Pneumocystis Elicits a STAT6-Dependent, Strain-Specific Innate Immune Response and Airway Hyperresponsiveness

Abstract

It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-g or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds.Keywords: STAT6; airway hyperresponsiveness; Pneumocystis; pulmonary inflammation; strain-specificThe immunological response to respiratory pathogens is normally calibrated to eliminate an infection without causing overt collateral damage to the respiratory tissue. In spite of this, an overexuberant or misdirected immune response can have pathological outcomes. This can range from phenomena that are transient and typically moderate, such as elevated airway hyperresponsiveness (AHR), to those that are permanent and progressive, such as pulmonary fibrosis. The health effects of these immunological responses depend on the context of the infection; those that are comorbid with other acute or chronic pulmonary conditions may incite serious respiratory distress in that context when otherwise they might have little noticeable effect.One area in which the effects of comorbid respiratory illnesses are especially relevant is that of exacerbation of preexisting asthma or chronic obstructive pulmonary disease (COPD). Many potential pathogens have been implicated as causing exacerbation; the most well known are various viruses, including rhinovirus, metapneumovirus, and respiratory syncytial virus (1). Several respiratory bacteria, most notably the atypical bacteria Mycoplasma pneumoniae and Chlamydia pneumoniae, have also been implicated in the exacerbation of asthma symptoms (2). Common fungi have also been widely imp...

Eosinophils Contribute to Early Clearance of Pneumocystis murina Infection

“…One clear role of CD4 + T-cells in response to Pneumocystis is to stimulate antibody responses by providing co-stimulatory signals to B cells (19, 23). Antibodies against Pneumocystis are protective; however, at day 14 of infection, prior to antibody production, Pneumocystis burden has already plateaued in wild type animals suggesting an antibody-independent function for CD4 cells (23). As such, CD4 + T-cells appear to recruit eosinophils early in infection while B cells are undergoing maturation into antibody-producing plasma cells and provide preliminary control of Pneumocystis burden.…”

“…Secondly, patients with a history of Pneumocystis or bacterial pneumonia had a significantly higher rate of physician-diagnosed asthma, a disease that has a well-established eosinophilic component in regards to pathogenesis (34). Murine models of Pneumocystis have also shown STAT6, a transcription factor required for Th2 responses, is necessary for the development of airway hyperresponsiveness early in the course of infection (23). While eosinophilia was also documented early in this murine model, the study further links a Th2 response, and potentially eosinophilia, with pathology in the context of Pneumocystis infection (23).…”

“…Murine models of Pneumocystis have also shown STAT6, a transcription factor required for Th2 responses, is necessary for the development of airway hyperresponsiveness early in the course of infection (23). While eosinophilia was also documented early in this murine model, the study further links a Th2 response, and potentially eosinophilia, with pathology in the context of Pneumocystis infection (23). Additionally studies have shown that CD8 + T-cells may moderate the interactions between CD4 + T-cells and eosinophils, although all three cell types may contribute to Pneumocystis driven pulmonary pathology (35).…”

“…The importance of CD4 + T-cells in protecting against Pneumocystis pneumonia has also been demonstrated in patients with genetic immunodeficiencies, such as forms of severe combined immunodeficiency, as well as in animal models of infection (17, 18). Although CD4 + T-cells have been shown to interact with various cell types throughout the course of Pneumocystis infection, such as B cells and macrophages, the ability of other immune cell types to contribute to Pneumocystis clearance in a CD4 + T-cell dependent manner is still an area of active investigation (19–23). Identifying novel cell types that mediate immunity to Pneumocystis could potentially suggest unique pathways for targeted therapeutic development.…”

Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia

“…Resolution of Pneumocystis infection is typically associated with an influx of macrophages, neutrophils, and lymphocytes into the lung. Reports implicate neutrophils as a cause of the lung damage associated with the Pneumocystis hyperinflammatory response in humans (45). Here, we enumerated the numbers of leukocytes present in the BALF during IR in untreated and treated mice by using a Coulter Counter and by differential counting (Fig.…”