Showing papers by "Jean-Pierre Gorvel published in 2019"

Post-bacterial infection chronic fatigue syndrome is not a latent infection.

Abstract: Post-infectious chronic fatigue syndrome is a public health problem. Etiologies and physiopathological mechanisms are unknown. Some viruses are known to be involved in post-infectious chronic fatigue syndrome, but the role of bacterial infection is still questioned, especially in cases of post-treatment Lyme disease syndrome where subjective symptoms are regularly attributed to the presence of the dormant bacterium without scientific evidence. However, the medical experience of recalcitrant infections, relapses, and reactivations questions the role of "dormant bacteria" in asymptomatic latent infections as well as in subjective symptoms. We summarized scientific literature data on post-bacterial infection chronic fatigue syndrome, the role of dormant bacteria in latent infections, and bacterial asymptomatic carriage. Subjective symptoms described in post-infectious chronic fatigue syndromes are still misunderstood and there is no evidence suggesting that such symptoms could be related to dormant bacterial infection or carriage of viable bacteria. Psychological trauma may be part of these subjective symptoms. Post-infectious chronic fatigue syndrome could nonetheless be due to unknown microorganisms. Antibiotic treatment is not required for latent infections, except for latent syphilis and latent tuberculosis infections to prevent, after the primary infection, progression to the secondary or tertiary stage of the disease.

Infection by Brucella melitensis or Brucella papionis modifies essential physiological functions of human trophoblasts.

Abstract: Brucellosis is a zoonosis caused by bacteria of the Brucella genus. In ruminants, brucellosis causes abortion, followed by chronic infection and secretion of bacteria in milk. In humans, it usually presents as flu-like symptoms, with serious complications if untreated. Epidemiological studies have only recently established that brucellosis can also cause pregnancy complications in women, but the pathogenic mechanisms are unknown. Pioneering studies in ruminants showed that Brucella infect trophoblasts and then colonise the placenta where they grow to high density. A recent study showed that the main zoonotic Brucella species can infect human cytotrophoblasts (CTB) and extravillous trophoblasts (EVT). In this work, we show that Brucella papionis (associated with stillbirth in primates) also infects human trophoblasts. However, it replicates actively in CTB, whereas its replication is very restricted within EVT. We also observed alteration of several trophoblastic functions upon infection by B. papionis or Brucella melitensis (the most prevalent species in human brucellosis). Infection altered the production of hormones, the ability of CTB to form syncytiotrophoblasts, and the invasion capacity of EVT. We also found that infection can spread between different types of trophoblasts. These findings constitute a new step in understanding how Brucella infection causes adverse pregnancy outcomes.

Brucella effector hijacks endoplasmic reticulum quality control machinery to prevent premature egress

Abstract: Perturbation of endoplasmic reticulum (ER) functions can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control (ERQC) ensures that only correctly assembled proteins reach their destination. Persistence of misfolded or improperly matured proteins upregulates the unfolded protein response (UPR) to cope with stress, activates ER associated degradation (ERAD) for delivery to proteasomes for degradation. We have identified a Brucella abortus type IV secretion system effector called BspL that targets Herp, a key component of ERQC and is able to augment ERAD. Modulation of ERQC by BspL results in tight control of the kinetics of autophagic Brucella-containing vacuole formation, preventing premature bacterial egress from infected cells. This study highlights how bacterial pathogens may hijack ERAD components for fine regulation of their intracellular trafficking.

The TIR-domain containing effectors BtpA and BtpB from Brucella abortus block energy metabolism

Abstract: Brucella species are facultative intracellular Gram-negative bacteria relevant to animal and human health Their ability to establish an intracellular niche and subvert host cell pathways to their advantage depends on the delivery of bacterial effector proteins through a type IV secretion system Brucella Toll/Interleukin-1 Receptor (TIR)-domain-containing proteins BtpA (also known as TcpB) and BtpB are among such effectors Although divergent in primary sequence, they interfere with Toll-like receptor (TLR) signaling to inhibit the innate immune responses However, the molecular mechanisms implicated still remain unclear To gain insight into the functions of BtpA and BtpB, we expressed them in the budding yeast Saccharomyces cerevisiae as a eukaryotic cell model We found that both effectors were cytotoxic and that their respective TIR domains were necessary and sufficient for yeast growth inhibition Growth arrest was concomitant with actin depolymerization, endocytic block and a general decrease in kinase activity in the cell, suggesting a failure in energetic metabolism Indeed, levels of ATP and NAD+ were low in yeast cells expressing BtpA and BtpB TIR domains, consistent with the recently described enzymatic activity of some TIR domains as NAD+ hydrolases In human epithelial cells, both BtpA and BtpB expression reduced intracellular total NAD levels In infected cells, both BtpA and BtpB contributed to reduction of total NAD, indicating that their NAD+ hydrolase functions are active intracellularly during infection Overall, combining the yeast model together with mammalian cells and infection studies our results show that BtpA and BtpB modulate energy metabolism in host cells through NAD+ hydrolysis, assigning a novel role for these TIR domain-containing effectors in Brucella pathogenesis