Over the last decades, research regarding innate immune responses has gained increasing importance. A growing body of evidence supports the notion that the innate arm of the immune system could show memory traits. Such traits are thought to be conserved throughout evolution and provide a survival advantage. Several models are available to study these mechanisms. Among them, we find the fruit fly, Drosophila melanogaster. This non-mammalian model has been widely used for innate immune research since it naturally lacks an adaptive response. Here, we aim to review the latest advances in the study of the memory mechanisms of the innate immune response using this animal model.
25 years after the declaration of a Global Emergency by the World Health Organization, tuberculosis (TB) remains a major enemy to the humankind. During this period, much progress has been done to better understand its natural history, revealing its huge complexity, which highlighted the need for implementing systems immunology approaches. Recent advances focused in understanding the role of macrophage subtypes and dendritic cells role, the importance of cytokine balance, and the antigenic repertoire. Identification of early irruption of polymorphonuclear neutrophils and extracellular growth of the bacilli seem to be the most disruptive factors to understand the evolution towards active TB. Their inclusion in future models will provide new tools for the better understanding of the tuberculosis.
Acinetobacter baumannii, a worldwide emerging nosocomial pathogen, acquires antimicrobial resistances in response to DNAdamaging agents, which increase the expression of multiple error-prone DNA polymerase components. Here we show that the aminocoumarin novobiocin, which inhibits the DNA damage response in Gram-positive bacteria, also inhibits the expression of error-prone DNA polymerases in this Gram-negative multidrug-resistant pathogen and, consequently, its potential acquisition of antimicrobial resistance through DNA damage-induced mutagenesis.A cinetobacter baumannii is a highly effective human colonizer in hospital settings worldwide. Its ability to acquire resistance to several extensively used antimicrobials has resulted in its emergence as a problematic nosocomial pathogen (1). As in other bacteria, A. baumannii achieves resistance against certain antimicrobials through single mutations in the corresponding target genes (i.e., point mutations in the rpoB gene can generate resistance to rifampin [2]). In previous works, we demonstrated that this bacterium contains multiple components of error-prone DNA polymerases, whose induction after DNA damage leads to the introduction of point mutations in the bacterial genome, including those conferring antibiotic resistance (3, 4).Topoisomerase enzymes maintain the topological state of DNA and are critical regulators of protein translation and cell replication. Specifically, DNA gyrase (a type II topoisomerase) catalyzes the removal of the torsional stress that accumulates in bacterial chromosomes at sites preceding replication forks and transcriptional complexes by forming double-stranded breaks in the DNA (5). The formation of these double-stranded breaks and, therefore, of single-stranded DNA activates the bacterial SOS response, which results in mutagenic repair through the expression of mutagenic genes, especially those encoding error-prone DNA polymerases. This response guarantees DNA repair and cell survival but also results in some mutations that are able to confer antimicrobial resistance (2, 6). In Escherichia coli and other bacteria, the DNA damage response is regulated by the LexA repressor. However, A. baumannii lacks the LexA repressor, and the errorprone DNA polymerase (UmuDAb) carries out its functional role (3, 4). Thus, the induction of this DNA repair response in A. baumannii also results in the introduction of point mutations, including those conferring antibiotic resistance.DNA gyrase inhibitors such as quinolones take advantage of the potential of topoisomerases to fragment the genome and thereby cause cell death. These drugs bind noncovalently at the enzyme-DNA interface in the cleavage-ligation active site to block ligation (5). Further, because quinolones also cause SOS induction, they ultimately promote antimicrobial resistance. Thus, one approach to combat the increasing prevalence of antimicrobialresistant infections is to prevent SOS activation. Antimicrobials such as novobiocin interfere with the ATPase activity of DNA gyrase, such t...
Drosophila melanogaster (Drosophila), the common fruit fly, is one of the most extensively studied animal models we have, with a broad, advanced, and organized research community with tools and mutants readily available at low cost. Yet, Drosophila has barely been exploited to understand the underlying mechanisms of mycobacterial infections, including those caused by the top-killer pathogen Mycobacterium tuberculosis (Mtb). In this study, we aimed to investigate whether Drosophila is a suitable host model to study mycobacterial virulence, using Mycobacterium marinum (Mmar) to model mycobacterial pathogens. First, we validated that an established mycobacterial virulence factor, EccB1 of the ESX-1 Type VII secretion system, is required for Mmar growth within the flies. Second, we identified Mmar virulence factors in Drosophila in a high-throughput genome-wide manner using transposon insertion sequencing (TnSeq). Of the 181 identified virulence genes, the vast majority (91%) had orthologs in Mtb, suggesting that the encoded virulence mechanisms may be conserved across Mmar and Mtb. Finally, we validated one of the novel Mmar virulence genes we identified, a putative ATP-binding protein ABC transporter encoded by mmar_1660, as required for full virulence during both Drosophila and human macrophage infection. Together, our results show that Drosophila is a powerful host model to study and identify novel mycobacterial virulence factors relevant to human infection.
Both the sex and the reproductive status of the host have a major impact on the regulation of the immune response against infection. The fruit fly Drosophila melanogaster has become a powerful model for study such interaction due to its well-characterized hormonal, metabolic and immune traits. In order to further characterize this in mycobacterial infections, we tested the systemic Mycobacterium marinum infection of D. melanogaster. We wanted to understand whether the sex or the reproductive status has an impact on the tolerance or resistance of the host to the infection. We measured gene expression by RT-qPCR of immune genes (diptericin and drosomycin) as well as host survival and bacillary load at time of death. We assessed the impact of metabolic (by expression of upd3 and impl2) and hormonal (by ecR expression) regulation in the protection against infection. Data showed that the effect of reproductive status (virgin and mated kept alone or together) in tolerance and resistance to infection is sex dependent. We found differences in protection according to the levels of expression in immune, metabolic and hormone-related genes which also showed differences between sex and reproductive status, highlighting the expression of impl2 in males and upd3 in females to face the infection. The results obtained allows further interpretation of the results when assessing the differences between sexes in D. melanogaster for other infections, since data demonstrated the importance of the reproductive status in resistance and tolerance against M. marinum infection.
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