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

Diego A Rojas,Pamela Bórquez,Miriam Gallo,Andrea Méndez,Carolina A Ponce,Sergio L Vargas,Pablo A Iturra,Rebeca Bustamante

doi:10.1038/s41598-019-39079-4

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.

Highlights

Airway mucus is a biological hydrogel barrier that protects the airway against physical, chemical and biological insults
We have reported increased mucin 5AC (MUC5AC) and CLCA1 associated to Pneumocystis primary infection in lungs of infants dying in the community[19,24]
We show that pulmonary Muc5b occurs earlier and is more abundant that Muc5ac, that the mechanism of Muc5b hypersecretion partly depends on STAT6 stimulation by Pneumocystis -that inhibits FoxA2 repressor, and that this mechanism can be reversed by pharmacological de-repression of FoxA2 using Kaempferol, a specific inhibitor of JAK3 that activates STAT630

Summary

Introduction

Airway mucus is a biological hydrogel barrier that protects the airway against physical, chemical and biological insults. Pneumocystis, a fungus well-known by the severe pneumonia of immunocompromised individuals, associates to increased severity of Chronic Obstructive Pulmonary Disease (COPD)[15], to respiratory distress syndrome of newborns[16], and is likely the most frequent and consistent infection of early infancy[17]. Increased MUC5AC is consistent with the intense Th2 (allergic type) airway immune response[25,26] and STAT6 pathway activation[27] plus induction of mucus-related genes such as Muc5ac and Clca[328] associated to mucus hypersecretion documented in animal models of Pneumocystis infection[26,27,29]. We show that pulmonary Muc5b occurs earlier and is more abundant that Muc5ac, that the mechanism of Muc5b hypersecretion partly depends on STAT6 stimulation by Pneumocystis -that inhibits FoxA2 repressor-, and that this mechanism can be reversed by pharmacological de-repression of FoxA2 using Kaempferol, a specific inhibitor of JAK3 that activates STAT630

Methods

Results

Conclusion