AUTHOR=Lázaro-Antón Leticia , Veiga-da-Cunha Maria , Elizalde-Bielsa Aitor , Chevalier Nathalie , Conde-Álvarez Raquel , Iriarte Maite , Letesson Jean Jacques , Moriyón Ignacio , Van Schaftingen Emile , Zúñiga-Ripa Amaia 

TITLE=A novel gluconeogenic route enables efficient use of erythritol in zoonotic Brucella

JOURNAL=Frontiers in Veterinary Science

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2024.1328293

DOI=10.3389/fvets.2024.1328293

ISSN=2297-1769

ABSTRACT=<p>Brucellosis is a worldwide extended zoonosis caused by pathogens of the genus <italic>Brucella</italic>. While most <italic>B. abortus</italic>, <italic>B. melitensis</italic>, and <italic>B. suis</italic> biovars grow slowly in complex media, they multiply intensely in livestock genitals and placenta indicating high metabolic capacities. Mutant analyses <italic>in vitro</italic> and in infection models emphasize that erythritol (abundant in placenta and genitals) is a preferred substrate of brucellae, and suggest hexoses, pentoses, and gluconeogenic substrates use in host cells. While <italic>Brucella</italic> sugar and erythritol catabolic pathways are known, growth on 3–4 carbon substrates persists in Fbp- and GlpX-deleted mutants, the canonical gluconeogenic fructose 1,6-bisphosphate (F1,6bP) bisphosphatases. Exploiting the prototrophic and fast-growing properties of <italic>B. suis</italic> biovar 5, we show that gluconeogenesis requires fructose-bisphosphate aldolase (Fba); the existence of a novel broad substrate bisphosphatase (Bbp) active on sedoheptulose 1,7-bisphosphate (S1,7bP), F1,6bP, and other phosphorylated substrates; that <italic>Brucella</italic> Fbp unexpectedly acts on S1,7bP and F1,6bP; and that, while active in <italic>B. abortus</italic> and <italic>B. melitensis</italic>, GlpX is disabled in <italic>B. suis</italic> biovar 5. Thus, two Fba-dependent reactions (dihydroxyacetone-phosphate + glyceraldehyde 3-phosphate ⇌ F1,6bP; and dihydroxyacetone-phosphate + erythrose 4-phosphate ⇌ S1,7bP) can, respectively, yield fructose 6-phosphate and sedoheptulose 7-phosphate for classical gluconeogenesis and the Pentose Phosphate Shunt (PPS), the latter reaction opening a new gluconeogenic route. Since erythritol generates the PPS-intermediate erythrose 4-phosphate, and the Fba/Fbp-Bbp route predicts sedoheptulose 7-phosphate generation from erythrose 4-phosphate, we re-examined the erythritol connections with PPS. Growth on erythritol required transaldolase or the Fba/Fbp-Bbp pathway, strongly suggesting that Fba/Fbp-Bbp works as a PPS entry for both erythritol and gluconeogenic substrates in <italic>Brucella</italic>. We propose that, by increasing erythritol channeling into PPS through these peculiar routes, brucellae proliferate in livestock genitals and placenta in the high numbers that cause abortion and infertility, and make brucellosis highly contagious. These findings could be the basis for developing attenuated brucellosis vaccines safer in pregnant animals.</p>