-
Mucosal Immunology Sep 2019Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary...
Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary pathogens of interest. IL-22 promotes S. aureus and S. pneumoniae host defense in the lung through epithelial integrity and induction of antimicrobial peptides and is inhibited by the soluble decoy receptor IL-22-binding protein (IL-22BP). Little is known about the effect of the IL-22/IL-22BP regulatory pathway on lung infection, and it has not been studied in the setting of super-infection. We exposed wild-type and IL-22BP mice to influenza A/PR/8/34 for 6 days prior to infection with S. aureus (USA300) S. pneumoniae. Super-infected IL-22BP mice had decreased bacterial burden and improved survival compared to controls. IL-22BP mice exhibited decreased inflammation, increased lipocalin 2 expression, and deletion of IL-22BP was associated with preserved epithelial barrier function with evidence of improved tight junction stability. Human bronchial epithelial cells treated with IL-22Fc showed evidence of improved tight junctions compared to untreated cells. This study revealed that IL-22BP mice are protected during influenza, bacterial super-infection, suggesting that IL-22BP has a pro-inflammatory role and impairs epithelial barrier function likely through interaction with IL-22.
Topics: Animals; Bacterial Infections; Bacterial Load; Blood-Air Barrier; Carrier Proteins; Disease Models, Animal; Gene Expression; Interleukins; Leukocyte Count; Male; Mice; Mice, Knockout; Monocytes; Orthomyxoviridae Infections; Permeability; Protein Binding; Staphylococcus aureus; Streptococcus pneumoniae; Superinfection; Tight Junctions; Interleukin-22
PubMed: 31296910
DOI: 10.1038/s41385-019-0188-7 -
Hepatology Communications May 2023HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic...
BACKGROUND AND AIMS
HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic transporter of bile acids (ie, Na+-taurocholate cotransporting polypeptide) to enter hepatocytes. We have previously shown that ligands of the farnesoid-X-receptor alpha (FXR), a master regulator of bile acids metabolism, inhibit HBV replication. Here we asked whether FXR ligands can also control HDV infection.
APPROACH AND RESULTS
In vitro HDV monoinfections or HDV/HBV coinfections and superinfections were performed in differentiated HepaRG cells (dHepaRG) and primary human hepatocytes. Following treatment with FXR ligands, HDV RNAs and antigens were analyzed by RT-qPCR, northern blot, immunofluorescence, and western blot. Virus secretion was studied by RNA quantification in supernatants, and the infectivity of secreted HDV particles was measured by reinfection of naive HuH7.5-Na+-taurocholate cotransporting polypeptide cells. In HDV/HBV superinfection models, a 10-day treatment with FXR ligand GW4064 decreased intracellular HDV RNAs by 60% and 40% in dHepaRG cells and primary human hepatocytes, respectively. Both HDV genomic and antigenomic RNAs were affected by treatment, which also reduced the amount of intracellular delta antigen. This antiviral effect was also observed in HDV monoinfected dHepaRG cells, abolished by FXR loss of function, and reproduced with other FXR ligands. In HBV/HDV coinfected dHepaRG cells, HDV secretion was decreased by 60% and virion-specific infectivity by >95%.
CONCLUSIONS
FXR ligands both inhibit directly (ie, independently of anti-HBV activity) and indirectly (ie, dependently of anti-HBV activity) the replication, secretion, and infectivity of HDV. The overall anti-HDV activity was superior to that obtained with interferon-α, highlighting the therapeutic potential of FXR ligands in HDV-infected patients.
Topics: Humans; Hepatitis B virus; Ligands; Bile Acids and Salts; Virion; Taurocholic Acid; Peptides
PubMed: 37058078
DOI: 10.1097/HC9.0000000000000078 -
Microbiology Spectrum Oct 2022Staphylococcus aureus can complicate preceding viral infections, including influenza virus. A bacterial infection combined with a preceding viral infection, known as...
Staphylococcus aureus can complicate preceding viral infections, including influenza virus. A bacterial infection combined with a preceding viral infection, known as superinfection, leads to worse outcomes than a single infection. Most of the pulmonary infection literature focuses on the changes in immune responses to bacteria between homeostatic and virally infected lungs. However, it is unclear how much of an influence bacterial virulence factors have in single or superinfection. Staphylococcal species express a broad range of cell wall-anchored proteins (CWAs) that have roles in host adhesion, nutrient acquisition, and immune evasion. We screened the importance of these CWAs using mutants lacking individual CWAs in both bacterial pneumonia and influenza superinfection. In bacterial pneumonia, the lack of individual CWAs leads to various decreases in bacterial burden, lung damage, and immune infiltration into the lung. However, the presence of a preceding influenza infection partially abrogates the requirement for CWAs. In the screen, we found that the uncharacterized CWA S. aureus surface protein D (SasD) induced changes in both inflammatory and homeostatic lung markers. We further characterized a SasD mutant (sasD A50.1) in the context of pneumonia. Mice infected with sasD A50.1 have decreased bacterial burden, inflammatory responses, and mortality compared to wild-type S. aureus. Mice also have reduced levels of interleukin-1β (IL-1β), likely derived from macrophages. Reductions in IL-1β transcript levels as well as increased macrophage viability point at differences in cell death pathways. These data identify a novel virulence factor for S. aureus that influences inflammatory signaling within the lung. Staphylococcus aureus is a common commensal bacterium that can cause severe infections, such as pneumonia. In the lung, viral infections increase the risk of staphylococcal pneumonia, leading to combined infections known as superinfections. The most common virus associated with S. aureus pneumonia is influenza, and superinfections lead to worse patient outcomes than either infection alone. While there is much known about how the immune system differs between healthy and virally infected lungs, the role of bacterial virulence factors in single and superinfection is less understood. The significance of our research is identifying bacterial components that play a role in the initiation of lung injury, which could lead to future therapies to prevent pulmonary single or superinfection with S. aureus.
Topics: Mice; Animals; Humans; Superinfection; Influenza, Human; Staphylococcus aureus; Interleukin-1beta; Mice, Knockout; Pneumonia, Staphylococcal; Staphylococcal Infections; Lung; Pneumonia, Bacterial; Cell Wall; Virulence Factors; Membrane Proteins
PubMed: 36040164
DOI: 10.1128/spectrum.01645-22 -
PloS One 2021COVID-19 represents high morbidity and mortality, its complications and lethality have increased due to bacterial superinfections. We aimed to determine the prevalence...
COVID-19 represents high morbidity and mortality, its complications and lethality have increased due to bacterial superinfections. We aimed to determine the prevalence of bacterial superinfection in adults with COVID-19, hospitalized in two clinics in Medellín-Colombia during 2020, and its distribution according to sociodemographic and clinical conditions. A cross sectional study was made with 399 patients diagnosed with COVID-19 by RT-PCR. We determined the prevalence of bacterial superinfection and its factors associated with crude and adjusted prevalence ratios by a generalized linear model. The prevalence of superinfection was 49.6%, with 16 agents identified, the most frequent were Klebsiella (pneumoniae and oxytoca) and Staphylococcus aureus. In the multivariate adjustment, the variables with the strongest association with bacterial superinfection were lung disease, encephalopathy, mechanical ventilation, hospital stay, and steroid treatment. A high prevalence of bacterial superinfections, a high number of agents, and multiple associated factors were found. Among these stood out comorbidities, complications, days of hospitalization, mechanical ventilation, and steroid treatment. These results are vital to identifying priority clinical groups, improving the care of simultaneous infections with COVID-19 in people with the risk factors exposed in the population studied, and identifying bacteria of public health interest.
Topics: Aged; COVID-19; Colombia; Drug Therapy; Female; Humans; Klebsiella Infections; Length of Stay; Male; Middle Aged; Prevalence; Respiration, Artificial; Staphylococcal Infections; Superinfection
PubMed: 34255801
DOI: 10.1371/journal.pone.0254671 -
Journal of Neuroinflammation Feb 2023Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine...
Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p < 0.01) higher in those with bacterial superinfection. RNA sequencing in the CSF revealed 101 linear RNAs comprising messenger RNAs, and two circRNAs being significantly differentially expressed in COVID-19 than in non-neuroinflammatory controls and neurodegenerative patients. Our findings may explain the absence of signs of intrathecal inflammation upon routine CSF testing despite the presence of SARS-CoV2 infection-associated neurological symptoms. The relevance of blood-derived mediators of inflammation in the CSF for neurological COVID-19 and post-COVID-19 symptoms deserves further investigation.
Topics: Humans; Proteome; RNA, Viral; Superinfection; COVID-19; SARS-CoV-2; Brain; Inflammation; Encephalitis, Herpes Simplex; Inflammation Mediators
PubMed: 36759861
DOI: 10.1186/s12974-023-02711-2 -
Infection Ecology & Epidemiology 2023The use of steroids has been proposed as a pharmacological approach to treat the SARS-CoV-2 infection to improve outcomes. However, there are doubts about safety... (Review)
Review
The use of steroids has been proposed as a pharmacological approach to treat the SARS-CoV-2 infection to improve outcomes. However, there are doubts about safety against the development of superinfections and their worse outcomes. To establish the relative frequency of superinfection associated with using steroids in patients with SARS-CoV-2 infection. We conducted a systematic literature review and meta-analysis using PRISMA standards in 5 databases (PubMed/Scopus/Cochrane/EMBASE/Google Scholar). The search was carried out between February 2020 and May 2023. The search terms were 'steroids' or 'superinfection' 'and' followed by 'SARS-CoV-2' or 'COVID-19'. We found 77 studies, but only 10 with 3539 patients were included in the systematic review. All patients developed severe disease. The documented OR for superinfection through the meta-analysis was 1.437 (95% IC 0.869-2.378) with a p-value of 0.158 without showing a risk attributed to steroids and the development of superinfections. In the Funnel-plot analysis, no publication biases were found. No relationship was found between using steroids and superinfection in patients with SARS-CoV-2.
PubMed: 38187166
DOI: 10.1080/20008686.2023.2277000 -
Clinical Infectious Diseases : An... Jul 2021The HIV Prevention Trials Network (HPTN) 075 study evaluated the feasibility of enrolling and retaining men who have sex with men (MSM) and transgender women (TGW) from...
Human Immunodeficiency Virus (HIV) Drug Resistance, Phylogenetic Analysis, and Superinfection Among Men Who Have Sex with Men and Transgender Women in Sub-Saharan Africa: HIV Prevention Trials Network (HPTN) 075 Study.
BACKGROUND
The HIV Prevention Trials Network (HPTN) 075 study evaluated the feasibility of enrolling and retaining men who have sex with men (MSM) and transgender women (TGW) from Kenya, Malawi, and South Africa. During the study follow-up, 21 participants acquired human immunodeficiency virus (HIV) (seroconverters). We analyzed HIV subtype diversity, drug resistance, transmission dynamics, and HIV superinfection data among MSM and TGW enrolled in HPTN 075.
METHODS
HIV genotyping and drug resistance testing were performed for participants living with HIV who had viral loads >400 copies/mL at screening (prevalent cases, n = 124) and seroconverters (n = 21). HIV pol clusters were identified using Cluster Picker. Superinfection was assessed by a longitudinal analysis of env and pol sequences generated by next-generation sequencing.
RESULTS
HIV genotyping was successful for 123/124 prevalent cases and all 21 seroconverters. The major HIV subtypes were A1 (Kenya) and C (Malawi and South Africa). Major drug resistance mutations were detected in samples from 21 (14.6%) of 144 participants; the most frequent mutations were K103N and M184V/I. Phylogenetic analyses identified 11 clusters (2-6 individuals). Clusters included seroconverters only (n = 1), prevalent cases and seroconverters (n = 4), and prevalent cases only (n = 6). Superinfections were identified in 1 prevalent case and 2 seroconverters. The annual incidence of superinfection was higher among seroconverters than among prevalent cases, and was higher than the rate of primary HIV infection in the cohort.
CONCLUSIONS
This report provides important insights into HIV genetic diversity, drug resistance, and superinfection among MSM and TGW in sub-Saharan Africa. These findings may help to inform future HIV prevention interventions in these high-risk groups.
Topics: Drug Resistance; Female; HIV; HIV Infections; Homosexuality, Male; Humans; Kenya; Malawi; Male; Phylogeny; Sexual and Gender Minorities; South Africa; Superinfection; Transgender Persons
PubMed: 32761071
DOI: 10.1093/cid/ciaa1136 -
PLoS Pathogens Oct 2023SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory...
SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
Topics: Humans; SARS-CoV-2; Toll-Like Receptor 4; Lipopolysaccharides; Superinfection; COVID-19; Lectins, C-Type; Cytokines; Dendritic Cells
PubMed: 37844099
DOI: 10.1371/journal.ppat.1011735 -
Journal of Clinical Medicine May 2023Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure defined by dysregulated immune homeostasis and alveolar epithelial and...
Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure defined by dysregulated immune homeostasis and alveolar epithelial and endothelial damage. Up to 40% of ARDS patients develop pulmonary superinfections, contributing to poor prognosis and increasing mortality. Understanding what renders ARDS patients highly susceptible to pulmonary superinfections is therefore essential. We hypothesized that ARDS patients who develop pulmonary superinfections display a distinct pulmonary injury and pro-inflammatory response pattern. Serum and BALF samples from 52 patients were collected simultaneously within 24 h of ARDS onset. The incidence of pulmonary superinfections was determined retrospectively, and the patients were classified accordingly. Serum concentrations of the epithelial markers soluble receptor for advanced glycation end-products (sRAGE) and surfactant protein D (SP-D) and the endothelial markers vascular endothelial growth factor (VEGF) and angiopoetin-2 (Ang-2) as well as bronchoalveolar lavage fluid concentrations of the pro-inflammatory cytokines interleukin 1ß (IL-1ß), interleukin 18 (IL-18), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-a) were analyzed via multiplex immunoassay. Inflammasome-regulated cytokine IL-18 and the epithelial damage markers SP-D and sRAGE were significantly increased in ARDS patients who developed pulmonary superinfections. In contrast, endothelial markers and inflammasome-independent cytokines did not differ between the groups. The current findings reveal a distinct biomarker pattern that indicates inflammasome activation and alveolar epithelial injury. This pattern may potentially be used in future studies to identify high-risk patients, enabling targeted preventive strategies and personalized treatment approaches.
PubMed: 37297845
DOI: 10.3390/jcm12113649 -
Open Forum Infectious Diseases Sep 2022Identification of bacterial coinfection in patients with coronavirus disease 2019 (COVID-19) facilitates appropriate initiation or withholding of antibiotics. The...
Detection of Viral Infection and Bacterial Coinfection and Superinfection in Coronavirus Disease 2019 Patients Presenting to the Emergency Department Using the 29-mRNA Host Response Classifier IMX-BVN-3: A Multicenter Study.
BACKGROUND
Identification of bacterial coinfection in patients with coronavirus disease 2019 (COVID-19) facilitates appropriate initiation or withholding of antibiotics. The Inflammatix Bacterial Viral Noninfected (IMX-BVN) classifier determines the likelihood of bacterial and viral infections. In a multicenter study, we investigated whether IMX-BVN version 3 (IMX-BVN-3) identifies patients with COVID-19 and bacterial coinfections or superinfections.
METHODS
Patients with polymerase chain reaction-confirmed COVID-19 were enrolled in Berlin, Germany; Basel, Switzerland; and Cleveland, Ohio upon emergency department or hospital admission. PAXgene Blood RNA was extracted and 29 host mRNAs were quantified. IMX-BVN-3 categorized patients into very unlikely, unlikely, possible, and very likely bacterial and viral interpretation bands. IMX-BVN-3 results were compared with clinically adjudicated infection status.
RESULTS
IMX-BVN-3 categorized 102 of 111 (91.9%) COVID-19 patients into very likely or possible, 7 (6.3%) into unlikely, and 2 (1.8%) into very unlikely viral bands. Approximately 94% of patients had IMX-BVN-3 unlikely or very unlikely bacterial results. Among 7 (6.3%) patients with possible (n = 4) or very likely (n = 3) bacterial results, 6 (85.7%) had clinically adjudicated bacterial coinfection or superinfection. Overall, 19 of 111 subjects for whom adjudication was performed had a bacterial infection; 7 of these showed a very likely or likely bacterial result in IMX-BVN-3.
CONCLUSIONS
IMX-BVN-3 identified COVID-19 patients as virally infected and identified bacterial coinfections and superinfections. Future studies will determine whether a point-of-care version of the classifier may improve the management of COVID-19 patients, including appropriate antibiotic use.
PubMed: 36111173
DOI: 10.1093/ofid/ofac437