A Novel CD4⁺ T Cell–Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology

Abstract

Rationale: Infection with Pneumocystis, an opportunistic fungal pathogen, can result in fulminant pneumonia in the clinical setting of patients with immunosuppression. In murine models, Pneumocystis has previously been shown to induce a CD4 1 T cell-dependent eosinophilic response in the lung capable of providing protection.Objectives: We sought to explore the role of Pneumocystis in generating asthma-like lung pathology, given the natural eosinophilic response to infection.Methods: Pneumocystis infection or antigen treatment was used to induce asthma-like pathology in wild-type mice. The roles of CD4 1 T cells and eosinophils were examined using antibody depletion and knockout mice, respectively. The presence of anti-Pneumocystis antibodies in human serum samples was detected by ELISA and Western blotting.Measurements and Main Results: Pneumocystis infection generates a strong type II response in the lung that requires CD4 1 T cells. Pneumocystis infection was capable of priming a Th2 response similar to that of a commonly studied airway allergen, the house dust mite. Pneumocystis antigen treatment was also capable of inducing allergic inflammation in the lung, resulting in anti-Pneumocystis IgE production, goblet cell hyperplasia, and increased airway resistance. In the human population, patients with severe asthma had increased levels of anti-Pneumocystis IgG and IgE compared with healthy control subjects. Patients with severe asthma with elevated antiPneumocystis IgG levels had worsened symptom scores and lung parameters such as decreased forced expiratory volume and increased residual volume compared with patients with severe asthma who had low anti-Pneumocystis IgG.Conclusions: The present study demonstrates for the first time, to our knowledge, that Pneumocystis is an airway allergen capable of inducing asthma-like lung pathology.

Pneumocystis -Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity

“…S7F,G). Furthermore, in agreement with previously published data in a sterile Pneumocystis antigen model (Eddens et al, 2016), the T-cell responses were unperturbed in dblGATA1 −/− mice (Fig. S7G).…”

“…Colonization with Pneumocystis in these infants was associated with increases in a chloride channel associated with mucus release, suggestive of potential pathologic response to the fungus (Pérez et al, 2014). Likewise, we have previously demonstrated that Pneumocystis exposure in mice led to asthma-like pathology, and that a subset of patients with severe asthma had increased antibody responses against Pneumocystis (Eddens et al, 2016). …”

New advances in understanding the host immune response to Pneumocystis

“…Additional patient groups at risk are patients with connective tissue disease with vasculitis or polymyositis/dermatomyositis. In addition treatments targeting B-cells in cancer or in autoimmune inflammation with anti-CD20 have been associated with Pneumocystis infection [9, 10]. This has been modelled in the mouse where anti-CD20 could perturb CD4 + T-cell priming and enhance susceptibility to infection [11].…”

“…In an immunocompromised host, components of aTh2-driven immune response have proven to be beneficial. In contrast, Th2 responses to Pneumocystis drive inflammation and asthma-like pathology in healthy individuals comparable to that of the common allergen, house dust mite [9]. Therefore, a consequence of chronic exposure to Pneumocystis could indeed be asthma.…”

“…Th2 responses to Pneumocystis drive an allergic reaction in healthy hosts. APCs = antigen presenting cells, Th = T helper, M1 = classically activated macrophages, M2 = alternatively activated macrophages [9, 10, 32, 34, 39]. …”