查看更多>>摘要：Abstract Malaria parasites are transmitted by mosquitoes and a substantial part of the parasite's complex life cycle takes place inside the insect. Parasite transmission starts with the uptake of parasite stages called gametocytes from the vertebrate host with the blood meal of a female vector mosquito, completing several weeks later with the injection of parasite stages called sporozoites into the vertebrate host by mosquito bite. The sporozoites form in their thousands inside ookinete‐derived oocysts situated on the abluminal side of the mosquito midgut epithelium by a process of cell division known as sporogony. After their formation, sporozoites egress from the oocyst into the haemolymph, invade the salivary glands and mature to become infective to the vertebrate. This MicroCommentary reviews recent reports describing a conserved plasma membrane‐associated protein of Plasmodium berghei, PBANKA_1422900, and its role in maintaining the shape and structural integrity of sporozoites in salivary glands and during inoculation into the vertebrate host. Combined results from three separate studies provide mechanistic insights into how this protein achieves structural maintenance of the sporozoite, and how in turn this promotes the sporozoite's ability to overcome several physical obstacles and allow it to establish infection in the vertebrate.
查看更多>>摘要：Abstract The intestine is the most densely colonized region of the body, inhabited by a diverse community of microbes. The functional significance of the intestinal microbiota is not yet fully understood, but it is known that the microbiota is implicated in numerous physiological processes of the host, such as metabolism, nutrition, the immune system, and regulation of behavior and mood. This article reviews recent findings on how bacteria of the intestinal microbiota interact with the host. Microbiota‐microbiota and microbiota‐host interactions are mediated by direct cell contact and by metabolites either produced by bacteria or produced by the host or the environment and metabolized by bacteria. Among them are short‐chain fatty, including butyrate, propionate, and acetate. Other examples include polyamines, linoleic acid metabolites, tryptophan metabolites, trimethylamine‐N‐oxide, vitamins, and secondary bile acids. These metabolites are involved in regulating the cell cycle, neurobiological signaling, cholesterol and bile acid metabolism, immune responses, and responses to antioxidants. Understanding the host‐microbiota pathways and their modulation will allow the identification of individualized therapeutic targets for many diseases. This overview helps to facilitate and promote further research in this field.
查看更多>>摘要：Abstract There has been considerable recent interest in the life cycle of Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2), the causative agent of the Covid‐19 pandemic. Practically every step in CoV replication—from cell attachment and uptake via genome replication and expression to virion assembly has been considered as a specific event that potentially could be targeted by existing or novel drugs. Interference with cellular egress of progeny viruses could also be adopted as a possible therapeutic strategy; however, the situation is complicated by the fact that there is no broad consensus on how CoVs find their way out of their host cells. The viral nucleocapsid, consisting of the genomic RNA complexed with nucleocapsid proteins obtains a membrane envelope during virus budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)–Golgi interface. From here, several alternative routes for CoV extracellular release have been proposed. Strikingly, recent studies have shown that CoV infection leads to the disassembly of the Golgi ribbon and the mobilization of host cell compartments and protein machineries that are known to promote Golgi‐independent trafficking to the cell surface. Here, we discuss the life cycle of CoVs with a special focus on different possible pathways for virus egress.
查看更多>>摘要：Abstract Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of congenital disabilities as well as a significant cause of disease in immunocompromised patients. The envelopment and egress of HCMV particles is an essential step of the viral life cycle as it determines viral spread and potentially tropism. Here we review the current literature on HCMV envelopment and egress with a particular focus on the role of virus‐containing multivesicular body‐like vesicles for virus egress and spread. We discuss the difficulties of determining the cellular provenance of these structures in light of viral redistribution of cellular marker proteins and provide potential paths to illuminate their genesis. Finally, we discuss how divergent egress pathways could result in virions of different tropisms.
Dipti SinghSmita PatriVeeda NarahariRameswara R. Segireddy...
16页
查看更多>>摘要：Abstract Plasmodium sporozoites are extracellular forms introduced during mosquito bite that selectively invade mammalian hepatocytes. Sporozoites are delimited by a cell membrane that is linked to the underlying acto‐myosin molecular motor. While membrane proteins with roles in motility and invasion have been well studied, very little is known about proteins that maintain the sporozoite shape. We demonstrate that in Plasmodium berghei (Pb) a conserved hypothetical gene, PBANKA_1422900 specifies sporozoite structural integrity maintenance protein (SIMP) required for maintaining the sporozoite shape and motility. Sporozoites lacking SIMP exhibited loss of regular shape, extensive membrane blebbing at multiple foci, and membrane detachment. The mutant sporozoites failed to infect hepatocytes, though the altered shape did not affect the organization of cytoskeleton or inner membrane complex (IMC). Interestingly, the components of IMC failed to extend under the membrane blebs likely suggesting that SIMP may assist in anchoring the membrane to IMC. Endogenous C‐terminal HA tagging localized SIMP to membrane and revealed the C‐terminus of the protein to be extracellular. Since SIMP is highly conserved among Plasmodium species, these findings have important implications for utilizing it as a novel sporozoite‐specific vaccine candidate.
Richard J. LamontAruna VashishtaMax N. RogersIrina Miralda...
12页
查看更多>>摘要：Abstract Periodontitis is a chronic inflammatory infectious disease that affects the integrity of tooth‐supporting tissues and has adverse systemic consequences. Advances in sequencing technologies have uncovered organisms that are exclusively found in high numbers in periodontal lesions, such as the gram‐positive anaerobic rod, Filifactor alocis. F. alocis can manipulate neutrophil effector functions, which allows the organism to survive within these granulocytes. Several neutrophil functions have been tested in the context of F. alocis challenge, but the effect of the organism on neutrophil apoptosis is still unknown. RNA sequencing of human neutrophils challenged with F. alocis showed that apoptosis pathways were differentially regulated. Compared to media‐cultured controls, F. alocis‐challenged neutrophils maintain their nuclear morphology, do not stain for Annexin V or 7‐AAD, and have decreased DNA fragmentation. Inhibition of apoptosis by F. alocis involved reduced caspase‐3, ?8, and???9 activation and upregulation of important anti‐apoptotic proteins. Prolonged lifespan was dependent on contact through TLR2/6, and F. alocis‐challenged neutrophils retained their functional capacity to induce inflammation for longer timepoints. This is the first in‐depth characterization of neutrophil apoptotic programs in response to an oral pathogen and provides key information on how bacteria manipulate immune cell mechanisms to maintain a dysregulated inflammatory response.
Albertina ScattoliniAntonela LavatelliPaola VacchinaDaniel A. Lambruschi...
14页
查看更多>>摘要：Abstract Lipoic acid (LA) is a sulfur‐containing cofactor covalently attached to key enzymes of central metabolism in prokaryotes and eukaryotes. LA can be acquired by scavenging, mediated by a lipoate ligase, or de novo synthesized by a pathway requiring an octanoyltransferase and a lipoate synthase. A more complex pathway, referred to as “lipoyl‐relay”, requires two additional proteins, GcvH, the glycine cleavage system H subunit, and an amidotransferase. This route was described so far in Bacillus subtilis and related Gram‐positive bacteria, Saccharomyces cerevisiae, Homo sapiens, and Caenorhabditis elegans. Using collections of S. cerevisiae and B. subtilis mutants, defective in LA metabolism, we gathered evidence that allows us to propose for the first time that lipoyl‐relay pathways are also present in parasitic protozoa. By a reverse genetic approach, we assigned octanoyltransferase and amidotransferase activity to the products of Tb927.11.9390 (TblipT) and Tb927.8.630 (TblipL) genes of Trypanosoma brucei, respectively. The B. subtilis model allowed us to identify the parasite amidotransferase as the target of lipoate analogs like 8‐bromo‐octanoic acid, explaining the complete loss of protein lipoylation and growth impairment caused by this compound in T. cruzi. This model could be instrumental for the screening of selective and more efficient chemotherapies against trypanosomiases.
查看更多>>摘要：Abstract Conjugative elements are widespread in bacteria and include plasmids and integrative and conjugative elements (ICEs). They transfer from donor to recipient cells via an element‐encoded type IV secretion system. These elements interact with and utilize host functions for their lifecycles. We sought to identify essential host genes involved in the lifecycle of the integrative and conjugative element ICEBs1 of Bacillus subtilis. We constructed a library of strains for inducible knockdown of essential B. subtilis genes using CRISPR interference. Each strain expressed one guide RNA in ICEBs1. We induced partial interference of essential genes and identified those that caused an acute defect in acquisition of ICEBs1 by recipient cells. This screen revealed that reducing expression of genes needed for synthesis of cell wall teichoic acids caused a decrease in conjugation. Using three different ways to reduce their synthesis, we found that wall teichoic acids were necessary in both donors and recipients for efficient conjugative transfer of ICEBs1. Further, we found that depletion of wall teichoic acids caused cells involved in ICEBs1 conjugation to die, most likely from damage to the cell envelope. Our results indicate that wall teichoic acids help protect against envelope stress caused by active conjugation machines.
查看更多>>摘要：Abstract Bacterial opportunistic pathogens make diverse secondary metabolites both in the natural environment and when causing infections, yet how these molecules mediate microbial interactions and their consequences for antibiotic treatment are still poorly understood. Here, we explore the role of three redox‐active secondary metabolites, pyocyanin, phenazine‐1‐carboxylic acid, and toxoflavin, as interspecies modulators of antibiotic resilience. We find that these molecules dramatically change susceptibility levels of diverse bacteria to clinical antibiotics. Pyocyanin and phenazine‐1‐carboxylic acid are made by Pseudomonas aeruginosa, while toxoflavin is made by Burkholderia gladioli, organisms that infect cystic fibrosis and other immunocompromised patients. All molecules alter the susceptibility profile of pathogenic species within the “Burkholderia cepacia complex” to different antibiotics, either antagonizing or potentiating their effects, depending on the drug’s class. Defense responses regulated by the redox‐sensitive transcription factor SoxR potentiate the antagonistic effects these metabolites have against fluoroquinolones, and the presence of genes encoding SoxR and the efflux systems it regulates can be used to predict how these metabolites will affect antibiotic susceptibility of different bacteria. Finally, we demonstrate that inclusion of secondary metabolites in standard protocols used to assess antibiotic resistance can dramatically alter the results, motivating the development of new tests for more accurate clinical assessment.
NSTL
Wiley