The Tragedy of Liberal Democratic Governance in the Face of Global Threats.

In hindsight, the early response of liberal governments to the SARS-CoV-2 pandemic was chaotic and generally inefficient. Though one might be tempted to attribute these failures to the incompetence of certain political decision-makers, we propose another explanation. Global threats require a coordinated international response, which is only possible if the threat is perceived in the same way by all, and if government priorities are similar. The effectiveness of the response also relies on massive adhesion of citizens to the measures imposed, which in turn requires trust in government. Our hypothesis is that certain fundamental features of liberalism complicate such global and collective responses: neutrality of the state and primacy of the individual over collective society. Liberalism considers that institutions and public policy must not be designed to favor any specific conception of the common good. That which is best for all is usually determined by a "competition of opinions," which frequently leads to scientific expertise being considered as only one opinion among many. Liberalism also imposes strict respect for individual freedoms and private interests and tends to reject any form of collectivism or dictate imposed by the common good. In order to solve these structural problems and improve society's management of global threats, we make several proposals, such as the introduction of a minimal and consensual definition of the common good and the promotion of a health policy guided by One Health-like concepts. Overall, our analysis suggests that because political ideologies provide their own definitions of the common good and the place of scientific knowledge in the governance process and can thus affect the response to global threats, they should be urgently taken into consideration by public health experts.

Genome-wide analysis of Brucella melitensis genes required throughout intranasal infection in mice.

Brucellae are facultative intracellular Gram-negative coccobacilli that chronically infect various mammals and cause brucellosis. Human brucellosis is among the most common bacterial zoonoses and the vast majority of cases are attributed to B. melitensis. Using transposon sequencing (Tn-seq) analysis, we showed that among 3369 predicted genes of the B. melitensis genome, 861 are required for optimal growth in rich medium and 186 additional genes appeared necessary for survival of B. melitensis in RAW 264.7 macrophages in vitro. As the mucosal immune system represents the first defense against Brucella infection, we investigated the early phase of pulmonary infection in mice. In situ analysis at the single cell level indicates a succession of killing and growth phases, followed by heterogenous proliferation of B. melitensis in alveolar macrophages during the first 48 hours of infection. Tn-seq analysis identified 94 additional genes that are required for survival in the lung at 48 hours post infection. Among them, 42 genes are common to RAW 264.7 macrophages and the lung conditions, including the T4SS and purine synthesis genes. But 52 genes are not identified in RAW 264.7 macrophages, including genes implicated in lipopolysaccharide (LPS) biosynthesis, methionine transport, tryptophan synthesis as well as fatty acid and carbohydrate metabolism. Interestingly, genes implicated in LPS synthesis and ß oxidation of fatty acids are no longer required in Interleukin (IL)-17RA-/- mice and asthmatic mice, respectively. This demonstrates that the immune status determines which genes are required for optimal survival and growth of B. melitensis in vivo.

PdeA is required for the rod shape morphology of Brucella abortus.

Cyclic-di-GMP plays crucial role in the cell cycle regulation of the α-Proteobacterium Caulobacter crescentus. Here we investigated its role in the α-Proteobacterium Brucella abortus, a zoonotic intracellular pathogen. Surprisingly, deletion of all predicted cyclic-di-GMP synthesizing or degrading enzymes did not drastically impair the growth of B. abortus, nor its ability to grow inside cell lines. As other Rhizobiales, B. abortus displays unipolar growth from the new cell pole generated by cell division. We found that the phosphodiesterase PdeA, the ortholog of the essential polar growth factor RgsP of the Rhizobiale Sinorhizobium meliloti, is required for rod shape integrity but is not essential for B. abortus growth. Indeed, the radius of the pole is increased by 31 ± 1.7% in a ΔpdeA mutant, generating a coccoid morphology. A mutation in the cyclic-di-GMP phosphodiesterase catalytic site of PdeA does not generate the coccoid morphology and the ΔpdeA mutant kept the ability to recruit markers of new and old poles. However, the presence of PdeA is required in an intra-nasal mouse model of infection. In conclusion, we propose that PdeA contributes to bacterial morphology and virulence in B. abortus, but it is not crucial for polarity and asymmetric growth.

Is Antibody-Dependent Enhancement of Trypanosoma cruzi Infection Contributing to Congenital/Neonatal Chagas Disease?

The newborns of women infected with the parasite Trypanosoma cruzi (the agent of Chagas disease) can be infected either before birth (congenitally), or after birth (as e.g., by vector route). Congenital Chagas disease can induce high levels of neonatal morbidity and mortality. Parasite-infected pregnant women transmit antibodies to their fetus. Antibodies, by opsonizing parasites, can promote phagocytosis and killing of T. cruzi by cells expressing FcγR, on the mandatory condition that such cells are sufficiently activated in an inflammatory context. Antibody-dependent enhancement (ADE) is a mechanism well described in viral infections, by which antibodies enhance entry of infectious agents into host cells by exploiting the phagocytic FcγR pathway. Previously reported Chagas disease studies highlighted a severe reduction of the maternal-fetal/neonatal inflammatory context in parasite-transmitting pregnant women and their congenitally infected newborns. Otherwise, experimental observations brought to light ADE of T. cruzi infection (involving FcγR) in mouse pups displaying maternally transferred antibodies, out of an inflammatory context. Herein, based on such data, we discuss the previously unconsidered possibility of a role of ADE in the trans-placental parasite transmission, and/or the development of severe and mortal clinical forms of congenital/neonatal Chagas disease in newborns of T. cruzi-infected mothers.

Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice.

Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, structural analysis suggests the binding of itaconate into the binding site of B. abortus isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ΔaceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ΔaceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.

The Brucella effector BspL targets the ER-associated degradation (ERAD) pathway and delays bacterial egress from infected cells.

Perturbation of the endoplasmic reticulum (ER), a central organelle of the cell, can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control ensures that cells can respond and adapt to stress via the unfolded protein response (UPR) and that only correctly assembled proteins reach their destination. Interestingly, several bacterial pathogens hijack the ER to establish an infection. However, it remains poorly understood how bacterial pathogens exploit ER quality-control functions to complete their intracellular cycle. Brucella spp. replicate extensively within an ER-derived niche, which evolves into specialized vacuoles suited for exit from infected cells. Here we present Brucella-secreted protein L (BspL), a Brucella abortus effector that interacts with Herp, a central component of the ER-associated degradation (ERAD) machinery. We found that BspL enhances ERAD at the late stages of the infection. BspL targeting of Herp and ERAD allows tight control of the kinetics of autophagic Brucella-containing vacuole formation, delaying the last step of its intracellular cycle and cell-to-cell spread. This study highlights a mechanism by which a bacterial pathogen hijacks ERAD components for fine regulation of its intracellular trafficking.

A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection.

In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8+ T cells and CD4+ T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia.

Occurrence and repair of alkylating stress in the intracellular pathogen Brucella abortus.

It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogen Brucella abortus does encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required by B. abortus to face this stress in vitro and in a mouse infection model. Among these genes, ogt is found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair in B. abortus displays distinct features that are not present in model organisms such as Escherichia coli.

Route of Infection Strongly Impacts the Host-Pathogen Relationship.

Live attenuated vaccines play a key role in the control of many human and animal pathogens. Their rational development is usually helped by identification of the reservoir of infection, the lymphoid subpopulations associated with protective immunity as well as the virulence genes involved in pathogen persistence. Here, we compared the course of Brucella melitensis infection in C57BL/6 mice infected via intraperitoneal (i.p.), intranasal (i.n.) and intradermal (i.d.) route and demonstrated that the route of infection strongly impacts all of these parameters. Following i.p. and i.n. infection, most infected cells observed in the spleen or lung were F4/80+ myeloid cells. In striking contrast, infected Ly6G+ neutrophils and CD140a+ fibroblasts were also observed in the skin after i.d. infection. The virB operon encoding for the type IV secretion system is considered essential to deflecting vacuolar trafficking in phagocytic cells and allows Brucella to multiply and persist. Unexpectedly, the ΔvirB Brucella strain, which does not persist in the lung after i.n. infection, persists longer in skin tissues than the wild strain after i.d. infection. While the CD4+ T cell-mediated Th1 response is indispensable to controlling the Brucella challenge in the i.p. model, it is dispensable for the control of Brucella in the i.d. and i.n. models. Similarly, B cells are indispensable in the i.p. and i.d. models but dispensable in the i.n. model. γδ+ T cells appear able to compensate for the absence of αß+ T cells in the i.d. model but not in the other models. Taken together, our results demonstrate the crucial importance of the route of infection for the host pathogen relationship.

Intrinsic Antibacterial Activity of Nanoparticles Made of ß-Cyclodextrins Potentiates Their Effect as Drug Nanocarriers against Tuberculosis.

Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10 000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-ß-cyclodextrins (pßCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pßCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pßCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pßCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pßCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pßCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.

Ethical control of innovation in a globalized and liberal world: Is good science still science?

The independence of science was long seen as of prime importance. This position has become less common today. The perception of scientific research as a public service has led to the opinion that it must be accountable to citizens and produce knowledge and innovation that meet their expectations. Numerous authors have voiced the need for anticipatory ethical control of innovation focusing on the scientific research process. This control is considered as the must-have guarantee for "good science." The current article attempts to trace the ideological origins of the ethical control of innovation, examines its effectiveness against the challenge of globalization and technology-derived major threats and its compatibility with scientific methodology. It also suggests ways to both regulate the innovation process and preserve the independence of science. On the whole, we conclude that truly effective ethical regulation of innovation, i.e. one that protects the greatest number from its adverse effects, is achieved first and foremost by questioning our liberal economic model and the place given to science in our societies.

Allergic Asthma Favors Brucella Growth in the Lungs of Infected Mice.

Allergic asthma is a chronic Th2 inflammatory disease of the lower airways affecting a growing number of people worldwide. The impact of infections and microbiota composition on allergic asthma has been investigated frequently. Until now, however, there have been few attempts to investigate the impact of asthma on the control of infectious microorganisms and the underlying mechanisms. In this work, we characterize the consequences of allergic asthma on intranasal (i.n.) infection by Brucella bacteria in mice. We observed that i.n. sensitization with extracts of the house dust mite Dermatophagoides farinae or the mold Alternaria alternata (Alt) significantly increased the number of Brucella melitensis, Brucella suis, and Brucella abortus in the lungs of infected mice. Microscopic analysis showed dense aggregates of infected cells composed mainly of alveolar macrophages (CD11c+ F4/80+ MHCII+) surrounded by neutrophils (Ly-6G+). Asthma-induced Brucella susceptibility appears to be dependent on CD4+ T cells, the IL-4/STAT6 signaling pathway and IL-10, and is maintained in IL-12- and IFN-γR-deficient mice. The effects of the Alt sensitization protocol were also tested on Streptococcus pneumoniae and Mycobacterium tuberculosis pulmonary infections. Surprisingly, we observed that Alt sensitization strongly increases the survival of S. pneumoniae infected mice by a T cell and STAT6 independent signaling pathway. In contrast, the course of M. tuberculosis infection is not affected in the lungs of sensitized mice. Our work demonstrates that the impact of the same allergic sensitization protocol can be neutral, negative, or positive with regard to the resistance of mice to bacterial infection, depending on the bacterial species.

Diversity Generator Mechanisms Are Essential Components of Biological Systems: The Two Queen Hypothesis.

Diversity is widely known to fuel adaptation and evolutionary processes and increase robustness at the population, species and ecosystem levels. The Neo-Darwinian paradigm proposes that the diversity of biological entities is the consequence of genetic changes arising spontaneously and randomly, without regard for their usefulness. However, a growing body of evidence demonstrates that the evolutionary process has shaped mechanisms, such as horizontal gene transfer mechanisms, meiosis and the adaptive immune system, which has resulted in the regulated generation of diversity among populations. Though their origins are unrelated, these diversity generator (DG) mechanisms share common functional properties. They (i) contribute to the great unpredictability of the composition and/or behavior of biological systems, (ii) favor robustness and collectivism among populations and (iii) operate mainly by manipulating the systems that control the interaction of living beings with their environment. The definition proposed here for DGs is based on these properties and can be used to identify them according to function. Interestingly, prokaryotic DGs appear to be mainly reactive, as they generate diversity in response to environmental stress. They are involved in the widely described Red Queen/arms race/Cairnsian dynamic. The emergence of multicellular organisms harboring K selection traits (longer reproductive life cycle and smaller population size) has led to the acquisition of a new class of DGs that act anticipatively to stress pressures and generate a distinct dynamic called the "White Queen" here. The existence of DGs leads to the view of evolution as a more "intelligent" and Lamarckian-like process. Their repeated selection during evolution could be a neglected example of convergent evolution and suggests that some parts of the evolutionary process are tightly constrained by ecological factors, such as the population size, the generation time and the intensity of selective pressure. The ubiquity of DGs also suggests that regulated auto-generation of diversity is a fundamental property of life.

STAT6 Mediates Footpad Immunopathology in the Absence of IL-12p40 Following Infection of Susceptible BALB/c Mice With Leishmania major.

Leishmania major (L. major) parasites are intracellular parasites belong to the Trypanosomatidae family and are the causative agent of cutaneous leishmaniasis. This disease affects approximately 1.5 million per year worldwide and there is currently no prophylactic vaccine available. L. major is transmitted by the bite of an infected sandfly and has been considered for decades now as a mouse model of choice to identify the factors implicated in T helper (Th)1 and Th2 polarization due to the natural resistance and susceptibility to infection of C57BL/6 and BALB/c mice, respectively. In this study, we refine the role of IL-12p40 cytokine, which is implicated the development of a protective Th1 response, and STAT6, a transcription factor involved in the signaling via detrimental interleukin (IL)-4 and IL-13 associated Th2 cytokines during L. major infection in the BALB/c model. In the absence of STAT6 and IL-12p40 signaling, double knockout (DKO) susceptible BALB/c mice displayed reduced footpad swelling and ulcerative lesion compared to IL-12p40-/- mice upon L. major infection. Hence, they expressed slower upregulation of keratinocyte markers implicated in the inhibition of wound healing, such as keratin 6a (Krt6a) and Krt16. This coincides with the presence of neutrophils displaying an altered phenotype characterized by a lower expression of surface markers Ly6C, CD11b, and Ly6G. These neutrophils exhibited very lower levels of apoptosis similarly to neutrophils present in resistant STAT6-/- mice. Interestingly, the reduced footpad swelling in DKO mice is associated with a high footpad parasite level similar to susceptible IL-12p40-/- mice. In conclusion, this study demonstrate that in the absence of both STAT6 and IL-12p40 signaling, L. major-infected mice display smaller and less ulcerated lesions, which does, however, not correlate with reduced parasite load. In addition, the presence of neutrophils with an altered phenotype is associated with reduced apoptosis and delayed immunopathologies, demonstrating the detrimental role of STAT6 in infected susceptible BALB/c mice.

Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen.

The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209+ MZ macrophages (MZMs) and the CD169+ marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-γ) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-αR1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-γ-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM- and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection.

The nonspecific face of adaptive immunity.

Memory T cells generated by infection or immunization persist in the organism and mediate specific protection upon rechallenge with microbial pathogens expressing the same molecular structures. However, multiple lines of evidence indicate that previously encountered or persisting pathogens influence the immune response to unrelated pathogens. We describe the acquisition of non-antigen specific memory features by both innate and adaptive immune cells explaining these phenomena. We also focus on the different mechanisms (homeostatic or inflammatory cytokine-driven) that lead to acquisition of memory phenotype and functions by antigen-inexperienced T lymphocytes. We discuss the implications of these new concepts for host defense, auto-immunity and vaccination strategies.

Trypanosoma Infection Favors Brucella Elimination via IL-12/IFNγ-Dependent Pathways.

This study develops an original co-infection model in mice using Brucella melitensis, the most frequent cause of human brucellosis, and Trypanosoma brucei, the agent of African trypanosomiasis. Although the immunosuppressive effects of T. brucei in natural hosts and mice models are well established, we observed that the injection of T. brucei in mice chronically infected with B. melitensis induces a drastic reduction in the number of B. melitensis in the spleen, the main reservoir of the infection. Similar results are obtained with Brucella abortus- and Brucella suis-infected mice and B. melitensis-infected mice co-infected with Trypanosoma cruzi, demonstrating that this phenomenon is not due to antigenic cross-reactivity. Comparison of co-infected wild-type and genetically deficient mice showed that Brucella elimination required functional IL-12p35/IFNγ signaling pathways and the presence of CD4+ T cells. However, the impact of wild type and an attenuated mutant of T. brucei on B. melitensis were similar, suggesting that a chronic intense inflammatory reaction is not required to eliminate B. melitensis. Finally, we also tested the impact of T. brucei infection on the course of Mycobacterium tuberculosis infection. Although T. brucei strongly increases the frequency of IFNγ+CD4+ T cells, it does not ameliorate the control of M. tuberculosis infection, suggesting that it is not controlled by the same effector mechanisms as Brucella. Thus, whereas T. brucei infections are commonly viewed as immunosuppressive and pathogenic, our data suggest that these parasites can specifically affect the immune control of Brucella infection, with benefits for the host.

Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection.

Erythritol is the preferential carbon source for most brucellae, a group of facultative intracellular bacteria that cause a worldwide zoonosis. Since this polyol is abundant in genital organs of ruminants and swine, it is widely accepted that erythritol accounts at least in part for the characteristic genital tropism of brucellae. Nevertheless, proof of erythritol availability and essentiality during Brucella intracellular multiplication has remained elusive. To investigate this relationship, we compared ΔeryH (erythritol-sensitive and thus predicted to be attenuated if erythritol is present), ΔeryA (erythritol-tolerant but showing reduced growth if erythritol is a crucial nutrient) and wild type B. abortus in various infection models. This reporting system indicated that erythritol was available but not required for B. abortus multiplication in bovine trophoblasts. However, mice and humans have been considered to lack erythritol, and we found that it was available but not required for B. abortus multiplication in human and murine trophoblastic and macrophage-like cells, and in mouse spleen and conceptus (fetus, placenta and envelopes). Using this animal model, we found that B. abortus infected cells and tissues contained aldose reductase, an enzyme that can account for the production of erythritol from pentose cycle precursors.