Interferon-Lambda 1 Inhibits Staphylococcus aureus Colonization in Human Primary Keratinocytes.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC8019897 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UNLABELLED:Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in Il28r(-/-) mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1. Il28r(-/-) mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIII?, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than Il28r(-/-) mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection. IMPORTANCE:S. aureus and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to S. aureus infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal S. aureus colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to S. aureus superinfection.
| S-EPMC4752601 | biostudies-literature
Project description:UnlabelledSkin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms.ImportanceHuman skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.
| S-EPMC4453558 | biostudies-literature
Project description:Staphylococcus aureus is a human commensal and pathogen that is capable of forming biofilms on a variety of host tissues and implanted medical devices. Biofilm-associated infections resist antimicrobial chemotherapy and attack from the host immune system, making these infections particularly difficult to treat. In order to gain insight into environmental conditions that influence S. aureus biofilm development, we screened a library of small molecules for the ability to inhibit S. aureus biofilm formation. This led to the finding that the polyphenolic compound tannic acid inhibits S. aureus biofilm formation in multiple biofilm models without inhibiting bacterial growth. We present evidence that tannic acid inhibits S. aureus biofilm formation via a mechanism dependent upon the putative transglycosylase IsaA. Tannic acid did not inhibit biofilm formation of an isaA mutant. Overexpression of wild-type IsaA inhibited biofilm formation, whereas overexpression of a catalytically dead IsaA had no effect. Tannin-containing drinks like tea have been found to reduce methicillin-resistant S. aureus nasal colonization. We found that black tea inhibited S. aureus biofilm development and that an isaA mutant resisted this inhibition. Antibiofilm activity was eliminated from tea when milk was added to precipitate the tannic acid. Finally, we developed a rodent model for S. aureus throat colonization and found that tea consumption reduced S. aureus throat colonization via an isaA-dependent mechanism. These findings provide insight into a molecular mechanism by which commonly consumed polyphenolic compounds, such as tannins, influence S. aureus surface colonization.
| S-EPMC3553799 | biostudies-other
Project description:More than 20% of adults are persistently colonized with Staphylococcus aureus. When hospitalized, these carriers have increased risks of infection with their own strains. However, a recent study demonstrated a lower incidence of bacteremia-related death among carriers than among noncarriers, raising the question whether the adaptive immune system plays a protective role. In fact, S. aureus carriers mount a highly specific neutralizing antibody response against superantigens of their colonizing strains. We now used 2-dimensional immunoblotting to investigate the profiles of antibodies from healthy individuals against S. aureus extracellular proteins. Moreover, we tested whether symptom-free experimental colonization of these individuals with an S. aureus strain of low virulence, 8325-4, is sufficient to induce an antibody response. Sera obtained before and 4 weeks after colonization were screened for immunoglobulin G (IgG) antibody binding to extracellular staphylococcal proteins. At baseline, most volunteers harbored IgG directed against conserved virulence factors, including alpha-hemolysin (Hla), beta-hemolysin (Hlb), phospholipase C (Plc), staphylococcal serine protease (SspA), and cysteine protease (SspB). However, the variability of spot patterns and intensities was striking and could be important in case of infection. Experimental nasal colonization with S. aureus 8325-4 did not elicit new antibodies or boost the humoral response. Thus, the high antibody prevalence in humans is likely not induced by short-term nasal colonization, and presumably minor infections are required to trigger anti-S. aureus antibody responses.
| S-EPMC2772373 | biostudies-literature
Project description:Staphylococcus aureus nasal colonization is an important risk factor for community and nosocomial infection. Despite the importance of S. aureus to human health, molecular mechanisms and host factors influencing nasal colonization are not well understood. To identify host factors contributing to nasal colonization, we collected human nasal secretions and analyzed their ability to promote S. aureus surface colonization. Some individuals produced secretions possessing the ability to significantly promote S. aureus surface colonization. Nasal secretions pretreated with protease no longer promoted S. aureus surface colonization, suggesting the involvement of protein factors. The major protein components of secretions were identified and subsequent analysis revealed that hemoglobin possessed the ability to promote S. aureus surface colonization. Immunoprecipitation of hemoglobin from nasal secretions resulted in reduced S. aureus surface colonization. Furthermore, exogenously added hemoglobin significantly decreased the inoculum necessary for nasal colonization in a rodent model. Finally, we found that hemoglobin prevented expression of the agr quorum sensing system and that aberrant constitutive expression of the agr effector molecule, RNAIII, resulted in reduced nasal colonization of S. aureus. Collectively our results suggest that the presence of hemoglobin in nasal secretions contributes to S. aureus nasal colonization.
| S-EPMC3131264 | biostudies-other
Project description:Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-?) as a therapeutic for influenza, as administration of pegylated IFN-? improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-? impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-? during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-? treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-? treatment during influenza superinfection in vivo Together, these data support the theory that IFN-? decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-? as therapy for influenza.
| S-EPMC6479047 | biostudies-literature
Project description:Nasal colonization with Staphylococcus aureus (SA) increases the risk of surgical site infection (SSI). We first (1) determined the prevalence of asymptomatic nasal colonization with SA, (2) assessed trends in methicillin resistance with time, (3) ascertained risk factors for nasal colonization; and (4) correlated SSI to nasal colonization status and procedure. We performed a cross-sectional analysis of SA nasal colonization among healthy preoperative orthopaedic outpatients between 2003-2005 who were within 2 weeks of surgery. Of 284 patients, 86 (30%) carried SA; of these, 81 (94%) were colonized with methicillin-sensitive and five (6%) with methicillin-resistant SA (MRSA). Total SA colonization increased from 25/78 (32%) in 2003 to 37/97 (38%) in 2005, and colonization with MRSA increased from 0/78 (0%) to four of 97 (4%), respectively. We found no associations between nasal carriage and demographics or procedures. Surgical site infection occurred in nine of 282 (3%), four of which were attributable to SA; these included 0/43 (0%) carriers who received decolonization with 2% mupirocin, two of 43 (4.7%) who declined decolonization, and two of 196 (1.0%) who were noncarriers. Nasal colonization with SA, including MRSA, among preoperative orthopaedic outpatients is increasing and their rates reflect community rates. Knowledge of colonization status may be important in decolonization, choosing perioperative or any subsequent empiric antibiotics.
| S-EPMC2565023 | biostudies-other
Project description:BACKGROUND:In viral disease, infection is controlled at the cellular level by type I interferon (IFN-I), but dengue virus (DENV) has the ability to inhibit this response. Type III interferon, also known as lambda IFN (IFN-III or IFN-?), is a complementary pathway to the antiviral response by IFN-I. This work analyzed the IFN-? (IFN-III) mediated antiviral response against DENV serotype 2 (DENV-2) infection. METHODS:Dengue fever patients were sampled to determine their IFN-? levels by ELISA. To study the IFN-? response during DENV infection we selected the epithelial cell line C33-A, and we demonstrated that it is permissive to DENV-2 infection. The effect of IFN-? on virus replication was determined in these cells, in parallel to the expression of IFN-stimulated genes (ISGs), and Suppressor of Cytokine Signaling (SOCS), genes measured by RT-qPCR. RESULTS:We found increased (~1.8 times) serological IFN-? in dengue fever patients compared to healthy blood donors. IFN-? inhibited DENV-2 replication in a dose-dependent manner in vitro. The reduction of viral titer corresponded with increased ISG mRNA levels (MX1 and OAS1), with the highest inhibition occurring at ISG's peak expression. Presence of IFN-negative regulators, SOCS1 and SOCS3, during DENV-2 infection was associated with reduced IFN-?1 expression. CONCLUSIONS:Evidence described here suggests that IFN-? is a good candidate inhibitor of viral replication in dengue infection. Mechanisms for the cellular and organismal interplay between DENV and IFN- ? need to be further studied as they could provide insights into strategies to treat this disease. Furthermore, we report a novel epithelial model to study dengue infection in vitro.
| S-EPMC4584467 | biostudies-literature
Project description:BackgroundStaphylococcus aureus is an important opportunistic pathogen and a commensal bacterium, thriving in the nasal cavities of 20% of the human population. Little is known about the dynamics of asymptomatic colonization and the occasional transition to infectious disease.ResultsIn this study, we inferred that S. aureus cells replicate every one to three hours on average while colonizing the human nose, based on two independent lines of genomic evidence. First, we collected nasal swab samples from human subjects, extracted and sequenced metagenomic DNA, and analyzed the distribution of sequencing coverage along the staphylococcal chromosome. Calibration of this data by comparison to a laboratory culture enabled measuring S. aureus cell division rates in nasal samples. Second, we applied mutation accumulation experiments paired with genome sequencing to measure spontaneous mutation rates at a genome scale. Relating these mutation rates to annual evolutionary rates confirmed that nasal S. aureus continuously pass several thousand cell divisions per year when averaged over large, globally distributed populations and over many years, corresponding to generation times of less than two hours.ConclusionsThe cell division rates we determined were higher than the fastest documented rates during fulminant disease progression (in a mouse model of systemic infection) and much higher than those previously measured in expectorated sputum from cystic fibrosis patients. This paper supplies absolute in-vivo generation times for an important bacterial commensal, indicating that colonization of the human upper respiratory tract is characterized by a highly dynamic equilibrium between bacterial growth and removal.
| S-EPMC6425579 | biostudies-literature
Project description:Herpes simplex virus Type I (HSV-1) is a neurotropic virus that is capable of infecting not only neurons, but also microglia and astrocytes and can establish latent infection in the central nervous system (CNS). We investigated whether IFN lambda (IFN-?), a newly identified member of IFN family, has the ability to inhibit HSV-1 infection of primary human astrocytes and neurons. Both astrocytes and neurons were found to be highly susceptible to HSV-1 infection. However, upon IFN-? treatment, HSV-1 replication in both astrocytes and neurons was significantly suppressed, which was evidenced by the reduced expression of HSV-1 DNA and proteins. This IFN-?-mediated action on HSV-1 could be partially neutralized by antibody to IFN-? receptor. Investigation of the mechanisms showed that IFN-? treatment of astrocytes and neurons resulted in the upregulation of endogenous IFN-?/? and several IFN-stimulated genes (ISGs). To block IFN-?/? receptor by a specific antibody could compromise the IFN-? actions on HSV-1 inhibition and ISG induction. In addition, IFN-? treatment induced the expression of IFN regulatory factors (IRFs) in astrocytes and neurons. Furthermore, IFN-? treatment of astrocytes and neurons resulted in the suppression of suppressor of cytokine signaling 1 (SOCS-1), a key negative regulator of IFN pathway. These data suggest that IFN-? possesses the anti-HSV-1 function by promoting Type I IFN-mediated innate antiviral immune response in the CNS cells.
| S-EPMC3082435 | biostudies-literature