Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child.
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ABSTRACT:
SUBMITTER: Khatami A
PROVIDER: S-EPMC8422068 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2, and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.
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Project description:BackgroundCharacterized by an inflammatory pathogenesis, acne is the most common skin disorder worldwide. Altered sebum production, abnormal proliferation of keratinocytes, and microbiota dysbiosis represented by disbalance in Cutibacterium acnes population structure, have a synergic effect on inflammation of acne-compromised skin. Although the role of C. acnes as a single factor in acne development is still under debate, it is known that skin and skin-resident immune cells recognize this bacterium and produce inflammatory markers as a result. Control of the inflammatory response is frequently the target for acne treatment, using diverse chemical or physical agents including antibiotics. However, some of these treatments have side effects that compromise patient adherence and drug safety and in the case of antibiotics, it has been reported C. acnes resistance to these molecules. Phage therapy is an alternative to treat antibiotic-resistant bacterial strains and have been recently proposed as an immunomodulatory therapy. Here, we explore this perspective about phage therapy for acne, considering the potential immunomodulatory role of phages.MethodologyLiterature review was performed using four different databases (Europe PubMed Central-ePMC, Google Scholar, PubMed, and ScienceDirect). Articles were ordered and selected according to their year of publication, number of citations, and quartile of the publishing journal.ResultsThe use of lytic bacteriophages to control bacterial infections has proven its promising results, and anti-inflammatory effects have been found for some bacteriophages and phage therapy. These effects can be related to bacterial elimination or direct interaction with immune cells that result in the regulation of pro-inflammatory cytokines. Studies on C. acnes bacteriophages have investigated their lytic activity, genomic structure, and stability on different matrices. However, studies exploring the potential of immunomodulation of these bacteriophages are still scarce.ConclusionsC. acnes bacteriophages, as well as other phages, may have direct immunomodulatory effects that are yet to be fully elucidated. To our knowledge, to the date that this review was written, there are only two studies that investigate anti-inflammatory properties for C. acnes bacteriophages. In those studies, it has been evidenced reduction of pro-inflammatory response to C. acnes inoculation in mice after bacteriophage application. Nevertheless, these studies were conducted in mice, and the interaction with the immune response was not described. Phage therapy to treat acne can be a suitable therapeutic alternative to C. acnes control, which in turn can aid to restore the skin's balance of microbiota. By controlling C. acnes colonization, C. acnes bacteriophages can reduce inflammatory reactions triggered by this bacterium.
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Project description:Sirtuin 5 (SIRT5) is a member of the family of NAD+-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, Escherichia coli peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development.
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Project description:In general, the last step in the vegetative cycle of bacterial viruses, or bacteriophages, is lysis of the host. dsDNA phages require multiple lysis proteins, including at least one enzyme that degrades the cell wall (peptidoglycan (PG)). In contrast, the lytic ssDNA and ssRNA phages have a single lysis protein that achieves cell lysis without enzymatically degrading the PG. Here, we review four "single-gene lysis" or Sgl proteins. Three of the Sgls block bacterial cell wall synthesis by binding to and inhibiting several enzymes in the PG precursor pathway. The target of the fourth Sgl, L from bacteriophage MS2, is still unknown, but we review evidence indicating that it is likely a protein involved in maintaining cell wall integrity. Although only a few phage genomes are available to date, the ssRNA Leviviridae are a rich source of novel Sgls, which may facilitate further unraveling of bacterial cell wall biosynthesis and discovery of new antibacterial agents.
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Project description:BACKGROUND:Bacterial keratitis is a serious ocular infectious disease that can lead to severe visual disability. Risk factors for bacterial corneal infection include contact lens wear, ocular surface disease, corneal trauma and previous ocular or eyelid surgery. Topical antibiotics constitute the mainstay of treatment in cases of bacterial keratitis where as the use of topical corticosteroids remains controversial. Topical corticosteroids are usually used to control inflammation using the smallest amount of the drug. Their use requires optimal timing, concomitant antibiotics and careful follow up. OBJECTIVES:The objective of the review was to assess the clinical effectiveness and adverse effects of corticosteroids as adjunctive therapy for bacterial keratitis. SEARCH STRATEGY:We searched CENTRAL, MEDLINE, EMBASE, and LILACS up to 15 January 2007. We also searched the Science Citation Index to identify additional studies that had cited the included trial, an online database of ongoing trials (www.clinicaltrials.gov), reference lists of included trials, earlier reviews and the American Academy of Ophthalmology guidelines. We also contacted experts to identify any unpublished and ongoing randomized trials. SELECTION CRITERIA:We included randomized controlled trials evaluating adjunctive therapy with topical corticosteroids in people with bacterial keratitis. DATA COLLECTION AND ANALYSIS:Two review authors independently screened all the retrieved articles. Methodological quality of the one included trial was assessed using forms developed using pre-specified criteria by at least two review authors. We planned to extract data on outcomes using forms developed for the purpose. We planned to report risk ratios for dichotomous outcomes and mean differences for continuous outcomes. MAIN RESULTS:A single trial was eligible for inclusion in the review. Participants in the trial were randomized using a random numbers table. Allocation concealment was not attempted. Masking of participants, and care-providers was also not attempted. Outcome assessment was conducted independently by two physicians. Neither was masked to the treatment allocation. The trial reported the healing rate of epithelial defects and improvement in visual acuity. AUTHORS' CONCLUSIONS:There are no good quality randomized trials evaluating the effects of adjunct use of topical corticosteroids in bacterial keratitis. The only randomized trial we identified in the literature suffered from major methodological inadequacies.
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