Engineering Mycoplasma pneumoniae to bypass the association with Guillain-Barré syndrome.

A non-pathogenic Mycoplasma pneumoniae-based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis.
Competing Interests: Declaration of competing interest The results published in this article are covered by patents PCT/EP2021/057122 and US2023/0310564 A1(licensed to Pulmobiotics S.L). L.S. and M.L.-S. are shareholders of Pulmobiotics S.L.. C.P.-L., R.M., and M.L.-S. are employees and have stock options of Pulmobiotics S.L. The remaining authors declare no competing interests.
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