Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Abstract

MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection.

Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus

“…We hypothesized that mucus may have played a role in the differences observed between these viruses in vitro and in vivo. NA is important in the release of viruses from cells, but there is also evidence that it plays a role early in infection, by freeing viruses bound to sialic acids present on mucus in the airway (18)(19)(20). To determine if pH1N1 low -1 was inhibited by mucus, we used washed and unwashed NHBE cells.…”

The cell surface mucin MUC1 limits the severity of influenza A virus infection

“…The family of mucin glycoproteins, which are highly conserved across species, have long been regarded as contributors to innate mucosal barrier function in IAV infection. 1 However, studies have been limited to the secreted and gel-forming mucins [2][3][4] with little or no attention given to the in vivo role of cell surface mucins (cs-mucins) in host defense against influenza infection.…”

Future treatment for asthma

“…Goblet cell hyperplasia is now regarded as a consequence of the remodelling process, mainly through an IL-13-dependent phenomenon [99], but this was not addressed in anti-IL13 trials. Muc5AC knockout mice are more sensitive to viral infections [123], and other pneumoproteins released into the airway lumen also offer interesting defensive activities against inhaled toxicants and microorganisms. Other known triggers involved in goblet cell hyperplasia (NOTCH, SPDEF and others) may represent new therapeutic avenues, but basic science studies are needed.…”