Abstract
Type 2 immunity is characterized by cytokines such as interleukin (IL)-4, IL-5, IL-13, IL-25, IL-33, and cells such as type 2 Innate Lymphoid cells (ILC2s), mast cells, T helper (Th)2 CD4+ T cells, and Immunoglobulin (Ig)E+ B cells. This immune response is most commonly associated with protection against helminth infections, and also for promoting allergy, asthma, and atopic dermatitis. However, the involvement of this branch of immunity has been observed outside these typical conditions, including during viral and bacterial infections. The contribution type 2 immunity plays during these noncanonical responses can be protective or deleterious, depending on the tissue site, pathogen, and other context-dependent factors. In this thesis, we will describe two pathogens, C. difficile and SARS-CoV-2, for which type 2 immunity contributes opposing roles in protecting the host from severe disease.
Clostridiodes difficile (C. difficile) is the leading cause of hospital-acquired gastrointestinal infections in the U.S. resulting in mild to severe diarrhea, pseudomembranous colitis, toxic megacolon, and even death. C. difficile Infection (CDI) is associated with elevated peripheral white blood cell (WBC) counts and intestinal inflammation as indicators of severe disease, suggesting that the host response to infection plays an important role in the outcome of patient morbidity and mortality. Our lab has recently shown that the alarmins IL-25 and IL-33 provide protection from CDI through induction via type 2 innate lymphoid cells (ILC2) that includes eosinophils and promotes the reduction of inflammatory cells and cytokines. ILC2s and eosinophils produce effector cytokines such as IL-4, IL-5, and IL-13, however the role for these have not been explored in CDI before. Here, we show that these cytokines provide protection from severe disease, further supporting the protective capabilities of type 2 immunity during the hyperinflammatory enteric infection caused by C. difficile. IL-5 protected from mortality and resulted in increased eosinophils within the colon, suggesting this cytokine is likely involved downstream of IL-25 in promoting protective eosinophilia. IL-4 and IL-13, however, promoted recovery from disease, highlighting that these two cytokines may be more important for reducing inflammation and tissue damage at later stages during disease. Additionally, the neutralization of IL-13 was associated with increased monocytes and reduced alternatively activated macrophages (AAMs). These data suggested that IL-13 is important for facilitating appropriate monocyte to macrophage transition as well as polarization of AAMs, and that dysregulated responses within these cells impedes effective recovery.
SARS-CoV-2, the causative agent of COVID-19, was first identified in December 2019 in the Wuhan province of China, where it caused severe viral pneumonia. Dysregulated immune responses are strongly associated with severe outcomes from disease, and characterization of these responses could highlight approaches for therapeutic interventions in patients. We identified IL-13 as being associated with the need for mechanical ventilation in two independent cohorts. The use of Dupilumab, a monoclonal antibody against IL-4Ra, in patients who subsequently acquired COVID-19 was associated with fewer severe outcomes. Neutralization of IL-13 in mice protected against severe disease, further supporting a pathogenic role for this cytokine. Following neutralization of IL-13 during COVID-19, we uncovered that the gene for hyaluronan synthase 1, Has1, was the most downregulated gene in the lung, implicating hyaluronan as being regulated by IL-13. Furthermore, deposition of the polysaccharide in lung tissue was reduced following IL-13 neutralization, and blockade of the receptor for hyaluronan, CD44, protected mice from severe disease as well. In patients, elevated hyaluronan was associated with disease in both plasma and lung biopsy samples, further suggesting that hyaluronan is involved in pathogenesis. Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, altogether suggesting a novel role for IL-13 to drive hyaluronan deposition.
The results from these studies support the observation that type 2 immunity can be involved in infections other than those caused by helminths, and can contribute protective or pathogenic roles depending on the tissue and microbe. This thesis will discuss the role type 2 immunity plays during these infections, as well as why there are seemingly opposing consequences for this immune response. Overall, this work increases our understanding of the role for the cytokines IL-4, IL-5, IL-13 in COVID-19 and CDI, and has implications for other infectious diseases.
