Cystic fibrosis: Why so many respiratory complications?

Date:
July 13, 2020
Source:
Universite' de Gene`ve
Summary:
Cystic fibrosis causes severe respiratory and digestive disorders.

Despite considerable therapeutic advances, this disease still
reduces life expectancy, in particular due to life-threatening
respiratory infections. Scientists have now discovered the reason
for this large number of lung infections: a protein, Vav3.



FULL STORY ========================================================================== Cystic fibrosis, one of the most common genetic diseases in Switzerland,
causes severe respiratory and digestive disorders. Despite considerable therapeutic advances, this disease still reduces life expectancy, in
particular due to life-threatening respiratory infections. Scientists from
the University of Geneva (UNIGE) have discovered the reason for this large number of lung infections: a protein, Vav3, promotes these infections by creating a "bacterial docking station" on airways' surface. Inhibiting
this protein might prevent bacteria from docking on airways' surface
and causing recurrent infections.

These results, to be read in the journal Cell Reports, pave the way of interesting therapeutic prospects for limiting respiratory complications
in people with cystic fibrosis.


========================================================================== Cystic fibrosis, affecting more than 700,000 people worldwide, is one of
the most common genetic diseases in Switzerland. It stems from mutations
in the gene responsible for a protein that participates in the secretion
of mucus, making it abnormally thick. The alteration of this single gene
leads to severe respiratory and digestive problems and limits both life
quality and life expectancy of those affected. In lungs for example, hyperviscous mucus stagnates and obstructs airways.

Recurrent infections Mucus accumulation does not only obstruct airways,
it also promotes persistent lung infections. Despite major therapeutic advances, these lung infections remain frequent and serious. They are
mostly due to a bacterium known for its resistance to antibiotics,
Pseudomonas aeruginosa. "While it is known that mucus viscosity plays
a role in trapping bacteria, the reason why they anchor so easily to
airways was unknown," explains Marc Chanson, Professor at the Department
of Cell Physiology and Metabolism of the Faculty of Medicine of the
UNIGE. "Anchoring of Pseudomonas aeruginosa to airways' cells is the
starting point for these often fatal infections. Understanding this
process could help preventing their occurrence." A bacterial docking
station UNIGE researchers compared airway cells from sick people with
healthy cells.

"The whole project began when we found that the protein Vav3, which
had not been shown to be involved in this disease until now, was
over-expressed in sick cells," enthuses Mehdi Badaoui, researcher in
Prof. Marc Chanson's team and first author of this work. After numerous
in vitro analyses, scientists discovered the key role of this protein:
it directs the construction of a true bacterial docking station. In
concrete terms, Vav3 forces two other proteins, fibronectin and integrin
b1, to associate with it on cell surface and create a complex that
promotes Pseudomonas aeruginosa infections. "This is the first time
that a mechanism creating a favourable microenvironment for a bacterium
before it even arrives has been observed," says Marc Chanson. "This
might explain the high number of chronic lung infections in people with
cystic fibrosis." Inhibiting Vav3 to limit respiratory infections How
to build on this mechanism to develop therapeutic options? By inhibiting
Vav3 in sick cells, scientists succeeded in preventing the expression of
the two other proteins that make up the docking station. "And, indeed, the absence of this structure limits the adhesion of Pseudomonas aeruginosa,"
adds Mehdi Badaoui. Although the exact link between the protein Vav3 and
the genetic defect that causes cystic fibrosis has yet to be determined,
this discovery is a promising therapeutic target for limiting respiratory complications.

This work has been made possible, in particular, thanks to the support
of the Swiss National Science Foundation (SNSF) and the Swiss Society
for Cystic Fibrosis.


========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mehdi Badaoui, Alice Zoso, Tahir Idris, Marc Bacchetta, Juliette
Simonin,
Sylvain Lemeille, Bernhard Wehrle-Haller, Marc Chanson. Vav3
Mediates Pseudomonas aeruginosa Adhesion to the Cystic Fibrosis
Airway Epithelium.

Cell Reports, 2020; 32 (1): 107842 DOI: 10.1016/j.celrep.2020.107842 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200713120024.htm

--- up 24 weeks, 6 days, 2 hours, 34 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)