016;Dalskov et al, 2020;LeMessurier et al, 2020). We therefore sought to determine if any of the genetic loci identified in our study showed an association with influenza A virus (IAV)-induced disease phenotypes.…”