Increase in secreted airway mucins and partial Muc5b STAT6/FoxA2 regulation during Pneumocystis primary infection

Abstract

Airway mucus responses to subclinical infections may explain variations in progression of chronic lung diseases and differences in clinical expression of respiratory infections across individuals. Pneumocystis associates to more severe Chronic Obstructive Pulmonary Disease (COPD), asthma, respiratory distress of premature newborns, and is a consistent subclinical infection between 2 and 5 months of age when hospitalizations for respiratory cause and infant mortality are higher. This atypical fungus associates to increased mucin 5AC (MUC5AC), a central effector of Th2-type allergic inflammation, in infant lungs. However, mucus progression, expression of MUC5B essential for airway defense, and potential for pharmacologic modulation of mucus during Pneumocystis infection remain unknown. We measured MUC5B and Pneumocystis in infant lungs, and progression of mucin levels and effect of inhibition of the STAT6/FoxA2 mucus pathway using Kaempferol, a JAK/STAT6 inhibitor, in immunocompetent rats during Pneumocystis primary infection. Pneumocystis associated to increased MUC5B in infant lungs. Muc5b increased earlier and more abundantly than Muc5ac during experimental primary infection suggesting an acute defensive response against Pneumocystis as described against bacteria, while increased Muc5ac levels supports an ongoing allergic, Th2 lymphocyte-type response during primary Pneumocystis infection. Kaempferol partly reversed Muc5b stimulation suggesting limited potential for pharmacological modulation via the STAT6-FoxA2 pathway.

Primary infection by Pneumocystis induces Notch-independent Clara cell mucin production in rat distal airways

“…Hence, is clear that Notch-independent mechanisms can mediate mucin induction [10, 51]. Regarding this, we have recently documented that kaempferol, a STAT6 pathway inhibitor, was associated to partial reduction of levels of mucins during Pneumocystis infection [23]. Nonetheless, whether STAT6 or other pathways are specifically involved in Clara cell expression of mucins described here remain to be elucidated.…”

The Role of Lung and Gut Microbiota in the Pathology of Asthma

“…These differences included increases in the relative abundance of Pneumocystis in the lungs of patients with severe asthma (Goldman et al, 2018), a microbe whose presence within the lungs has been linked to the induction of host type 2 immune responses in humans and animal models (Eddens et al, 2016). Subclinical colonization of the lungs with Pneumocystis at 2-5 months of age has been suggested to be one of the most common infections in infancy (Vargas et al, 2001(Vargas et al, , 2005 and is associated with increased mucin gene expression (Pé rez et al, 2014;Vargas et al, 2001Vargas et al, , 2005Vargas et al, , 2013Rojas et al, 2019). Early lung colonization with Pneumocystis may therefore represent a risk factor for the induction of Th2 cell-skewed immune responses in the lung and predispose infants to asthma (Rojas et al, 2019).…”

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia

“…Recent reports describe increased production of mucus and of specific MUC5AC and MUC5B mucus proteins during Pneumocystis primary infection in infants (Vargas et al, 2013; Perez F. J. et al, 2014; Rojas et al, 2019) and in immunocompetent rodent models (Meissner et al, 2005; Hernandez-Novoa et al, 2008; Vargas et al, 2013; Eddens et al, 2016; Rojas et al, 2019). Importantly, mucus excess as a pathologic feature in PcP remains unexplored.…”