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Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45 + lineage – CD90.2 + NK1.1 – NKp46 – ST2 – KLRG1 + IL-17RB + memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7 . ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence. TCF1 and TOX have been shown to be important in T memory cell formation. Here the authors show that TCF1 and TOX contribute to the regulation and persistence of memory-like ILC2 cells in mouse asthma models and persons with asthma.

The relative contributions of mutation rate variation, selection, and recombination in shaping genomic variation in bacterial populations remain poorly understood. Here we analyze 3318 Yersinia pestis genomes, spanning nearly a century and including 2336 newly sequenced strains, to shed light on the patterns of genetic diversity and variation distribution at the population level. We identify 45 genomic regions (“hot regions”, HRs) that, although comprising a minor fraction of the genome, are hotbeds of genetic variation. These HRs are distributed non-randomly across Y. pestis phylogenetic lineages and are primarily linked to regulatory genes, underscoring their potential functional significance. We explore various factors contributing to the shaping and maintenance of HRs, including genomic context, homologous recombination, mutation rate variation and natural selection. Our findings suggest that positive selection is likely the primary driver behind the emergence of HRs, but not the sole force, as evidenced by the pronounced trend of variation purging within these regions. The relative contributions of mutation rate variation, selection, and recombination in shaping genomic variation in bacterial populations remain poorly understood. Here, the authors analyze over 3,300 Yersinia pestis genomes, spanning nearly a century, to shed light on the patterns of genetic diversity and variation distribution at the population level.

Toxin-antitoxin (TA) modules enable bacteria to persist under stressful environments. However, they are typically absent from host-associated prokaryotes due to their potential host toxicity. Here, the obligate intracellular bacterium spotted fever group (SFG) rickettsiae, which causes mild to severe human illness, was shown to harbor two vapBC TA modules. One of the vapBC modules ( vapBC 1) is crucial for Rickettsia to withstand accumulated host reactive oxidative species (ROS), via induction of bacterial dormancy through cleavage on the anti-codon loop of tRNA fMet , thereby facilitating intracellular survival and infection in a mouse model. Another vapBC module ( vapBC 2) was found to be activated and toxin exposed to host cytoplasm, contributing to Rickettsia ’s virulence and adaptability in its human host by non-specifically degrading host rRNAs rather than regulating rickettsial growth. Recognition of these rickettsial effectors contributes to understanding the intracellular adaptability and pathogenicity of all host-associated pathogens that harbor TA modules.

Post-translational addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins is commonly associated with a variety of stress responses and cellular processes in eukaryotes, but its potential roles in bacteria are unclear. Here, we show that protein HmwC acts as an O-GlcNAc transferase (OGT) responsible for O-GlcNAcylation of multiple proteins in Yersinia pestis , a flea-borne pathogen responsible for plague. We identify 64 O-GlcNAcylated proteins (comprising 65 sites) with differential abundance under conditions mimicking the mammalian host (Mh) and flea vector (Fv) environments. Deletion of hmwC , encoding a putative OGT, structurally distinct from any existing member of the GT41 family, results in reduced O-GlcNAcylation, reduced growth, and alterations in virulence properties and survival under stress. Purified HmwC can modify target proteins in vitro using UDP-GlcNAc as sugar donor. One of the target proteins, OsdY, promotes Y. pestis survival under oxidative stress conditions. Thus, our results support that regulation of antioxidative responses through O-GlcNAcylation may be a conserved process shared by prokaryotes and eukaryotes. Post-translational addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins is associated with stress responses in eukaryotes. Here, the authors identify a protein that acts as an O-GlcNAc transferase for modification of multiple proteins and regulates antioxidative stress responses in the bacterial pathogen Yersinia pestis .

Albeit fluticasone propionate suspension is effective in treating variant cough in children, there is limited research on the use of Xuanfei Zhisou mixture, and even fewer studies on its combination application. This study aimed to estimate the role of Xuanfei Zhisou mixture (XZM) plus fluticasone propionate suspension (FPS) in the treatment of cough variant in children. 122 children with variant cough from March 2020 to May 2023 were classified into observation therapy (XZM + FPS, = 60) and control therapy (FPS, = 60) using block randomization. The clinical effect, inflammatory factor, pulmonary function, peripheral eosinophil count, daytime and nighttime cough scores, immune function and untoward reactions were contrasted in two groups. The clinical effect, Forced Vital Capacity (FVC), FEV1 (Forced Expiratory Volume)/FVC, CD , CD as well as CD /CD of the observation therapy were higher than control therapy. After treatment, interleukin-4 (IL-4), tumor necrosis factor-α (TNF-α), serum amyloid A (SAA), c-reactive protein (CRP), eosinophil count as well as daytime and nighttime cough scores in observation therapy were lower than control therapy. Howbeit, there was no diversity in untoward reactions between the two groups. Xuanfei Zhisou mixture plus FPS had conspicuous role in children with variant cough, which assisted in diminishing cough symptoms, raising pulmonary function, reduce inflammatory factor level and upgrading immune function of children.

We recently identified two virulence-associated small open reading frames (sORF) of Yersinia pestis , named yp1 and yp2 , and null mutants of each individual genes were highly attenuated in virulence. Plague vaccine strain EV76 is known for strong reactogenicity, making it not suitable for use in humans. To improve the immune safety of EV76, three mutant strains of EV76, Δ yp1 , Δ yp2 , and Δ yp1&yp2 were constructed and their virulence attenuation, immunogenicity, and protective efficacy in mice were evaluated. All mutant strains were attenuated by the subcutaneous ( s . c .) route and exhibited more rapid clearance in tissues than the parental strain EV76. Under iron overload conditions, only the mice infected with EV76Δ yp1 survived, accompanied by less draining lymph nodes damage than those infected by EV76. Analysis of cytokines secreted by splenocytes of immunized mice found that EV76Δ yp2 induced higher secretion of multiple cytokines including TNF-α, IL-2, and IL-12p70 than EV76. On day 42, EV76Δ yp2 or EV76Δ yp1&yp2 immunized mice exhibited similar protective efficacy as EV76 when exposed to Y . pestis 201, both via s . c . or intranasal ( i . n .) routes of administration. Moreover, when exposed to 200–400 LD 50 Y . pestis strain 201Δ caf1 (non-encapsulated Y . pestis ), EV76Δ yp2 or EV76Δ yp1&yp2 are able to afford about 50% protection to i . n . challenges, significantly better than the protection afforded by EV76. On 120 day, mice immunized with EV76Δ yp2 or EV76Δ yp1&yp2 cleared the i . n . challenge of Y . pestis 201- lux as quickly as those immunized with EV76, demonstrating 90–100% protection. Our results demonstrated that deletion of the yp2 gene is an effective strategy to attenuate virulence of Y . pestis EV76 while improving immunogenicity. Furthermore, EV76Δ yp2 is a promising candidate for conferring protection against the pneumonic and bubonic forms of plague.

Chlamydia are Gram-negative, obligate intracellular bacterial pathogens that infect eukaryotic cells and reside within a host-derived vacuole known as the inclusion. To facilitate intracellular replication, these bacteria must engage in host-pathogen interactions to obtain nutrients and membranes required for the growth of the inclusion, thereby sustaining prolonged bacterial colonization. Autophagy is a highly conserved process that delivers cytoplasmic substrates to the lysosome for degradation. Pathogens have developed strategies to manipulate and/or exploit autophagy to promote their replication and persistence. This review delineates recent advances in elucidating the interplay between Chlamydia trachomatis infection and autophagy in recent years, emphasizing the intricate strategies employed by both the Chlamydia pathogens and host cells. Gaining a deeper understanding of these interactions could unveil novel strategies for the prevention and treatment of Chlamydia infection.

The emergence of Y. pestis as a highly lethal pathogen is driven by extensive gene pseudogenization and acquisition of exogenous plasmids pPCP1 and pMT1. However, the interplay between these two plasmids during evolution remains largely unexplored. Our study reveals intricate interactions between Ymt and Pla, two crucial virulence determinants encoded on these plasmids. Pla-mediated cleavage of Ymt significantly decreases Y. pestis survival in mouse blood and enhances its virulence in mice. The prevalent Pla-I259T variant in modern strains displays reduced Ymt cleavage, thereby extending the survival of infected animals and potentially increasing strain transmissibility. Our findings shed light on the nuanced evolution of Y. pestis , wherein reduced cleavage efficiency is a positive selection force, shaping the pathogen's natural trajectory.

Plague has caused three worldwide pandemics in history, including the Black Death in medieval ages. Yersinia pestis , the etiological agent of plague, has evolved a powerful arsenal to disrupt host immune defenses during evolution from enteropathogenic Y. pseudotuberculosis . Here, we find that two functionally redundant E3 ligase of Y. pestis , YspE1 and YspE2, can be delivered via type III secretion injectisome into host cytosol where they ubiquitinate multiple guanylate-binding proteins (GBPs) for proteasomal degradation. However, Y. pseudotuberculosis has no such capability due to lacking functional YspE1/2 homologs. YspE1/2-mediated GBP degradations significantly promote the survival of Y. pestis in macrophages and strongly inhibit inflammasome activation. By contrast, Gbp chr3−/−, chr5−/− macrophages exhibit much lowered inflammasome activation independent of YspE1/2, accompanied with an enhanced replication of Y. pestis . Accordingly, Gbp chr3−/−, chr5−/− mice are more susceptible to Y. pestis . We demonstrate that Y. pestis utilizes E3 ligases to subvert GBP-mediated host defense, which appears to be newly acquired by Y. pestis during evolution. Guanylate-binding proteins (GBPs) recognize pathogen containing vacuoles, leading to lysis of this intracellular niche and induction of inflammasomes. Here, Cao et al. show that Y. pestis , the causative agent of plague, secret two functionally redundant E3 ligase, YspE1 and YspE2, into the host’s cytosol to ubiquitinate multiple GBPs for proteasomal degradation to subvert host immune defense. This capability appears to be newly acquired by Y. pestis during evolution, since its closely related progenitor Y. pseudotuberculosis is unable to do so.

Yersinia pestis is transmitted from fleas to rodents when the bacterium develops an extensive biofilm in the foregut of a flea, starving it into a feeding frenzy, or, alternatively, during a brief period directly after feeding on a bacteremic host. These two transmission modes are in a trade-off regulated by the amount of biofilm produced by the bacterium. Here by investigating 446 global isolated Y. pestis genomes, including 78 newly sequenced isolates sampled over 40 years from a plague focus in China, we provide evidence for strong selection pressures on the RNA polymerase ω-subunit encoding gene rpoZ . We demonstrate that rpoZ variants have an increased rate of biofilm production in vitro, and that they evolve in the ecosystem during colder and drier periods. Our results support the notion that the bacterium is constantly adapting—through extended phenotype changes in the fleas—in response to climate-driven changes in the niche. Yersinia pestis , the causative agent of plague, can change its biofilm production to influence the dynamics of flea-borne transmission. Here, the authors sequence Y. pestis isolates sampled over 40 years in China and show evidence for climate-associated selection on rpoZ to increase biofilm production.