Sepsis-Related Lung Injury and the Complication of Extrapulmonary Pneumococcal Pneumonia.

Globally, sepsis and pneumonia account for significant mortality and morbidity. A complex interplay of immune-molecular pathways underlies both sepsis and pneumonia, resulting in similar and overlapping disease characteristics. Sepsis could result from unmanaged pneumonia. Similarly, sepsis patients have pneumonia as a common complication in the intensive care unit. A significant percentage of pneumonia is misdiagnosed as septic shock. Therefore, our knowledge of the clinical relationship between pneumonia and sepsis is imperative to the proper management of these syndromes. Regarding pathogenesis and etiology, pneumococcus is one of the leading pathogens implicated in both pneumonia and sepsis syndromes. Growing evidence suggests that pneumococcal pneumonia can potentially disseminate and consequently induce systemic inflammation and severe sepsis. Streptococcus pneumoniae could potentially exploit the function of dendritic cells (DCs) to facilitate bacterial dissemination. This highlights the importance of pathogen-immune cell crosstalk in the pathophysiology of sepsis and pneumonia. The role of DCs in pneumococcal infections and sepsis is not well understood. Therefore, studying the immunologic crosstalk between pneumococcus and host immune mediators is crucial to elucidating the pathophysiology of pneumonia-induced lung injury and sepsis. This knowledge would help mitigate clinical diagnosis and management challenges.

The Potential of Bacteriophage-Antibiotic Combination Therapy in Treating Infections with Multidrug-Resistant Bacteria.

The growing threat of antibiotic resistance is a significant global health challenge that has intensified in recent years. The burden of antibiotic resistance on public health is augmented due to its multifaceted nature, as well as the slow-paced and limited development of new antibiotics. The threat posed by resistance is now existential in phage therapy, which had long been touted as a promising replacement for antibiotics. Consequently, it is imperative to explore the potential of combination therapies involving antibiotics and phages as a feasible alternative for treating infections with multidrug-resistant bacteria. Although either bacteriophage or antibiotics can potentially treat bacterial infections, they are each fraught with resistance. Combination therapies, however, yielded positive outcomes in most cases; nonetheless, a few combinations did not show any benefit. Combination therapies comprising the synergistic activity of phages and antibiotics and combinations of phages with other treatments such as probiotics hold promise in the treatment of drug-resistant bacterial infections.

Microbial Contamination of Herbal Preparations on the Ghanaian Market, Accra.

In developing countries, an estimated 80% of the population use traditional herbal medicines as part of their primary health care. As the market for herbal medicine expands in many African countries, partly due to their use in the treatment of COVID-19, there is the need to address all the associated safety issues. The aim of the study was to evaluate the microbial contamination of locally prepared, as well as imported foreign herbal products sold in Accra. Standard microbiological methods were employed in the enumeration of coliforms and the identification of pathogenic microbes in 60 herbal preparations that were sampled. A larger proportion (76.7%) of local herbal preparations was contaminated with bacteria as compared with imported ones (63.3%). Bacillus species and Pseudomonas aeruginosa were the predominant bacteria obtained from foreign and locally manufactured herbal preparations, respectively. A proportion of 36.7% (11) of the local samples were positive for coliform and the coliform counts ranged from 3.0 × 101 cfu/ml to 2.0 × 104 cfu/ml. Two foreign herbal samples (6.7%) were positive for coliforms; one had a count of 1.7 × 105 cfu/g while the other had 2 × 104 cfu/g. Herbal preparations sold in markets of Accra harbour several microbial pathogens; the risk is relatively higher for locally produced herbal preparations compared to imported herbal preparations. As a result, it is recommended that quality assurance in the production of local herbal preparations should be thoroughly monitored from the beginning of production to the final selling of the preparations. There is also the need to strengthen microbiological safety monitoring of imported herbal preparations.

The Spike Glycoprotein of SARS-CoV-2 Binds to ß1 Integrins Expressed on the Surface of Lung Epithelial Cells.

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl-glycyl-aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the ß1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular ß1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the ß1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.

Irisin supports integrin-mediated cell adhesion of lymphocytes.

Irisin, a myokine released from skeletal muscle, has recently been found to act as a ligand for the integrins αVß5, αVß1, and α5ß1 expressed on mesenchymal cells, thereby playing an important role in the metabolic remodeling of the bone, skeletal muscle and adipose tissues. Although the immune-modulatory effects of irisin in chronic inflammation have been documented, its interactions with lymphocytic integrins have yet to be elucidated. Here, we show that irisin supports the cell adhesion of human and mouse lymphocytes. Cell adhesion assays using a panel of inhibitory antibodies to integrins have shown that irisin-mediated lymphocyte adhesion involves multiple integrins including not only α4ß1 and α5ß1, but also leukocyte-specific αLß2 and α4ß7. Importantly, mouse lymphocytic TK-1 cells that lack the expression of ß1 integrins have exhibited αLß2- and α4ß7-mediated cell adhesion to irisin. Irisin has also been demonstrated to bind to purified recombinant integrin αLß2 and α4ß7 proteins. Thus, irisin represents a novel ligand for integrin αLß2 and α4ß7, capable of supporting lymphocyte cell adhesion independently of ß1 integrins. These results suggest that irisin may play an important role in regulating lymphocyte adhesion and migration in the inflamed vasculature.

The Lectin-Like Domain of Thrombomodulin Inhibits ß1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin.

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between ß1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca2+ and Mg2+ but not under strong integrin-activation conditions in the presence of Mg2+ without Ca2+. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of ß1 integrin of breast cancer cell lines to fibronectin.

Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin.

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.

Sepsis Induces Deregulation of IL-13 Production and PD-1 Expression in Lung Group 2 Innate Lymphoid Cells.

ABSTRACT: Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expression. Furthermore, using IL-33 knockout mice, we have shown that IL-33 regulates the capacity of ILC2s to produce IL-13, possibly through the modulation of ST2 and PD-1 expression and signaling in the septic lung. To the best of our knowledge, this is the first report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.

Renewable energy consumption in Africa: Evidence from a bias corrected dynamic panel.

Our study investigates the determinants of renewable energy consumption in Sub-Sahara Africa. We explore the driving factors of renewable energy consumption in the context of carbon intensity for 32 Sub-Saharan African countries from 1990 to 2015. Using carbon emission intensity to identify group-specific heterogeneity, we recognize carbon-efficient and least carbon-efficient countries in the region. By relying on the corrected least squares dummy variable estimator (LSDVC), we provide evidence on the driving factors of renewable energy consumption in Sub-Saharan Africa. Consequently, the findings point to varying degrees of impact on renewable energy consumption in the region. For instance, we observe advancement in technology, quality of governance, economic progress, biomass consumption, and climatic conditions influence renewable energy consumption. With a common occurrence across all groups, the implications indicate environmental, socio-economic, and climatic factors playing an important role in renewable energy consumption. The study further shows that urbanization and economic globalization depress efforts towards renewable energy consumption. Apart from these common factors, other controlling variables including; GDP per capita, environmental awareness, and biomass affect each group differently. We conclude that, policy implications can be drawn from common factors towards harmonization of clean energy markets and developing a policy mix that combines environmental, economic, and social factors in attaining the Sustainable Development Goals.

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin.

Integrins are transmembrane proteins that mediate cellular adhesion and migration to neighboring cells or the extracellular matrix, which is essential for cells to undertake diverse physiological and pathological pathways. For integrin activation and ligand binding, bidirectional signaling across the cell membrane is needed. Integrins aberrantly activated under pathologic conditions facilitate cellular infiltration into tissues, thereby causing inflammatory or tumorigenic progressions. Thus, integrins have emerged to the forefront as promising targets for developing therapeutics to treat autoimmune and cancer diseases. In contrast, it remains a fact that integrin-ligand interactions are beneficial for improving the health status of different tissues. Among these ligands, irisin, a myokine produced mainly by skeletal muscles in an exercise-dependent manner, has been shown to bind to integrin αVß5, alleviating symptoms under unfavorable conditions. These findings may provide insights into some of the underlying mechanisms by which exercise improves quality of life. This review will discuss the current understanding of integrin-ligand interactions in both health and disease. Likewise, we not only explain how diverse ligands play different roles in mediating cellular functions under both conditions via their interactions with integrins, but also specifically highlight the potential roles of the emerging ligand irisin in inflammation, cancer, and metabolic disease.

Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-a and IL-17A Expression in Mucosal Inflammation.

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-a and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-a and IL-17A. These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.

Differential Roles of Dendritic Cells in Expanding CD4 T Cells in Sepsis.

Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses in sepsis. We identified a differential impact of the systemic and mucosal DCs on proliferating allogenic CD4 T cells in a mouse model of sepsis. Despite the fact that the frequency of CD4 T cells was reduced in septic mice, septic mesenteric lymph node (MLN) DCs proved superior to septic spleen (SP) DCs in expanding allogeneic CD4 T cells. Moreover, septic MLN DCs markedly augmented the surface expression of MHC class II and CD40, as well as the messaging of interleukin-1ß (IL-1ß). Interestingly, IL-1ß-treated CD4 T cells expanded in a dose-dependent manner, suggesting that this cytokine acts as a key mediator of MLN DCs in promoting septic inflammation. Thus, mucosal and systemic DCs were found to be functionally different in the way CD4 T cells respond during sepsis. Our study provides a molecular basis for DC activity, which can be differential in nature depending on location, whereby it induces septic inflammation or immune-paralysis.

Anti-adhesive effects of human soluble thrombomodulin and its domains.

We reported previously that leukocyte ß2 integrins (LFA-1 and Mac-1) bind to the serine/threonine-rich domain of thrombomodulin (TM) expressed on vascular endothelial cells (VECs). Recombinant human soluble TM (rhsTM, TMD123) has been approved as a therapeutic drug for septic disseminated intravascular coagulation. However, the roles of TMD123 on the adhesion of leukocyte integrins to VECs remain unclear. In the current study, we have revealed that an integrin-dependent binding between human peripheral blood mononuclear cells (PBMCs) and VECs was inhibited by TMD123. Next, using mutant proteins composed of isolated TM extracellular domains, we examined the structural characteristics responsible for the anti-adhesion properties of TMD123. Namely, we investigated whether the effects of the binding of TM and leukocytes was inhibited by the administration of TMD123. In fact, we confirmed that TMD123, TMD1, and TMD3 inhibited the binding of PBMCs to the immobilized recombinant proteins TMD123 and TMD3. These results indicate that TMD123 inhibited the adhesion of leukocytes to endothelial cells via ß2 integrins and endothelial TM. Moreover, since TMD1 might bind to leukocytes via other adhesion receptors than integrins, TMD1 and TMD3 appear to inhibit leukocyte binding to TM on VECs via different mechanisms. In summary, TMD123 (rhsTM), TMD1 or TMD3 is a promising treatment option for sepsis that attenuates integrin-dependent binding of leukocytes to VECs, and may inhibit the undesirable adhesion and migration of leukocytes to VECs in sepsis.

Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis.

Extracellular vesicles (EVs) in the plasma mediate important intercellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programmed cell death ligand 1 and 2 (PD-L1 and 2) that suppress lymphocyte activation. However, the roles of these molecules on EVs in systemic inflammatory response syndrome (SIRS) and sepsis remain little understood. This study aimed to investigate how the EV expression of integrins and PD-1 ligands might differ in SIRS and sepsis, compared with healthy controls, and to correlate their expression with the clinical parameters reflecting pathogenesis. Twenty-seven SIRS patients without sepsis, 27 sepsis patients, and 18 healthy volunteers were included. EVs were isolated from plasma samples. The expression of three major integrins (ß1, ß2, ß3 integrins) and PD-L1 and 2 were measured. The EV expression of ß2 integrin and PD-L2 was significantly increased in sepsis patients compared with healthy controls. EV expression of PD-L1 was not elevated in sepsis and SIRS; however, circulating soluble PD-L1 levels were significantly higher in sepsis. Furthermore, EV expression of ß2 integrin in sepsis patients correlated with hypotension and reduced kidney function. In addition, soluble PD-L1 levels correlated with sepsis severity, impaired kidney function, and impaired central nervous system function. These results suggest the potential involvements of the EV ß2 integrin, as well as EV PD-L2 and soluble PD-L1, in the septic pathogenesis that occurs with the systemic immune activation leading to multiple organ dysfunctions.

Exosomal regulation of lymphocyte homing to the gut.

Exosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4ß7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4ß7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4ß7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.

Post-Stroke Bacteriuria: A Longitudinal Study among Stroke Outpatients and Inpatients at the Korle-Bu Teaching Hospital in Ghana.

Infections of the urinary tract constitute an important post-stroke complication but in Africa, little is known about such infections in relation to stroke patients. The aim of the study was to investigate the epidemiology of bacteriuria among stroke patients at the Korle-Bu Teaching Hospital (KBTH) in Ghana including the prevalence, incidence, risk factors and aetiological agents. This was a longitudinal study involving 55 outpatients and 16 inpatients of stroke from the physiotherapy clinic and stroke admission ward of KBTH respectively. Urine cultures for inpatient subjects were done each day until the patient was discharged. With outpatients, urine specimens were analysed every week or two for 6 months. Information on demographics and clinical history of the study participants were extracted from their clinical records. The results showed that the prevalence of bacteriuria among stroke outpatients and inpatients were 10.9% (6/55) and 18.8% (3/16) respectively (p = 0.411). Among both the outpatients and inpatients, there was one new case of bacteriuria each during the period of follow-up. Overall, 1/9 (11%) of the bacteriuria cases among the stroke patients was symptomatic. Severe stroke (OR = 17.7, p = 0.008) and pyuria (OR = 38.7, p = 0.002) were identified as predictors of bacteriuria. Escherichia coli was the most common organism implicated in bacteriuria and was susceptible to amikacin, but resistant to augmentin, ampicillin, cefuroxime, cotrimoxazole, meropenem, norfloxacin and tetracycline. Overall, bacteriuria is a common complication among both stroke inpatients and outpatients at KBTH, though it appears to be more common among the former. Stroke severity appears to be the main stroke-related determinant of bacteriuria among stroke patients. Bacteriuria among stroke patients is mainly asymptomatic and E. coli is the most important aetiological agent.

Risk of Asymptomatic Bacteriuria among People with Sickle Cell Disease in Accra, Ghana.

Asymptomatic bacteriuria (ASB) is benign except in certain medical conditions such as pregnancy and immunosuppression. In Ghana, there are hardly any studies on urinary infections among sickle cell disease (SCD) patients, and the few studies carried out in Africa focused on pediatric SCD populations. The current study aimed to investigate the risk of ASB among SCD patients at a tertiary hospital in Ghana. This was a cross-sectional study involving 110 SCD patients and 110 age and sex matched healthy controls. Urine specimens were collected from all the study subjects and analyzed by standard microbiological methods. Demographic information were also collected from the study subjects. The overall ASB prevalence was significantly higher among SCD patients (17.2%) than among the control group (8.2%), and the relative risk was 2.11 (p = 0.0431; CI = 1.00-4.45). Being female was as a predictor of ASB among the SCD patients (OR = 14.76; CI = 11.23-18.29; p = 0.0103). The most common organism isolated from the study participants was coagulase negative Staphylococcus species (4.1%), followed by Escherichia coli (2.7%); etiology of ASB in the SCD patients was more diverse compared to healthy people. All the E. coli isolates were susceptible to amikacin, sparfloxacin and norfloxacin but resistant to ampicillin.