Biology subjects

Faivre, B.

Publications and source records attributed to Faivre, B..

7 recordsLinked to original sources

bioRxiv2026

UbiB proteins mediate an ATP-dependent decarboxylation step in bacterial ubiquinone biosynthesis

Polyisoprenoid quinones such as ubiquinone (UQ) play an essential role in cellular physiology, acting as membrane-bound electron and proton carriers in respiratory chains and other biological processes across all domains of life. In Escherichia coli, the canonical UQ biosynthesis pathway is well characterized. It involves twelve proteins (UbiA-UbiK and UbiX), most of which catalyzing one of the eight modifications of the aromatic ring derived from 4-hydroxybenzoic acid (4-HB), while others (UbiB, UbiJ, UbiK) act as accessory factors ensuring efficient UQ production. Following prenylation by UbiA and subsequent decarboxylation by the UbiX/UbiD system, the final six reactions are catalyzed within a soluble Ubi-complex. UbiB, an atypical protein kinase-like enzyme, was proposed to extract decarboxylated intermediates from the membrane and mediate their delivery to the Ubi-complex. In this study, we demonstrate the existence of an alternative decarboxylation system in E. coli, as UQ biosynthesis can proceed in the absence of the UbiX/UbiD system. Our results show that this alternative decarboxylation activity depends on UbiB and requires its ATPase activity. Bioinformatic analyses further revealed that approximately 27% of Pseudomonadota species lack UbiX/UbiD homologs, and we found that UbiB proteins from two such species enhance the alternative decarboxylation activity when expressed in E. coli. In addition, we identified conserved residues in UbiB that are specifically required for decarboxylation but dispensable for the delivery of UQ intermediates to the Ubi-complex. Taken together, our findings support a model in which UbiB acts as an ATP-dependent decarboxylase, thereby broadening the functional scope of this poorly characterized protein. ImportancePolyisoprenoid quinones, including ubiquinone (UQ, also known as coenzyme Q), are essential electron and proton carriers in respiratory chains across all domains of life. After prenylation and decarboxylation, the final six steps of UQ biosynthesis are carried out by a soluble Ubi-complex. The only decarboxylation system currently identified in the UQ pathway, the UbiX/UbiD system, is absent from numerous bacterial genomes, and no isofunctional enzymes have been described to date. UbiB, an atypical protein kinase-like enzyme, has been proposed to mediate the extraction of UQ precursors from the membrane, thereby rendering them accessible to the soluble Ubi-complex. Here, we show that UbiB proteins fulfill an additional function in bacteria. Specifically, they contribute to the decarboxylation of UQ precursors through a mechanism that remains unknown but depends on ATP hydrolysis. Given that UbiB is conserved in all UQ-producing bacteria, it may represent a widespread decarboxylation system within this essential metabolic pathway.

biochemistry↗

bioRxiv2025

Experimental evolution of Plasmodium yoelii in single and helminth-coinfected mice

Coinfection has the potential to affect key traits describing the infection dynamics, the severity of the disease and in fine parasite fitness. However, despite its pervasiveness, experimental work investigating how parasites adapt to the conditions provided by a coinfected host is mostly missing. Here, we adopted an experimental evolution approach to investigate if coinfection with the nematode Heligmosomoides polygyrus (Hp) affected the infection dynamics and virulence of the murine malaria parasite Plasmodium yoelii (Py). To this purpose, lines of Py were passaged either in single infected hosts (SI-lines) or in hosts that had been previously infected with Hp (COI-lines). After five and seven passages, the infection dynamics and virulence of evolved lines were compared to the ancestral Py population during single infection trials. As expected, we found that serial passages increased parasitemia and Py virulence, due to the competitive advantage of genotypes with the fastest replication rate, but SI-lines and COI-lines had similar replication rate and virulence. Hosts infected with evolved lines of Py were also less tolerant (steeper slope between red blood cell counts and parasitemia) but again there was no difference between SI-lines and COI-lines. In a second experiment, COI-lines were also used to infect hosts during coinfection trials, allowing us to compare within-host Py replication when the environment during the evaluation trials matched the environment experienced during the passages and when they were mismatched. The results showed that COI-lines used during single infection trials (mismatched environment) had a slower replication rate compared to both SI-lines and COI-lines used during matched-environment trials. Overall, although we did not find any difference in the virulence of SI-lines and COI-lines after seven passages, Py rapidly adapted to the environmental conditions provided by single infected or coinfected hosts, as shown by the slower replication rate found in mismatched-environment trials. Author SummaryCoinfection can alter infection dynamics, disease severity, and parasite fitness, yet experimental evidence on parasite adaptation to coinfected hosts is scarce. Here we used experimental evolution to assess whether coinfection with the nematode Heligmosomoides polygyrus influences the infection dynamics and virulence of the murine malaria parasite Plasmodium yoelii. Parasite lines were serially passaged in either single infected hosts or hosts previously infected with Heligmosomoides polygyrus. After multiple passages, evolved lines exhibited increased parasitemia and virulence compared to the ancestral strain, but no significant differences were found between lines evolved in single or coinfected hosts. Notably, parasite replication was reduced when lines evolved in coinfected hosts were tested in single infection environments, indicating rapid adaptation to host infection context. This suggests that while coinfection shapes within-host conditions, Plasmodium adapts rapidly to these conditions. These results have possible implications for understanding parasite evolution in fluctuating host environments, and the microevolutionary consequences for malaria of the deworming campaigns that are implemented to control helminthiases.

evolutionary biology↗

bioRxiv2025

Coinfection with malaria alters the dynamics and fitness of an intestinal nematode

Infections with soil transmitted helminths (STHs) are highly prevalent in humans living in the intertropical region. While, in most cases, STHs can establish chronic infections, the dynamics of the infection can be altered when other parasites exploit the same host. These changes can have consequences in terms of the health of the host, the epidemiology of the disease (e.g., the duration of the infection and the inter-host transmission success) and the fitness of the parasite. Here, we investigated if the coinfection with Plasmodium yoelii alters the dynamics and the fitness of the murine nematode Heligmosomoides polygyrus. We found that, compared to single infected mice, coinfection produced an increase in the number of excreted eggs, while the biomass of adult worms in the intestine did not differ between single infected and coinfected mice. Moreover, the increase in egg excretion was also observed when Plasmodium infected hosts that had been harboring the nematode during the past four weeks (i.e., when the population size of adult worms can only decrease due to mortality). Therefore, the enhanced shedding of eggs reflects a plastic adjustment of worm fecundity to the environment provided by a coinfected host. This plastic response was modulated by the host Th2 immunity, as coinfection inhibited IL-4 and IL-13 gene expression, plasma levels of IL-5 and IL-13, and the expansion of GATA-3+ CD4+ T cells in the spleen. In agreement with this, experimentally inhibiting IL-13 with neutralizing antibodies reproduced the results observed in coinfected mice (an increase in egg excretion), while the administration of recombinant IL-13 reduced egg shedding. Interestingly, coinfection had a net positive effect on parasite fitness as shown by a longer persistence within the host and higher cumulative number of eggs excreted up to 99 days post-infection. Although the gene expression of Th2 cytokines was lower at day 99 p.i., coinfected mice still had a downregulated expression compared to single infected hosts. These results show that coinfection with Plasmodium has the potential to affect the epidemiology of STHs by increasing the number of eggs excreted over the whole infectious period and maintaining a larger environmental reservoir of transmissible stages. Author SummaryCoinfection between soil-transmitted helminths and malaria is common in several countries of the intertropical region, especially among the most vulnerable populations. Coinfection has the potential to worsen the symptoms caused by malaria, therefore it is important to understand what are the epidemiological and ecological factors that promote the occurrence of coinfection. Transmission of soil-transmitted helminths usually requires human contact with transmissible stages (parasitic eggs or larvae) in the environment; therefore, high egg excretion in the feces of infected people is a key factor contributing to maintain a reservoir of infective stages from which humans can get infected. In this study, we experimentally investigated whether coinfection with malaria alters the dynamics (egg excretion, infection persistence) of a murine intestinal nematode. We found that hosts infected with malaria and subsequently infected with the nematode, excreted more nematode eggs for a longer period, compared to single infected hosts. These changes were mediated by an impaired Th2 immune response in coinfected hosts. These results suggest that malaria coinfection produces positive feedback on key epidemiological traits of the nematode that can further enhance the risk of malaria/helminths cooccurrence.

evolutionary biology↗

bioRxiv2025

Parasite virulence in coinfected hosts: the importance of infection order

When hosts are simultaneously infected by different pathogens, the severity of the disease might be altered compared to hosts harboring single infections. The reasons underlying these changes in parasite virulence are manifold. Here, we investigated the importance of order and timing of infection. We used a model of rodent coinfection between two parasites that do not compete for common resources, an intestinal nematode (Heligmosomoides polygyrus, Hp) and an apicomplexan protozoan (Plasmodium yoelii, Py). During single infections, Hp induced only mild disease symptoms. Plasmodium produced a substantial reduction in the number of red blood cells but all mice recovered from the infection. A different picture emerged in coinfected hosts. Hp maintained a profile of mostly asymptomatic infection when infecting hosts that had been previously infected with Py. On the contrary, Py incurred substantially higher costs in hosts that had been previously infected with Hp. We then investigated the possible reasons underlying the increase of Py virulence in hosts that had been previously infected with Hp. We found that coinfected hosts were less able to control Py multiplication and to recover from infection-induced anemia. Coinfected hosts had similar levels of erythropoietin and similar renewal of lost red blood cells compared to single Py infected hosts, resulting in decreased tolerance to Py infection. Experimental administration of erythropoietin in coinfected (Hp infecting first) hosts, partially decreased the severity of disease symptoms and improved tolerance. The detoxification of free heme released during the lysis of red blood cells, and the expression of Th1 and anti-inflammatory cytokine genes were also similar between coinfected and single infected hosts. However, coinfected mice had higher proportions of regulatory T cells expressing the CTLA-4 immune checkpoint, suggesting an enhanced immunosuppressive activity of Tregs. Py infection also induced the exhaustion of CD8+ T cells, as coinfected mice had higher proportions of both PD-1+ and LAG-3+ CD8+ T cells, and an increase in the CD4+/CD8+ ratio. Overall, these results stress the importance of the order of infection as a major determinant of malaria severity in hosts harboring a gastrointestinal nematode infection. We discuss the possible epidemiological and evolutionary consequences of these results.

evolutionary biology↗

bioRxiv2023

Tick-borne zoonotic flaviviruses and Borrelia infections in wildlife hosts: what have field studies contributed?

Tick-borne flaviviruses and Borrelia spp. are globally spread pathogens of zoonotic potential that are maintained by a transmission cycle at the interface between ticks and vertebrate hosts, mainly wild animals. Aside data on pathogen burden in ticks, information on the status of various hosts relative to infection could be critical. We reviewed how those infections have been studied in wildlife species in the field to discuss how collected data provided relevant epidemiological information and identify needs for further studies. The literature was screened for populational studies on direct or antibody detection for tick-borne Borrelia spp. and flaviviruses in animals, in the wild. Overall, Borrelia spp. were more studied (73% of case studies, representing 297 host species) than flaviviruses (27% of case studies, representing 114 host species). Studies on both Borrelia spp. and flaviviruses focused mainly on the same species, namely bank vole and yellow-necked mouse. Most studies were order-specific and cross-sectional, reporting prevalence at various locations, but with little insight into the underlying epidemiological dynamics. Species with potential to act as reservoir hosts were overlooked, notably passerine birds. We highlight the necessity of collecting both demographics and infection data in wildlife studies, and to consider communities of species, to better estimate zoonotic risk potential in the One Health context.

ecology↗

bioRxiv2020

The O2-independent pathway of ubiquinone biosynthesis is essential for denitrification in Pseudomonas aeruginosa

Many proteobacteria, such as Escherichia coli, contain two main types of quinones, benzoquinones represented by ubiquinone (UQ) and naphthoquinones such as menaquinone (MK) and dimethyl-menaquinone (DMK). MK and DMK function predominantly in anaerobic respiratory chains, whereas UQ is the major electron carrier used for reduction of dioxygen. However, this division of labor is probably not so stric. Indeed, a pathway that produces UQ under anaerobic conditions in an UbiU-, UbiV- and UbiT-dependent manner has been recently discovered in E. coli while its physiological relevance is not yet understood because of the presence of MK and DMK in this bacterium. In the present study, we established that UQ9 is the single quinone of P. aeruginosa and that is required for growth under anaerobic respiration (denitrification). We demonstrated that ORFs PA3911, PA3912 and PA3913, which are homologues to the E. coli ubiT, ubiV and ubiU genes, respectively, were essential for UQ9 biosynthesis and thus for denitrification in P. aeruginosa. These three genes were hereafter called ubiTPa, ubiVPa and ubiUPa. We showed that UbiVPa accommodates a [4Fe-4S] cluster. Moreover, we demonstrated that UbiUPa and UbiTPa were able to bind UQ and that the isoprenoid tail of UQ was the structural determinant for the recognition by these Ubi proteins. Since the denitrification metabolism of P. aeruginosa is believed to be important for pathogenicity in cystic fibrosis patients, our results highlight the O2-independent UQ biosynthesis pathway as a new possible target to develop innovative antibiotics.

biochemistry↗

bioRxiv2019

Ubiquinone biosynthesis over the entire O2 range: characterization of a conserved, O2-independent pathway

Most bacteria can generate ATP by respiratory metabolism, in which electrons are shuttled from reduced substrates to terminal electron acceptors, via quinone molecules like ubiquinone. Dioxygen (O2) is the terminal electron acceptor of aerobic respiration and serves as a co-substrate in the biosynthesis of ubiquinone. Here, we characterize a novel, O2-independent pathway for the biosynthesis of ubiquinone. This pathway relies on three proteins UbiT (YhbT), UbiU (YhbU) and UbiV (YhbV). UbiT contains an SCP2 lipid-binding domain and is likely an accessory factor of the biosynthetic pathway, while UbiU-UbiV are involved in hydroxylation reactions and represent a novel class of O2-independent hydroxylases. We demonstrate that UbiU-UbiV form a heterodimer, wherein each protein binds a 4Fe-4S cluster via conserved cysteines that are essential for activity. The UbiT, -U, -V proteins are found in -, {beta}-, {gamma}-proteobacterial clades including several human pathogens, supporting the widespread distribution of a previously-unrecognized capacity to synthesize ubiquinone in the absence of O2. Together, the O2-dependent and O2-independent ubiquinone biosynthesis pathways contribute to optimize bacterial metabolism over the entire O2 range.\n\nIMPORTANCEIn order to colonize environments with large O2 gradients or fluctuating O2 levels, bacteria have developed metabolic responses that remain incompletely understood. Such adaptations have been recently linked to antibiotic resistance, virulence and the capacity to develop in complex ecosystems like the microbiota. Here, we identify a novel pathway for the biosynthesis of ubiquinone, a molecule with a key role in cellular bioenergetics. We link three uncharacterized genes of Escherichia coli to this pathway and show that the pathway functions independently from O2. In contrast, the long-described pathway for ubiquinone biosynthesis requires O2 as substrate. In fact, we find that many proteobacteria are equipped with the O2-dependent and O2-independent pathways, supporting that they are able to synthesize ubiquinone over the entire O2 range. Overall, we propose that the novel O2-independent pathway is part of the metabolic plasticity developed by proteobacteria to face varying environmental O2 levels.

microbiology↗