scholarly journals Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

2021 ◽  
Author(s):  
Jenna E. Beam ◽  
Nikki J. Wagner ◽  
John C. Shook ◽  
Edward S.M. Bahnson ◽  
Vance G. Fowler ◽  
...  
Keyword(s):  
Pure Culture ◽  
Host Response ◽  
Therapeutic Strategy ◽  
Antibiotic Tolerance ◽  
Activated Macrophages ◽  
Human Pathogen ◽  
Persister Cells ◽  
Host Interaction ◽  
Bacterial Interaction ◽  
Antibiotic Failure

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia and recent work has identified a role for oxidative burst in the formation of antibiotic tolerant S. aureus . We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation, established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

scholarly journals Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

2021 ◽  
Author(s):  
Jenna E Beam ◽  
Nikki J Wagner ◽  
John C Shook ◽  
Edward S.M. Bahnson ◽  
Vance G Fowler ◽  
...  
Keyword(s):  
Pure Culture ◽  
Host Response ◽  
Therapeutic Strategy ◽  
Antibiotic Tolerance ◽  
Activated Macrophages ◽  
Human Pathogen ◽  
Persister Cells ◽  
Host Interaction ◽  
Bacterial Interaction ◽  
Antibiotic Failure

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia and recent work has identified a role for oxidative burst in the formation of antibiotic tolerant S. aureus. We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation, established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

scholarly journals The Arginine Deiminase Pathway Impacts Antibiotic Tolerance during Biofilm-Mediated Streptococcus pyogenes Infections

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Jeffrey A. Freiberg ◽  
Yoann Le Breton ◽  
Janette M. Harro ◽  
Devon L. Allison ◽  
Kevin S. McIver ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Antibiotic Treatment ◽  
Streptococcus Pyogenes ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Arginine Deiminase ◽  
Antibiotic Tolerance ◽  
Human Pathogen ◽  
Biofilm Growth ◽  
Content Type

ABSTRACT Bacterial biofilms are responsible for a variety of serious human infections and are notoriously difficult to treat due to their recalcitrance to antibiotics. Further work is necessary to elicit a full understanding of the mechanism of this antibiotic tolerance. The arginine deiminase (ADI) pathway is responsible for bacterial pH maintenance and is highly expressed during biofilm growth in multiple bacterial species. Using the group A Streptococcus (GAS) as a model human pathogen, the ADI pathway was demonstrated to contribute to biofilm growth. The inability of antibiotics to reduce GAS populations when in a biofilm was demonstrated by in vitro studies and a novel animal model of nasopharyngeal infection. However, disruption of the ADI pathway returned GAS biofilms to planktonic levels of antibiotic sensitivity, suggesting the ADI pathway is influential in biofilm-related antibiotic treatment failure and provides a new strategic target for the treatment of biofilm infections in GAS and potentially numerous other bacterial species. IMPORTANCE Biofilm-mediated bacterial infections are a major threat to human health because of their recalcitrance to antibiotic treatment. Through the study of Streptococcus pyogenes, a significant human pathogen that is known to form antibiotic-tolerant biofilms, we demonstrated the role that a bacterial pathway known for responding to acid stress plays in biofilm growth and antibiotic tolerance. This not only provides some insight into antibiotic treatment failure in S. pyogenes infections but also, given the widespread nature of this pathway, provides a potentially broad target for antibiofilm therapies. This discovery has the potential to impact the treatment of many different types of recalcitrant biofilm infections.

scholarly journals Listeria meningitis: identification of a cerebrospinal fluid inhibitor of macrophage listericidal function as interleukin 10.

1993 ◽  
Vol 178 (4) ◽  
pp. 1255-1261 ◽  
Author(s):  
K Frei ◽  
D Nadal ◽  
H W Pfister ◽  
A Fontana
Keyword(s):  
Cerebrospinal Fluid ◽  
Host Response ◽  
Interleukin 10 ◽  
Local Concentration ◽  
Activated Macrophages ◽  
Intracellular Killing ◽  
Ifn Gamma ◽  
Time Points ◽  
The Central Nervous System ◽  
Listeria Meningitis

The killing of bacteria gaining access to the central nervous system is insufficient and requires bactericidal antibiotics for treatment. The inefficient host response in cerebrospinal fluid (CSF) is thought to be due to impaired phagocytosis in CSF, and low local concentration of antibody and complement. In addition, the CSF may contain inhibitors, disabling phagocytes to eliminate bacteria. We have assessed the bactericidal activity of macrophages in the presence of CSF from mice infected intracerebrally with Listeria monocytogenes (LM). Pretreatment of J774A.1 macrophages with interferon gamma (IFN-gamma) resulted in high levels of nitric oxide-dependent intracellular killing of LM. CSF taken from mice 24 h after infection (CSF-LM 24) contained IFN-gamma and induced killing of LM by macrophages. However, pulsing J774A.1 cells with IFN-gamma in the presence of CSF obtained from mice at later time points (48 h) rendered macrophages partly permissive for intracellular Listeria growth. The inhibitor detected in CSF-LM 48 was identified as IL-10 since: (a) IL-10 dose dependently impaired the listericidal activity of IFN-gamma-activated macrophages; (b) anti-IL-10 antibodies abrogated the bacterial growth permissive effect of CSF-LM 48; and (c) IL-10 was detected in CSF-LM 48 but not in CSF-LM 24 or CSF of mock-injected animals (CSF-Co). Likewise, IL-10 was found in the CSF of 95% of patients with bacterial meningitis.

scholarly journals Selective Target Inactivation Rather than Global Metabolic Dormancy Causes Antibiotic Tolerance in Uropathogens

2014 ◽  
Vol 58 (4) ◽  
pp. 2089-2097 ◽  
Author(s):  
Lee W. Goneau ◽  
Nigel S. Yeoh ◽  
Kyle W. MacDonald ◽  
Peter A. Cadieux ◽  
Jeremy P. Burton ◽  
...  
Keyword(s):  
Differential Susceptibility ◽  
Type I ◽  
Antibiotic Tolerance ◽  
Persister Cells ◽  
Content Type ◽  
E Coli ◽  
Cellular Processes ◽  
Multidrug Tolerance ◽  
External Stimuli ◽  
Susceptibility Patterns

ABSTRACTPersister cells represent a multidrug-tolerant (MDT), physiologically distinct subpopulation of bacteria. The ability of these organisms to survive lethal antibiotic doses raises concern over their potential role in chronic disease, such as recurrent urinary tract infection (RUTI). Persistence is believed to be conveyed through global metabolic dormancy, which yields organisms unresponsive to external stimuli. However, recent studies have contested this stance. Here, various antibiotics that target different cellular processes were used to dissect the activity of transcription, translation, and peptidoglycan turnover in persister cells. Differential susceptibility patterns were found in type I and type II persisters, and responses differed betweenStaphylococcus saprophyticusandEscherichia coliuropathogens. Further, SOS-deficient strains were sensitized to ciprofloxacin, suggesting DNA gyrase activity in persisters and indicating the importance of active DNA repair systems for ciprofloxacin tolerance. These results indicate that global dormancyper secannot sufficiently account for antibiotic tolerance. Rather, the activity of individual cellular processes dictates multidrug tolerance in an antibiotic-specific fashion. Furthermore, the susceptibility patterns of persisters depended on their mechanisms of onset, with subinhibitory antibiotic pretreatments selectively shutting down cognate targets and increasing the persister fraction against the same agent. Interestingly, antibiotics targeting transcription and translation enhanced persistence against multiple agents indirectly related to these processes. Conducting these assays with uropathogenicE. coliisolated from RUTI patients revealed an enriched persister fraction compared to organisms cleared with standard antibiotic therapy. This finding suggests that persister traits are either selected for during prolonged antibiotic treatment or initially contribute to therapy failure.

scholarly journals Interrelationships of Interferon and Immunity During Viral Infections

1970 ◽  
Vol 56 (1) ◽  
pp. 212-226 ◽  
Author(s):  
Lowell A. Glasgow
Keyword(s):  
Immune Responses ◽  
Vaccinia Virus ◽  
Host Resistance ◽  
Host Response ◽  
Viral Infections ◽  
Cell Interaction ◽  
Relative Importance ◽  
Host Interaction ◽  
Interferon Responses

Interferon is one determinant of host resistance. The immune responses, cellular or humoral, are other components. Cell-mediated responses appear to be involved in host resistance to certain viral infections, particularly the herpesvirus group and vaccinia virus. It is suggested that immune and interferon responses may complement one another and contribute to host resistance. The relative importance of each component depends upon the virus-host interaction. Finally, evidence has been presented which suggests that production of interferon as a result of antigen-sensitized cell interaction may further link these two components of the host response.

scholarly journals Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

2018 ◽  
Author(s):  
Bettina Couderc ◽  
Augustin Le Naour ◽  
Mélissa Prat ◽  
Renaud Mevel ◽  
Benoit Thibault ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Strategy ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Activated Macrophages ◽  
High Concentrations ◽  
Ovarian Tumor Cells

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naïve MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.

scholarly journals Stringent Response in Mycobacteria: From Biology to Therapeutic Potential

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1417
Author(s):  
Kuldeepkumar Ramnaresh Gupta ◽  
Gunjan Arora ◽  
Abid Mattoo ◽  
Andaleeb Sajid
Keyword(s):  
Immune Cells ◽  
Biofilm Formation ◽  
Host Response ◽  
Latent Infection ◽  
Therapeutic Potential ◽  
Stringent Response ◽  
Host Immunity ◽  
Stress Conditions ◽  
Human Pathogen ◽  
Synthesis And Degradation

Mycobacterium tuberculosis is a human pathogen that can thrive inside the host immune cells for several years and cause tuberculosis. This is due to the propensity of M. tuberculosis to synthesize a sturdy cell wall, shift metabolism and growth, secrete virulence factors to manipulate host immunity, and exhibit stringent response. These attributes help M. tuberculosis to manage the host response, and successfully establish and maintain an infection even under nutrient-deprived stress conditions for years. In this review, we will discuss the importance of mycobacterial stringent response under different stress conditions. The stringent response is mediated through small signaling molecules called alarmones “(pp)pGpp”. The synthesis and degradation of these alarmones in mycobacteria are mediated by Rel protein, which is both (p)ppGpp synthetase and hydrolase. Rel is important for all central dogma processes—DNA replication, transcription, and translation—in addition to regulating virulence, drug resistance, and biofilm formation. Rel also plays an important role in the latent infection of M. tuberculosis. Here, we have discussed the literature on alarmones and Rel proteins in mycobacteria and highlight that (p)ppGpp-analogs and Rel inhibitors could be designed and used as antimycobacterial compounds against M. tuberculosis and non-tuberculous mycobacterial infections.

scholarly journals Borrelia burgdorferi RevA Significantly Affects Pathogenicity and Host Response in the Mouse Model of Lyme Disease

2015 ◽  
Vol 83 (9) ◽  
pp. 3675-3683 ◽  
Author(s):  
Rebecca Byram ◽  
Robert A. Gaultney ◽  
Angela M. Floden ◽  
Christopher Hellekson ◽  
Brandee L. Stone ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Host Response ◽  
Collagen Deposition ◽  
Wild Type ◽  
Content Type ◽  
Cardiac Tissues ◽  
Monocyte Chemoattractant ◽  
Bacterial Interaction ◽  
Mammalian Infection

The Lyme disease spirochete,Borrelia burgdorferi, expresses RevA and numerous outer surface lipoproteins during mammalian infection. As an adhesin that promotes bacterial interaction with fibronectin, RevA is poised to interact with the extracellular matrix of the host. To further define the role(s) of RevA during mammalian infection, we created a mutant that is unable to produce RevA. The mutant was still infectious to mice, although it was significantly less well able to infect cardiac tissues. Complementation of the mutant with a wild-typerevAgene restored heart infectivity to wild-type levels. Additionally,revAmutants led to increased evidence of arthritis, with increased fibrotic collagen deposition in tibiotarsal joints. The mutants also induced increased levels of the chemokine CCL2, a monocyte chemoattractant, in serum, and this increase was abolished in the complemented strain. Therefore, whilerevAis not absolutely essential for infection, deletion ofrevAhad distinct effects on dissemination, arthritis severity, and host response.

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