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The ability to sense, import, and detoxify copper (Cu) has been shown to be crucial for microbial pathogens to survive within an infected host. Previous studies conducted with the opportunistic human fungal pathogen Cryptococcus neoformans (Cn) have revealed two extreme Cu environments encountered during infection: a high Cu environment within the lung, and a low Cu environment within the brain. However, how Cn senses these different host Cu microenvironments and the consequences of a blunted Cu stress adaptation for pathogenesis are not well understood. In contrast to ascomycete model fungi, the basidiomycete Cn has a single transcription factor (TF), CnCuf1, to regulate adaptive responses to both high and low Cu stress. Sequence comparison with other fungal Cu-responsive TFs identified three conserved cysteine (Cys)-rich motifs located within the CnCuf1 N-terminal domain, which were therefore predicted to play a role in Cu sensing. Mutation of these conserved Cys-rich motifs demonstrated that the 1st Cys-rich motif is functionally relevant for CnCuf1 transcriptional activity during high Cu stress, while it is dispensable for low Cu stress adaptation. An inhalation model of murine infection showed that strains with defective high Cu stress regulation present a distinct and anatomically constrained pattern of yeast distribution within the infected lungs compared to a more widespread infection observed in lungs infected with the wild-type strain. Based on these findings, we hypothesize that Cuf1-driven high Cu responses modulate not absolute fitness, but the containment of Cn cells at the initial site of infection within the lung.IMPORTANCECopper is an essential micronutrient required for survival in all kingdoms of life, as it is used as a catalytic cofactor for many essential processes in the cell. In turn, this reactivity of copper ions makes elevated levels of free copper toxic to the cell. This dual nature of copper—essential for life but toxic at elevated levels—is used by our innate immune system in a process called nutritional immunity to combat and kill invading pathogens. In this work, we explore how the fungal human pathogen Cryptococcus neoformans senses high copper stress, a copper microenvironment encountered within the host lung. We identified a specific cysteine-rich motif within the copper-responsive transcription factor Cuf1 to be essential for high copper stress sensing. Mutation of this motif led to an impaired high copper stress adaptation, which did not affect the fitness of the yeast but did impact the containment and distribution of yeast cells inside the host lung.

, a coastal marine bacterium and opportunistic pathogen, poses increasing health risks due to rising sea water temperatures. While it harbors diverse virulence factors, its disease mechanisms remain poorly understood. To address this, we sequenced 82 environmental isolates from the Baltic Sea and combined them with 325 published genomes (clinical and environmental) for comparative analysis. Phylogenetic reconstruction revealed four major lineages, with Baltic strains restricted to L2 and L4. Clinical and environmental strains were found across all lineages, suggesting phylogeny reflects environmental adaptation more than pathogenicity. Using our newly developed PhyloBOTL pipeline, we identified 128 orthologs enriched in clinical isolates, grouped into 36 co-localization clusters. These include both known and novel virulence candidates, such as chaperone-usher pili, type VI secretion effectors, and spermidine synthases. Some clusters showed convergent loss across clades, implying niche-specific evolution. We also designed PCR primers targeting these genes to aid in the surveillance of pathogenic strains.IMPORTANCE is a naturally occurring marine bacterium that can cause life-threatening infections, with incidence increasing as coastal waters warm due to climate change. Determining which environmental strains pose the greatest risk remains a major challenge for public health surveillance. By analyzing hundreds of genomes from globally distributed strains, including extensive sampling from the rapidly warming Baltic Sea, this study shows that pathogenic potential is not restricted to specific evolutionary lineages but is instead associated with distinct sets of genes enriched in clinical strains. To support pathogen detection, we developed PCR primers targeting a subset of these clinically associated genes. Together, these findings provide new insight into the molecular basis of infections and offer practical tools for improved detection, monitoring, and risk assessment of harmful strains in coastal waters and seafood under ongoing climate change.

Bacterial pathogens coordinate the expression of metabolically expensive virulence programs during host colonization. While the impact of environmental cues on virulence has been extensively studied, direct sensing of metabolic intermediates to inform virulence expression is less understood. Competition with the resident microbiota in the case of an infection has a massive impact on the bacteria's central metabolism, which can be used as a cue for the timely expression of virulence factors. Here, we identify how fluctuations in the intracellular folate pool can affect the expression of virulence factors in the enteric pathogen enterohemorrhagic (EHEC). Using transcriptomics, mutagenesis, and ligand-binding assays, we demonstrate that the EHEC's type III secretion system, which is a syringe-like apparatus employed by multiple pathogens to infect and manipulate host cell function, is repressed when the bacteria's folate biosynthetic pathway is pharmacologically disrupted, and that this effect is mediated by two regulatory proteins: PurR and McbR. Additionally, we identify dihydrofolate as a ligand of the previously orphaned McbR transcription regulator. It is notable that folate (vitamin B9) is an essential building block for DNA synthesis, cell formation, and division throughout the tree of life. Host colonization requires enteric pathogens to tightly regulate their virulence program in response to a multitude of factors. In this work, we show that the bacterial physiological state directly informs pathogenic behavior in enterohemorrhagic (EHEC). Through the study of folate-starved bacterial cultures, we identified dihydrofolate as the endogenous ligand of the McbR transcription factor and demonstrated that McbR is directly linking one-carbon metabolism to virulence gene expression. These findings reveal how metabolites can act as regulatory signals controlling horizontally acquired pathogenicity islands.

is a prominent pathogen causing life-threatening bloodstream infections. Although biofilm formation and resistance to human serum are well-recognized virulence traits, their interrelatedness during bloodstream infections remains unclear. Here, we hypothesize that biofilm production is related to 's ability to thrive in human serum and, therefore, may predict the strains' ability for serum survival. We analyzed 57 clinical, genetically diverse classical strains and characterized their survival and biofilm-producing ability in human serum. Serum survival patterns revealed three serum resistance categories-Low, Mid, and High. In addition, the biofilm biomass produced by the strains correlated with their serum resistance level ( < 0.001), and 3D biofilm visualization using confocal microscopy further confirmed that biofilm extracellular polysaccharide substances and biomass patterns were consistent with the serum resistance categories. Moreover, we revealed a direct correlation between the level of biofilm formation and the strain's serum survival level ( = 0.696), a prerequisite for systemic dissemination. As biofilm formation in serum reflects both survival and biofilm-forming ability, we assessed biofilm formation in defined modified basal medium (BM2), to rule out serum-mediated killing, and discovered a strong and significant association between the serum resistance category and BM2 biofilm biomass ( < 0.0001). By applying regression models, we discovered that biofilm formation serves as a significant predictor for bacterial survival in serum. Overall, our findings establish biofilm production in as a biomarker of serum survival and may open a new avenue for predicting bloodstream infection risk in clinical settings.IMPORTANCEBloodstream infections caused by are devastating life-threatening infections worldwide. Understanding the survival strategies of in the bloodstream is critical for elucidating key aspects of bacterial pathogenicity and developing new diagnostic and therapeutic modalities. Although serum survival is a recognized virulence trait necessary to thrive in the bloodstream, the relationship between serum resistance and biofilm formation, a multicellular organization that may protect bacteria from bloodstream stressors, remains poorly understood. In this article, we demonstrate biofilm production in human serum by clinical classical strains for the first time and discovered a direct correlation between the level of biofilm biomass formation and the degree of serum survival in human serum and in defined modified basal medium. These findings offer insights into the importance of biofilm production in serum resistance and may be used to develop future therapeutic strategies targeting bloodstream infections.

The plasmid-borne gene poses a significant threat to global health by conferring resistance to colistin, a critical last-resort antibiotic. While its spread is well documented, the adaptations enabling its concurrent antibiotic resistance and clinical pathogenicity remain unknown. The metabolism of bacterial pathogens has evolved to support virulence in nutrient-limiting host environments. Here, we show that sorbose metabolism promotes the fitness and virulence of positive (MCRPEC), but does not affect its resistance to colistin or polymyxin B. Notably, the virulence contribution is also observed in an -negative background. Genetic disruption of sorbose catabolism (Δ ) attenuated MCRPEC virulence and fitness both and . Integrated transcriptomic and metabolomic analyses suggest that this attenuation is associated with impaired expression of two major virulence determinants. First, defective sorbose metabolism limits the supply of monosaccharide precursors required for LPS biosynthesis, leading to reduced LPS content. Second, metabolic disruption decreases intracellular cAMP levels, which downregulates expression via a cAMP-dependent signaling pathway, thereby compromising bacterial adhesion. Notably, although deletion enhances biofilm formation, this increase is insufficient to rescue the virulence defect. Restoration of the sorbose metabolic pathway partially rescues MCRPEC pathogenicity. These findings suggest that sorbose metabolism contributes to MCRPEC pathogenicity by supporting LPS synthesis and regulating expression via cAMP signaling. This study indicates a metabolic link between sorbose utilization and MCRPEC pathogenicity, raising the possibility that sorbose, a common food additive, could facilitate MCRPEC pathogenicity.IMPORTANCEThe spread of colistin-resistant ( ) limits treatment options for life-threatening infections. This study shows that sorbose metabolism, which utilizes a common dietary sugar, contributes to the fitness and virulence of such resistant bacteria without affecting their colistin resistance. Using -positive , we find that this metabolic pathway supports lipopolysaccharide synthesis and, via a cAMP-dependent mechanism, promotes bacterial adhesion. Disabling sorbose catabolism attenuates the pathogen in animal models. These findings suggest a previously unrecognized link between a specific carbohydrate metabolism and pathogenesis in drug-resistant , raising the possibility that dietary components may influence infection outcomes.

Valley Fever is a disease caused by inhalation of the spores of the fungus, Coccidioides spp. It can present like the flu, pneumonia, bone infections, or meningitis. Once inhaled, the spores change into a pathogenic form that allows the fungus to spread throughout the body and cause disease. How the spores make this transition in the body is not well understood. We investigated how immune cells affected this transition. We found that engulfment of spores by innate immune cells stimulated the transition to the pathogenic form of the fungus. We determined which fungal genes are induced during interactions with innate immune cells, potentially identifying genes that may be critical for the development of the pathogenic form. This work helps us understand how this pathogen is taking advantage of our immune system to survive and cause disease.

Streptococcus pyogenes is a major human pathogen, responsible for diverse clinical manifestations of both superficial and invasive infections, and can lead to post-infection sequelae like rheumatic heart disease, whose prevalence on a global scale rivals that of the most serious pathogens. Invasive S. pyogenes infections are currently on the rise worldwide, notably correlating with increasing pediatric cases of scarlet fever and enhancing the concern for long-term complications. There is much that remains unknown about S. pyogenes virulence and pathogenicity, and studies focused on understanding basic systems regulating virulence factors could lead to better therapeutics and translational research. We show here one such example, where a bacterial communication system regulating a virulence mechanism relevant to in vivo infection confers the ability to alter the host’s innate immune response. We find that modifications to the cell wall arise when this virulence system is activated, which has a direct role in host-pathogen interactions. Further research into this system could provide a mechanism for disruption and serve to treat S. pyogenes infection.

Mycobacterium tuberculosis ESX type VII secretion systems play important roles in pathogenesis, but the functions of ESX-5 are not well characterized because it is essential for growth in standard lab culture conditions. We used a strain that conditionally expresses a central membrane component of the ESX-5 secretion apparatus to determine how ESX-5 impacts growth in lab cultures and in a mouse infection model. We found that M. tuberculosis requires ESX-5 to grow using several carbon sources and to grow in the lungs of infected mice. Inhibiting production of the ESX-5 secretion system in mice also led to clearance of M. tuberculosis from lung tissues. Our results demonstrate that the M. tuberculosis ESX-5 system is a critical virulence factor and suggest that ESX-5 is a strong candidate for antitubercular drug development.

To gain a full understanding of how bacteria infect tissues, it is necessary to characterize both the bacteria and the tissue at the time of infection. However, this analysis is very complex because it involves obtaining infected tissue directly from patients and analyzing it with minimal processing to preserve the characteristics of the natural state of infection. In this study, we examined the gene expression profiles of replaced heart valves from patients with Staphylococcus aureus infection and compared them with pig valves experimentally infected with the same bacteria. Our findings provide a detailed insight into the changes occurring in the infected tissue and the bacterial adaptations required for multiplication and survival on the valve tissue. Notably, the strong similarity observed between human and porcine valves confirms that the porcine endocarditis model closely mirrors the human condition, making it a valuable tool for testing new therapies against this serious infection.

Host cell death plays a critical role as an intrinsic defense mechanism against infection and disease. However, many pathogens subvert cell death signaling to enhance their replication and survival. Here, we show that the mono-ADP ribosyl transferase family of toxins encoded by pathogens of global importance, including Salmonella spp., Neisseria spp. and C. difficile induces actin depolymerization leading to MAP4K activation and JNK-dependent cell death. Through mechanistically characterizing this atypical cell death pathway, our study identifies and positions key components of a previously undescribed cell death pathway and broadens our understanding of bacterial pathogenesis and virulence.