Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections.
To compare the ...activity of CLR and AZM in experimental models.
We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erythromycin ribosome methyltransferase gene (erm)(41) expression in experimental models of M. abscessus and M. massiliense infections.
In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration MIC on Day 3 versus Day 14; P < 0.001). Whereas the AZM MIC increased on Day 14 (P < 0.01 versus Day 3), the level was significantly lower than the CLR MIC on Day 14 (P < 0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared with CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P < 0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher after exposure to CLR than after exposure to AZM (P < 0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance.
CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense.
The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of ...dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota–brain axis. The gut microbiota–brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota–brain axis is a novel target for Alzheimer’s disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota–brain axis and neuroinflammation in the onset and development of Alzheimer’s disease, limitations of current research, and potential for gut microbiota–brain axis targeted therapies.
Host-associated bacteria and fungi, comprising the microbiota, are critical to host health. In the airways, the composition and diversity of the mucosal microbiota of patients are associated with ...airway health status. However, the relationship between airway microbiota and respiratory inflammation is not well-understood. Chronic rhinosinusitis (CRS) is a complex disease that affects up to 14% of the US population. Previous studies have shown decreased microbial diversity in CRS patients and enrichment of either
or
. Although bacterial community composition is variable across CRS patients,
is a dominant fungal genus in the upper airways of the majority of healthy and CRS subjects. We hypothesize that distinct bacterial-fungal interactions differentially influence host mucosal immune response. Thus, we investigated
and
interactions between
, and
. The
interactions were evaluated using the modified Kirby-Bauer Assay, Crystal Violet assay for biofilm, and FISH. A pilot murine model of acute sinusitis was used to investigate relationships with the host immune response.
and
were intranasally instilled in the presence or absence of
(
= 66 total mice; 3-5/group). Changes in the microbiota were determined using 16S rRNA gene sequencing and host immune response was measured using quantitative real-time PCR (qRT-PCR).
, only late stage planktonic
and its biofilms inhibited
. Co-infection of mice with
and
or
differently influenced the immune response. In co-infected mice, we demonstrate different expression of fungal sensing (Dectin-1), allergic responses (IL-5, and IL-13) and inflammation (IL-10, and IL-17) in murine sinus depending on the bacterial species that co-infected with
(
< 0.05). The pilot results suggest that species-specific interactions in airway-associated microbiota may be implicated driving immune responses. The understanding of the role of bacterial-fungal interactions in CRS will contribute to development of novel therapies toward manipulation of the airway microbiota.
Indigenous microbes inside the host intestine maintain a complex self-regulating community. The mechanisms by which gut microbes interact with intestinal pathogens remain largely unknown. Here we ...identify a commensal Escherichia coli strain whose expansion predisposes mice to infection by Vibrio cholerae, a human pathogen. We refer to this strain as 'atypical' E. coli (atEc) because of its inability to ferment lactose. The atEc strain is resistant to reactive oxygen species (ROS) and proliferates extensively in antibiotic-treated adult mice. V. cholerae infection is more severe in neonatal mice transplanted with atEc compared with those transplanted with a typical E. coli strain. Intestinal ROS levels are decreased in atEc-transplanted mice, favouring proliferation of ROS-sensitive V. cholerae. An atEc mutant defective in ROS degradation fails to facilitate V. cholerae infection when transplanted, suggesting that host infection susceptibility can be regulated by a single gene product of one particular commensal species.
RpfB regulates innate immunity and activates adaptive immunity through TLR4; a potential design for more effective vaccines.
The failure of Mycobacterium bovis BCG as a TB vaccine against TB ...reactivation suggests that latency‐associated proteins should be included in alternative TB vaccine development. Further, antigens known to generate protective immunity against the strong Th1 stimulatory response to reactivated TB should be included in novel vaccine design. Recent studies have emphasized the importance of Rpfs from Mycobacterium tuberculosis in the reactivation process and cellular immunity. However, little is known about how RpfB mediates protective immunity against M. tuberculosis. Here, we investigated the functional roles and signaling mechanisms of RpfB in DCs and its implications in the development of T cell immunity. DCs treated with RpfB displayed features of mature and functional status, with elevated expression of cell surface molecules (CD80, CD86, and MHC class I and II) and proinflammatory cytokine production (TNF‐α, IL‐1β, IL‐6, and IL‐12p70). Activation of DCs was mediated by direct binding of RpfB to TLR4, followed by MyD88/TRIF‐dependent signaling to MAPKs and NF‐κB signaling pathways. Specifically, we found that the RpfB G5 domain is the most important part in RpfB binding to TLR4. RpfB‐treated DCs effectively polarized naïve CD4+ and CD8+ T cells to secrete IFN‐γ and IL‐2. Importantly, RpfB induced the expansion of memory CD4+/CD8+CD44highCD62Llow T cells in the spleen of M. tuberculosis‐infected mice. Our data suggest that RpfB regulates innate immunity and activates adaptive immunity through TLR4, a finding that may help in the design of more effective vaccines.
Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human ...medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn(2+) or Mn(2+) ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection.
Recent studies leveraging next-generation sequencing and functional approaches to understand the human microbiota have demonstrated the presence of diverse, niche-specific microbial communities at ...nearly every mucosal surface. These microbes contribute to the development and function of physiologic and immunological features that are key to host health status. Not surprisingly, several chronic inflammatory diseases have been attributed to dysbiosis of microbiota composition or function, including chronic rhinosinusitis (CRS). CRS is a heterogeneous disease characterized by inflammation of the sinonasal cavity and mucosal microbiota dysbiosis. Inflammatory phenotypes and bacterial community compositions vary considerably across individuals with CRS, complicating current studies that seek to address causality of a dysbiotic microbiome as a driver or initiator of persistent sinonasal inflammation. Murine models have provided some experimental evidence that alterations in local microbial communities and microbially-produced metabolites influence health status. In this perspective, we will discuss the clinical implications of distinct microbial compositions and community-level functions in CRS and how mucosal microbiota relate to the diverse inflammatory endotypes that are frequently observed. We will also describe specific microbial interactions that can deterministically shape the pattern of co-colonizers and the resulting metabolic products that drive or exacerbate host inflammation. These findings are discussed in the context of CRS-associated inflammation and in other chronic inflammatory diseases that share features observed in CRS. An improved understanding of CRS patient stratification offers the opportunity to personalize therapeutic regimens and to design novel treatments aimed at manipulation of the disease-associated microbiota to restore sinus health.
A biofilm is a community of microbes that typically inhabit on surfaces and are encased in an extracellular matrix. Biofilms display very dissimilar characteristics to their planktonic counterparts. ...Biofilms are ubiquitous in the environment and influence our lives tremendously in both positive and negative ways.
is a bacterium known to produce robust biofilms.
biofilms cause severe problems in immunocompromised patients, including those with cystic fibrosis or wound infection. Moreover, the unique biofilm properties further complicate the eradication of the biofilm infection, leading to the development of chronic infections. In this review, we discuss the history of biofilm research and general characteristics of bacterial biofilms. Then, distinct features pertaining to each stage of
biofilm development are highlighted. Furthermore, infections caused by biofilms on their own or in association with other bacterial species (
, multispecies biofilms) are discussed in detail.
Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 ...on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
Two closely related bacterial species, Segniliparus rotundus and Segniliparus rugosus, have emerged as important human pathogens, but little is known about the immune responses they elicit or their ...comparative pathophysiologies. To determine the virulence and immune responses of the two species, we compared their abilities to grow in phagocytic and non-phagocytic cells. Both species maintained non-replicating states within A549 epithelial cells. S. rugosus persisted longer and multiplied more rapidly inside murine bone marrow-derived macrophages (BMDMs), induced more pro-inflammatory cytokines, and induced higher levels of macrophage necrosis. Activation of BMDMs by both species was mediated by toll-like receptor 2 (TLR2), followed by mitogen-activated protein kinases (MAPK) and nuclear factor κB (NF-κB) signaling pathways, indicating a critical role for TLR2 in Segniliparus-induced macrophage activation. S. rugosus triggered faster and stronger activation of MAPK signaling and IκB degradation, indicating that S. rugosus induces more pro-inflammatory cytokines than S. rotundus. Multifocal granulomatous inflammations in the liver and lung were observed in mice infected with S. rugosus, but S. rotundus was rapidly cleared from all organs tested within 15 days post-infection. Furthermore, S. rugosus induced faster infiltration of innate immune cells such as neutrophils and macrophages to the lung than S. rotundus. Our results suggest that S. rugosus is more virulent and induces a stronger immune response than S. rotundus.
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