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1.
FEMS Microbiol Rev ; 48(3)2024 May 08.
Article in English | MEDLINE | ID: mdl-38734892

ABSTRACT

Bloodstream infection is a major public health concern associated with high mortality and high healthcare costs worldwide. Bacteremia can trigger fatal sepsis whose prevention, diagnosis, and management have been recognized as a global health priority by the World Health Organization. Additionally, infection control is increasingly threatened by antimicrobial resistance, which is the focus of global action plans in the framework of a One Health response. In-depth knowledge of the infection process is needed to develop efficient preventive and therapeutic measures. The pathogenesis of bloodstream infection is a dynamic process resulting from the invasion of the vascular system by bacteria, which finely regulate their metabolic pathways and virulence factors to overcome the blood immune defenses and proliferate. In this review, we highlight our current understanding of determinants of bacterial survival and proliferation in the bloodstream and discuss their interactions with the molecular and cellular components of blood.


Subject(s)
Bacteria , Humans , Bacteremia/microbiology , Virulence Factors , Blood/microbiology , Microbial Viability
2.
Nat Commun ; 12(1): 4547, 2021 07 27.
Article in English | MEDLINE | ID: mdl-34315900

ABSTRACT

The human pathogen Neisseria meningitidis can cause meningitis and fatal systemic disease. The bacteria colonize blood vessels and rapidly cause vascular damage, despite a neutrophil-rich inflammatory infiltrate. Here, we use a humanized mouse model to show that vascular colonization leads to the recruitment of neutrophils, which partially reduce bacterial burden and vascular damage. This partial effect is due to the ability of bacteria to colonize capillaries, venules and arterioles, as observed in human samples. In venules, potent neutrophil recruitment allows efficient bacterial phagocytosis. In contrast, in infected capillaries and arterioles, adhesion molecules such as E-Selectin are not expressed on the endothelium, and intravascular neutrophil recruitment is minimal. Our results indicate that the colonization of capillaries and arterioles by N. meningitidis creates an intravascular niche that precludes the action of neutrophils, resulting in immune escape and progression of the infection.


Subject(s)
Arterioles/microbiology , Dermis/blood supply , Neisseria meningitidis/growth & development , Neutrophils/microbiology , Adult , Animals , Arterioles/pathology , Bacterial Adhesion , Capillaries/microbiology , Capillaries/pathology , Cell Adhesion Molecules/metabolism , Colony Count, Microbial , E-Selectin/metabolism , Endothelium, Vascular/microbiology , Endothelium, Vascular/pathology , Female , Fimbriae, Bacterial/metabolism , Heterografts , Humans , Inflammation/pathology , Male , Meningococcal Infections/microbiology , Meningococcal Infections/pathology , Mice, SCID , Middle Aged , Neutrophil Infiltration , Phagocytosis , Time Factors , Up-Regulation , Young Adult
3.
Infect Immun ; 88(4)2020 03 23.
Article in English | MEDLINE | ID: mdl-32014893

ABSTRACT

Oral administration is a preferred model for studying infection by bacterial enteropathogens such as Yersinia spp. In the mouse model, the most frequent method for oral infection consists of oral gavage with a feeding needle directly introduced in the animal stomach via the esophagus. In this study, we compared needle gavage to bread feeding as an alternative mode of bacterial administration. Using bioluminescence-expressing strains of Yersinia pseudotuberculosis and Yersinia enterocolitica, we detected very early upon needle gavage a bioluminescent signal in the neck area together with a signal in the abdominal region, highlighting the presence of two independent sites of bacterial colonization and multiplication. Bacteria were often detected in the esophagus and trachea, as well as in the lymph nodes draining the salivary glands, suggesting that lesions made during needle introduction into the animal oral cavity lead to rapid bacterial draining to proximal lymph nodes. We then tested an alternative mode of bacterial administration using pieces of bread containing bacteria. Upon bread feeding infection, mice exhibited a stronger bioluminescent signal in the abdominal region than with needle gavage, and no signal was detected in the neck area. Moreover, Y. pseudotuberculosis incorporated in the bread is less susceptible to the acidic environment of the stomach and is therefore more efficient in causing intestinal infections. Based on our observations, bread feeding constitutes a natural and more efficient administration method which does not require specialized skills, is less traumatic for the animal, and results in diseases that more closely mimic foodborne intestinal infection.


Subject(s)
Animal Feed , Bread , Disease Models, Animal , Feeding Methods , Gastrointestinal Diseases/microbiology , Yersinia Infections/microbiology , Yersinia enterocolitica/growth & development , Yersinia pseudotuberculosis/growth & development , Administration, Oral , Animals , Mice
4.
Infect Immun ; 79(11): 4308-21, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21844231

ABSTRACT

Neisseria meningitidis NhhA (Neisseria hia/hsf homologue A) is an oligomeric outer membrane protein belonging to the family of trimeric autotransporter adhesins. NhhA mediates the interaction of N. meningitidis with human epithelial cells and components of the extracellular matrix. The recombinant protein is able to induce bactericidal antibodies and hence has also been considered a potential vaccine candidate. In this study, we analyzed the production of NhhA in a large panel of N. meningitidis strains belonging to different serogroups and clonal complexes. We found that trimeric NhhA was produced at different levels by the various strains tested. In some strains belonging to the clonal complex ST41/44, the protein is detectable only as a monomer. Sequencing of the nhhA gene and generation of complementing strains in different genetic backgrounds have proved that a single mutation (Gly to Asp) in the translocator domain affected both trimerization and surface localization of NhhA. In vitro infection assays showed that this mutation impairs meningococcal NhhA-mediated adhesion, suggesting that strains carrying the mutation may rely on different strategies or molecules to mediate interaction with host cells. Finally, we demonstrated that N. meningitidis ST41/44 strains producing the mutated form did not induce killing mediated by NhhA-specific bactericidal antibodies. Our data help to elucidate the secretion mechanisms of trimeric autotransporters and to understand the contribution of NhhA in the evolutionary process of host-Neisseria interactions. Also, they might have important implications for the evaluation of NhhA as a vaccine candidate.


Subject(s)
Adhesins, Bacterial/metabolism , Amino Acid Substitution , Bacterial Adhesion/physiology , Neisseria meningitidis/metabolism , Adhesins, Bacterial/genetics , Amino Acid Sequence , Bacterial Adhesion/genetics , Cell Line , Humans , Models, Molecular , Molecular Sequence Data , Mutation , Neisseria meningitidis/genetics , Protein Conformation , Protein Structure, Tertiary , Protein Transport
5.
PLoS Pathog ; 7(5): e1002027, 2011 May.
Article in English | MEDLINE | ID: mdl-21589640

ABSTRACT

During infection Neisseria meningitidis (Nm) encounters multiple environments within the host, which makes rapid adaptation a crucial factor for meningococcal survival. Despite the importance of invasion into the bloodstream in the meningococcal disease process, little is known about how Nm adapts to permit survival and growth in blood. To address this, we performed a time-course transcriptome analysis using an ex vivo model of human whole blood infection. We observed that Nm alters the expression of ≈30% of ORFs of the genome and major dynamic changes were observed in the expression of transcriptional regulators, transport and binding proteins, energy metabolism, and surface-exposed virulence factors. In particular, we found that the gene encoding the regulator Fur, as well as all genes encoding iron uptake systems, were significantly up-regulated. Analysis of regulated genes encoding for surface-exposed proteins involved in Nm pathogenesis allowed us to better understand mechanisms used to circumvent host defenses. During blood infection, Nm activates genes encoding for the factor H binding proteins, fHbp and NspA, genes encoding for detoxifying enzymes such as SodC, Kat and AniA, as well as several less characterized surface-exposed proteins that might have a role in blood survival. Through mutagenesis studies of a subset of up-regulated genes we were able to identify new proteins important for survival in human blood and also to identify additional roles of previously known virulence factors in aiding survival in blood. Nm mutant strains lacking the genes encoding the hypothetical protein NMB1483 and the surface-exposed proteins NalP, Mip and NspA, the Fur regulator, the transferrin binding protein TbpB, and the L-lactate permease LctP were sensitive to killing by human blood. This increased knowledge of how Nm responds to adaptation in blood could also be helpful to develop diagnostic and therapeutic strategies to control the devastating disease cause by this microorganism.


Subject(s)
Bacteremia/microbiology , Meningococcal Infections/microbiology , Neisseria meningitidis, Serogroup B/physiology , Transcriptome , Virulence Factors/genetics , Adaptation, Physiological , Adult , Antigens, Bacterial/genetics , Bacteremia/blood , Bacterial Proteins/genetics , Cluster Analysis , Down-Regulation/genetics , Female , Gene Expression Regulation, Bacterial/genetics , Genes, Bacterial/genetics , Genome, Bacterial/genetics , Host-Pathogen Interactions/genetics , Humans , Male , Meningococcal Infections/blood , Models, Biological , Neisseria meningitidis, Serogroup B/genetics , Neisseria meningitidis, Serogroup B/growth & development , Neisseria meningitidis, Serogroup B/pathogenicity , RNA, Bacterial/genetics , Sequence Deletion , Up-Regulation/genetics
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