The Rickettsia actin-based motility effectors RickA and Sca2 contribute differently to cell-to-cell spread and pathogenicity

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Rickettsia parkeri is an obligate intracellular, tick-borne bacterial pathogen that can cause eschar-associated rickettsiosis in humans. R. invades host cells, escapes from vacuoles into the cytosol, and undergoes two independent modes of actin-based motility mediated by effectors RickA or Sca2. Actin-based enables bacteria to enter protrusions cell plasma membrane are engulfed neighboring cells. However, whether how Sca2 independently contribute cell-to-cell spread vitro pathogenicity vivo has been unclear. Using live imaging rickA::Tn sca2::Tn mutants, we discovered both different spread. Compared with Sca2-spread, RickA-spread involves formation longer exhibit larger fluctuations length take a time be We further compared roles following intradermal (i.d.) infection Ifnar1-/-; Ifngr1-/- mice carrying knockout mutations genes encoding receptors for IFN-I (Ifnar1) IFN-γ (Ifngr1), which eschars succumb wild-type (WT) parkeri. observed important severe eschar formation, whereas contributes foci skin dissemination internal organs. Our results suggest drive distinct forms differently mammalian host.IMPORTANCERickettsia parkeri, bacterium spotted fever group species, transmitted ticks humans, leading symptoms including fever, rash, muscle aches, lesion at site tick bite. During infection, invade cells within animal host, proliferate cell's move using process called motility, unusual having proteins mediate motility. The significance our research reveal each these between signs mouse model disease. understanding contribution as well other viral pathogens require this

Language: Английский

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Beyond antibiotics: exploring multifaceted approaches to combat bacterial resistance in the modern era: a comprehensive review

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: March 18, 2025

Antibiotics represent one of the most significant medical breakthroughs twentieth century, playing a critical role in combating bacterial infections. However, rapid emergence antibiotic resistance has become major global health crisis, significantly complicating treatment protocols. This paper provides narrative review current state resistance, synthesizing findings from primary research and comprehensive articles to examine various mechanisms bacteria employ counteract antibiotics. One sources is improper use antibiotics livestock industry. The drug-resistant microorganisms human activities industrial production presented environmental public concerns. Today, resistant nosocomial infections occur following long-term hospitalization patients, causing death many people, so there an urgent need for alternative treatments. In response this non-antibiotic therapeutic strategies have been proposed, including bacteriophages, probiotics, postbiotics, synbiotics, fecal microbiota transplantation (FMT), nanoparticles (NPs), antimicrobial peptides (AMPs), antibodies, traditional medicines, toxin-antitoxin (TA) system. While these approaches offer innovative solutions addressing preserving efficacy therapies, challenges such as safety, cost-effectiveness, regulatory hurdles, large-scale implementation remain. examines potential limitations strategies, offering balanced perspective on their managing mitigating broader impact resistance.

Language: Английский

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The cell division protein FzlA performs a conserved function in diverse alphaproteobacteria

Journal of Bacteriology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

ABSTRACT In almost all bacteria, the tubulin-like GTPase FtsZ polymerizes to form a “Z-ring” that marks site of division. recruits other proteins, collectively known as divisome, together remodel and constrict envelope. Constriction is driven by peptidoglycan (PG) cell wall synthesis glycosyltransferase FtsW transpeptidase FtsI (FtsWI), but these enzymes require activation function. How recruitment division leads FtsWI constriction remains largely unknown. Previous work in our laboratory demonstrated an FtsZ-binding protein, FzlA, essential for alphaproteobacterium Caulobacter crescentus . Additionally, we found FzlA binds DNA translocase called FtsK, suggesting it may link chromosome segregation. conserved throughout Alphaproteobacteria has only been examined detail C. Here, explored whether function diverse Alphaproteobacteria. We assessed homologs from Rickettsia parkeri Agrobacterium tumefaciens , that, similar they bind directly localize midcell. The FtsZ-FzlA interaction interface conserved, each three species can any vitro Finally, determined A. fulfill when produced indicating conservation These results suggest serves important regulator coordinates segregation with envelope across IMPORTANCE Cell bacterial replication must be highly regulated ensure robust remodeling coordination genome daughter cells. plays major role regulating this process activating manner couples broadly Alphaproteobacteria, class bacteria. have shown indeed, biochemical interactions are Because Alphaproteobacterial human pathogens, understanding protein its interactome could present therapeutic benefits identifying potential antibiotic targets treat infections.

Language: Английский

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The Rickettsia actin-based motility effectors RickA and Sca2 contribute differently to cell-to-cell spread and pathogenicity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 20, 2024

Abstract Rickettsia parkeri is an obligate intracellular, tick-borne bacterial pathogen that can cause eschar-associated rickettsiosis in humans. R. invades host cells, escapes from vacuoles into the cytosol, and undergoes two independent modes of actin-based motility mediated by effectors RickA or Sca2. Actin-based enables bacteria to enter protrusions cell plasma membrane are engulfed neighboring cells. However, whether how Sca2 independently contribute cell-to-cell spread vitro pathogenicity vivo has been unclear. Using live imaging rickA ::Tn sca2 mutants, we discovered both different spread. Compared with Sca2-spread, RickA-spread involves formation longer exhibit larger fluctuations length take a time be We further compared roles following intradermal infection Ifnar1 -/- ; Ifngr1 double-knockout mice, which eschars succumb wild-type . observed important for severe eschar formation, whereas contributes foci skin dissemination internal organs. Our results suggest drive distinct forms differently mammalian host.

Language: Английский

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Identification of common sequence motifs shared exclusively among selectively packed exosomal pathogenic microRNAs during rickettsial infections

Journal of Cellular Physiology, Journal Year: 2023, Volume and Issue: 238(8), P. 1937 - 1948

Published: June 19, 2023

Abstract We previously reported that microRNA (miR)23a and miR30b are selectively sorted into exosomes derived from rickettsia‐infected endothelial cells ( R ‐ECExos). Yet, the mechanism remains unknown. Cases of spotted fever rickettsioses have been increasing, infections with these bacteria cause life‐threatening diseases by targeting brain lung tissues. Therefore, goal present study is to further dissect molecular underlying ‐ECExos‐induced barrier dysfunction normal recipient microvascular (MECs), depending on their exosomal RNA cargos. Infected ticks transmit rickettsiae human hosts following a bite injections skin. In study, we demonstrate treatment ‐ECExos, which were group parkeri infected dermal MECs, induced disruptions paracellular adherens junctional protein VE‐cadherin, breached function in pulmonary MECs (PMECs) an RNA‐dependent manner. did not detect different levels miRs parent rickettsial infections. However, demonstrated microvasculopathy‐relevant miR23a‐27a‐24 cluster enriched ‐ECExos. Bioinformatic analysis revealed common sequence motifs shared exclusively among exosomal, selectively‐enriched miR23a at levels. Taken together, data warrant functional identification characterization monopartition, bipartition, or tripartition ACA, UCA, CAG guide recognition miR30b, subsequently results selective enrichments

Language: Английский

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Rodents as Key Hosts of Zoonotic Pathogens and Parasites in the Neotropics

Springer eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 143 - 184

Published: Jan. 1, 2024

Language: Английский

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The Cell Division Protein FzlA Performs a Conserved Function in Diverse Alphaproteobacteria

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 29, 2024

Abstract In almost all bacteria, the tubulin-like GTPase FtsZ polymerizes to form a “Z-ring” that marks site of division. recruits other proteins, collectively known as divisome, together remodel and constrict envelope. Constriction is driven by peptidoglycan (PG) cell wall synthesis glycosyltransferase FtsW transpeptidase FtsI (FtsWI), but these enzymes require activation function. How recruitment division leads FtsWI constriction remains largely unknown. Previous work in our laboratory demonstrated an FtsZ-binding protein, FzlA, essential for alphaproteobacterium Caulobacter crescentus . Additionally, we found FzlA also binds DNA translocase called FtsK, suggesting it may link chromosome segregation. conserved throughout alphaproteobacteria has only been examined detail C. Here, explored whether function diverse alphaproteobacteria. We assessed homologs from Rickettsia parkeri Agrobacterium tumefaciens , that, similar they bind directly localize midcell. The FtsZ-FzlA interaction interface conserved, each three species can any vitro determined A. fulfill when produced indicating conservation These results suggest serves important regulator coordinates segregation with envelope across Importance Cell bacterial replication must be highly regulated ensure robust remodeling coordination genome daughter cells. plays major role regulating this process activating manner couples broadly class bacteria. Here have shown indeed, biochemical interactions are Because alphaproteobacterial human pathogens, understanding protein its interactome could present therapeutic benefits identifying potential antibiotic targets treat infections.

Language: Английский

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Identification of common sequence motifs shared exclusively among selectively packed exosomal pathogenic microRNAs during rickettsial infections

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 7, 2023

We previously reported that microRNA (miR)23a and miR30b are selectively sorted into rickettsia-infected, endothelial cell-derived exosomes ( R -ECExos). Yet, the mechanism remains unknown. The number of cases spotted fever rickettsioses has been increasing in recent years, infections with these bacteria cause life-threatening diseases by targeting brain lung tissues. Therefore, aim present study is to continue dissect molecular underlying -ECExos-induced barrier dysfunction normal recipient microvascular cells (MECs), depending on their exosomal RNA cargos. Rickettsiae transmitted human hosts bite an infected tick skin. In we demonstrate treatment -ECExos, which were derived from group parkeri dermal MECs, induced disruptions paracellular adherens junctional protein VE-cadherin breached function pulmonary MECs (PMECs) RNA-dependent manner. Similarly, did not detect different levels miRs parent following rickettsial infections. However, demonstrated microvasculopathy-relevant miR23a-27a-24 cluster enriched -ECExos. Bioinformatic analysis revealed common sequence motifs shared exclusively among exosomal, selectively-enriched miR23a at levels. Taken together, data warrant further functional identification characterization a single, bipartition, or tripartition ACA, UCA, CAG guide recognition miR30b, subsequently results selective enrichments

Language: Английский

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