Phage-Bacterial Interaction Alters Phenotypes Associated with Virulence in Acinetobacter baumannii.

Bacteriophages exert strong selection on their bacterial hosts to evolve resistance. At the same time, the fitness costs on bacteria following phage resistance may change their virulence, which may affect the therapeutic outcomes of phage therapy. In this study, we set out to assess the costs of phage resistance on the in vitro virulence of priority 1 nosocomial pathogenic bacterium, Acinetobacter baumannii. By subjecting phage-resistant variant Ev5-WHG of A. baumannii WHG40004 to several in vitro virulence profiles, we found that its resistance to phage is associated with reduced fitness in host microenvironments. Also, the mutant exhibited impaired adhesion and invasion to mammalian cells, as well as increased susceptibility to macrophage phagocytosis. Furthermore, the whole-genome sequencing of the mutant revealed that there exist multiple mutations which may play a role in phage resistance and altered virulence. Altogether, this study demonstrates that resistance to phage can significantly alter phenotypes associated with virulence in Acinetobacter baumannii.

Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.

The cyclic-oligonucleotide-based anti-phage signalling system (CBASS) is a type of innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS uses cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homologue of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, using biochemical, genetic, cryo-electron microscopy and mass spectrometry investigations, we discover that the E2 enzyme from Serratia marcescens regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.

Regulating Protein-RNA Interactions: Advances in Targeting the LIN28/Let-7 Pathway.

Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding.

Understanding key vectors and vector-borne diseases associated with freshwater ecosystem across Africa: Implications for public health.

The emerging and re-emerging vector-borne diseases transmitted by key freshwater organisms have remained a global concern. As one of the leading biodiversity hotspots, the African ecoregion is suggested to harbour the highest number of freshwater organisms globally. Among the commonly found organisms in the African ecoregion are mosquitoes and snails, with a majority of their life cycle in freshwater, and these freshwater organisms can transmit diseases or serve as carriers of devastating diseases of public health concerns. However, synthetic studies to link the evident abundant presence and wide distribution of these vectors across the freshwater ecosystems in Africa with the increasing emerging and re-emerging vector-borne diseases in Africa are still limited. Here, we reviewed documented evidence on vector-borne diseases and their transmission pathways in Africa to reduce the knowledge gap on the factors influencing the increasing emerging and re-emerging vector-borne diseases across Africa. We found the population distributions or abundance of these freshwater organisms to be increasing, which is directly associated with the increasing emerging and re-emerging vector-borne diseases across Africa. Furthermore, we found that although the current changing environmental conditions in Africa affect the habitats of these freshwater organisms, current changing environmental conditions may not be suppressing the population distributions or abundance of these freshwater organisms. Instead, we found that these freshwater organisms are extending their geographic ranges across Africa, which may have significant public health implications in Africa. Thus, our study demonstrates the need for future studies to integrate the environmental conditions of vectors' habitats to understand if these environmental conditions directly or indirectly influence the vectorial capacities and transmission abilities of vectors of diseases. We propose that such studies will be necessary to guide policymakers in making informed policies to help control vector-borne diseases.

Phage-bacterial evolutionary interactions: experimental models and complications.

Phage treatment of bacterial infections has offered some hope even as the crisis of antimicrobial resistance continues to be on the rise. However, bacterial resistance to phage is another looming challenge capable of undermining the effectiveness of phage therapy. Moreover, the consideration of including phage therapy in modern medicine calls for more careful research around every aspect of phage study. In an attempt to adequately prepare for the events of phage resistance, many studies have attempted to experimentally evolve phage resistance in different bacterial strains, as well as train phages to evolve counter-infectivity of resistant bacterial mutants, in view of answering such questions as coevolutionary dynamics between phage and bacteria, mechanisms of phage resistance, fitness costs of phage resistance on bacteria, etc. In this review, we summarised many such studies and by careful examination, highlighted critical issues to the outcome of phage therapy. We also discuss the insufficiency of many of these in vitro studies to represent actual disease conditions during phage application, alongside other complications that exist in phage-bacterial evolutionary interactions. Conclusively, we present the exploitation of phage-bacterial interactions for successful infection managements, as well as some future perspectives to direct phage research.

Acinetobacter baumannii: More ways to die.

Acinetobacter baumannii is an important nosocomial and opportunistic pathogen. It causes infections worldwide, especially in intensive care units. It is clinically significant owing to its ability to persist for long periods on surfaces, as well as its resistance to multiple antibiotics. This pathogen has been reported to defy the available therapeutic options to combat it. In this dire circumstance, the need for new approaches to treating A. baumannii infections is undeniable. In this minireview, we summarize three important treatment options for controlling A. baumannii pathogen, including the use of bacteriophage / bacteriophage cocktails, phage-antibiotic combinations and resistance-driven fitness losses. It is hoped that, as resources to treat its infection expand, A. baumannii can become less scary.

Genetic Signatures from Adaptation of Bacteria to Lytic Phage Identify Potential Agents To Aid Phage Killing of Multidrug-Resistant Acinetobacter baumannii.

With the increasing morbidity and mortality rates associated with multidrug-resistant bacteria, interest in bacteriophage therapy has been revived. However, bacterial resistance to phage infection threatens the usefulness of phage therapy, especially its inclusion in modern medicine. Multidrug-resistant Acinetobacter baumannii is a top-priority pathogen requiring urgent intervention and new therapeutic approaches, such as phage therapy. Here, we experimentally adapted A. baumannii WHG40004 to its lytic phage P21 and thereafter isolated a phage-resistant bacterial mutant, named Ev5-WHG. We then aimed to identify potential agents to aid phage killing of Ev5-WHG by analyzing its genome and that of the wild-type strain. The enriched Gene Ontology (GO) analysis based on genetic alterations in minor alleles and mutations showed that pathways such as zinc ion transport and cell membrane synthesis could play certain roles in phage resistance. Remarkably, the combination of zinc acetate and P21 showed increased bactericidal effect on Ev5-WHG. Significantly also, we showed that P21 completely prevented the growth of wild-type WHG40004 in the presence of antibiotics (meropenem and imipenem). The results from this study indicate that the analysis of phage resistance signatures during adaptation of bacteria to a lytic phage can inform the choice of agents to work cooperatively with phage to limit and/or reverse resistance. This approach could be important for guiding future successful phage therapy. IMPORTANCE Bacteriophages have proven very useful as alternative therapeutic agents in combating multidrug-resistant bacterial infections; however, bacterial resistance to phages threatens their use. In this study, we showed a new strategy of leveraging genetic signatures that accompany phage resistance in bacteria to predict agents that can be used with lytic phages to combat multidrug-resistant Acinetobacter baumannii. Significantly, this approach was helpful in suggesting the use of zinc acetate to reduce resistance in phage-resistant bacteria, as well as the use of phage with antibiotics meropenem and imipenem to prevent resistance in a wild-type strain of multidrug-resistant A. baumannii. The approach of this study will be helpful for improving the outcome of phage therapy and in overcoming antimicrobial resistance.

Multidrug-resistant enteric bacteria in Nigeria and potential use of bacteriophages as biocontrol.

Enteric bacterial pathogens have been implicated in many cases of gastroenteritis in Nigeria, a West African country. This situation is worsened by some reports of the high prevalence of multidrug-resistant enteric bacteria. To better prepare for situations in which even antibiotics of last resort would fail to treat infections caused by these pathogens, attention should be paid to alternative antimicrobial strategies. Here, we summarize existing reports of multidrug-resistant enteric bacterial infections in Nigeria, and importantly present the use of bacteriophages (viruses of bacteria) as an attractive antimicrobial alternative to combat these pathogens. It is hoped that this review will encourage research into the use of lytic bacteriophages against multidrug-resistant enteric bacteria in Nigeria.