Pneumocystis murinaInfection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction. The main risk factor for developing COPD is cigarette smoking; however, only about 20% of smokers develop lung disease. The mechanisms by which cigarette smoke leads to pathological changes in both airways and lung parenchyma are unclear. Pulmonary inflammation, localized to the airways, is a pathological feature in the lungs of COPD patients. A predominance of macrophages and CD8 ϩ T lymphocytes are found both in bronchial biopsies (43,44) and in the lung parenchyma at sites of parenchymal destruction (29). These findings suggest that CD8 ϩ T lymphocytes may be responsible for damage to the lung, either by directly injuring neighboring cells, by secreting molecules that injure the lung, or by recruiting and activating additional inflammatory cells.The stimuli responsible for triggering inflammation are not known, but infectious pathogens likely play a role in the initiation or perpetuation of pulmonary inflammation in COPD. Much of the work examining the role of infection in the course and pathogenesis of COPD has focused on bacterial colonization (45), but bacterial or viral colonization may be insufficient to explain pathogenesis. An intriguing alternate pathogen that has received recent attention is the fungus Pneumocystis jirovecii. Although it was previously thought to be an opportunistic pathogen that caused serious pneumonia only in severely immunocompromised patients, recent investigations substantiate the exi...

HIV and Chronic Obstructive Pulmonary Disease: Is It Worse and Why?

“…Animal models also support the role of Pc colonization in COPD. Christensen and colleagues recently reported that in immunocompetent mice, exposure to cigarette smoke and Pc colonization resulted in pulmonary function deficits and airspace enlargement greater than that from smoke exposure alone (24). Similar changes have been found in models of Pc colonization in nonhuman primates infected with simian immunodeficiency virus or simian/human immunodeficiency virus.…”

Topographic Diversity of the Respiratory Tract Mycobiome and Alteration in HIV and Lung Disease

“…We could not determine the causal role of alterations in lung fungal communities in development of HIVassociated COPD, but prior animal studies have shown that Pneumocystis colonization results in COPD-like changes in both an HIV-like nonhuman primate model and in an immunocompetent, smoke-exposed rodent model (8,45). Differences between the populations could have affected our results, although we took steps to minimize these differences.…”

“…Pneumocystis detection was previously reported in both HIVinfected and HIV-uninfected individuals with COPD in studies using PCR (21,39,44). Pneumocystis also results in COPD-like changes in rodent and nonhuman primate models (8,45). Pneumocystis colonization has been postulated to contribute to COPD by stimulating inflammation and release of matrix metalloproteases, which can damage the lung (8,39).…”

Combined Quantification of Pulmonary Pneumocystis jirovecii DNA and Serum (1→3)-β- d -Glucan for Differential Diagnosis of Pneumocystis Pneumonia and Pneumocystis Colonization

“…Pneumocystis colonization duration was estimated as Ͻ1 month to 6 months in free-living immunocompetent macaques (31). Studies in rodents and primates showed that Pneumocystis colonization induced chronic obstructive pulmonary disease develop- ment (32,33). Moreover, using the experimental SCID-BALB/c mouse transmission model, it was shown that Pneumocystis-carrying BALB/c mice were able to transmit the infection to susceptible SCID mice and to naive healthy mice.…”