Primary Site Of Infection Research Articles

Sepsis and the Microbiome: A Vicious Cycle.

Sepsis has been characterized as a dysregulated host response to infection, and the role of the microbiome as a key influencer of this response is emerging. Disruption of the microbiome while treating sepsis with antibiotics can itself result in immune dysregulation. Alterations in the gut microbiome resulting from sepsis and its treatment have been implicated in organ dysfunction typical of sepsis across multiple tissues including the lung, kidney, and brain. Multiple microbiota-directed interventions are currently under investigation in the setting of sepsis, including fecal transplant, the administration of dietary fiber, and the use of antibiotic scavengers that attenuate the effects of antibiotics on the gut microbiota while allowing them to concentrate at the primary sites of infection. The emerging evidence shows that the gut microbiome interacts with various elements of the septic response, and provides yet another reason to consider the judicious use of antibiotics via antibiotic stewardship programs.

Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host.

Chagas disease is a neglected tropical disease, which affects an estimate of 6-7 million people worldwide. Chagas disease is caused by Trypanosoma cruzi, which is a eukaryotic flagellate unicellular organism. At the primary infection sites, these parasites are phagocytized by macrophages, which produce reactive oxygen species (ROS) in response to the infection with T. cruzi. The ROS produce damage to the host tissues; however, macrophage-produced ROS is also used as a signal for T. cruzi proliferation. At the later stages of infection, mitochondrial ROS is produced by the infected cardiomyocytes that contribute to the oxidative damage, which persists at the chronic stage of the disease. The oxidative damage leads to a functional impairment of the heart. In this review article, we will discuss the mechanisms by which T. cruzi is able to deal with the oxidative stress and how this helps the parasite growth at the acute phase of infection and how the oxidative stress affects the cardiomyopathy at the chronic stage of the Chagas disease. We will describe the mechanisms used by the parasite to deal with ROS and reactive nitrogen species (RNS) through the trypanothione and the mechanisms used to repair the damaged DNA. Also, a description of the events produced by ROS at the acute and chronic stages of the disease is presented. Lastly, we discuss the benefits of ROS for T. cruzi growth and proliferation and the possible mechanisms involved in this phenomenon. Hypothesis is put forward to explain the molecular mechanisms by which ROS triggers parasite growth and proliferation and how ROS is able to produce a long persisting damage on cardiomyocytes even in the absence of the parasite.

The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a “cytokine storm,” featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.

The role of recombinant human thrombopoietin in critically ill patients with sepsis-associated thrombocytopenia: a clinical study

To investigate the effect of recombinant human thrombogenin (rhTPO) on sepsis-associated thrombocytopenia. A prospective randomized controlled study was conducted. One hundred patients with sepsis-associated thrombocytopenia admitted to the department of critical care medicine of the First Affiliated Hospital of Zhengzhou University from August 2019 to October 2020 were enrolled. The enrolled patients were divided into rhTPO-using group (TPO group) and routine group (control group) by random number table method, with 50 cases in each group. Both groups were treated according to the guideline of Sepsis-3. In addition, TPO group received rhTPO 15 000 U, once daily for 7 days. Geneal information and acute physiology and chronic health evaluation II (APACHE II) were recorded. The levels of platelet count (PLT), blood coagulation function [prothrombin time (PT) and prothrombin activity (PTA)], myocardial enzyme indexes [troponin (Tn) and creatine kinase (CK)], liver and kidney function [aspartate aminotransferase (AST), total bilirubin (TBil) and creatinine (Cr)] and inflammatory biomarkers [procalcitonin (PCT) and C-reactive protein (CRP)] were recorded before treatment and 1, 3, 5 and 7 days after treatment. The infusion volume of blood components, duration of mechanical ventilation, length of stay in ICU, total length of hospitalization, total cost of hospitalization and 28-day outcome were recorded. According to whether the PLT was lower than 50×109/L, the patients in TPO group were divided into the TPO A group (PLT ≥ 50×109/L, 16 cases) and TPO B group (PLT < 50×109/L, 34 cases), and the absolute value of PLT increase, duration of mechanical ventilation, length of stay in ICU, total length of hospitalization, total cost of hospitalization and 28-day outcome of the two groups were compared. (1) In TPO and control groups, there were no statistically significant differences in gender, age, proportion of patients with primary infection site, APACHEII score, PLT, coagulation function, myocardial enzymes, liver and kidney function and inflammation indexes before treatment (all P > 0.05). (2) The PLT levels of the TPO group were significantly higher than those of the control group on the 5th and 7th day after treatment (×109/L: day 5, 63.94±44.01 vs. 49.85±29.26, day 7, 125.85±112.31 vs. 76.81±50.87, both P < 0.05), and there were no statistically significant differences in PT, PTA, Tn, CK, AST, TBil, Cr, PCT or CRP before and on the 1, 3, 5, 7 days after treatment between TPO and control groups (all P > 0.05). (3) The amount of platelet transfusion in the TPO group was lower than that in the control group [treatment amount: 0 (0, 0) vs 0 (0, 2.00), P = 0.001]. (4) There were no statistically significant differences in mechanical ventilation time, length of stay in ICU, total length of hospitalization, total cost of hospitalization or 28-day outcome between TPO and control groups (all P > 0.05). The mechanical ventilation time, ICU stay time and total hospitalization time of TPO A group were longer than those in TPO B group, but the differences were not statistically significant [mechanical ventilation time (hours): 131.00 (0, 311.00) vs. 50.00 (0, 192.00), ICU stay time (days): 14.44±8.57 vs. 11.73±9.24, total hospitalization time (days): 15.00 (6.00, 23.50) vs. 18.00 (8.00, 31.00), all P > 0.05]. The absolute value of PLT increase in TPO A group was higher than that of TPO B group, but the difference was not statistically significant [×109/L: 65.00 (16.50, 131.50) vs. 36.00 (18.00, 130.00), P > 0.05]. RhTPO can significantly increase the PLT of patients with sepsis-related thrombocytopenia, thereby reduce the amount of platelet transfusion, but it cannot shorten the length of ICU stay time and total hospitalization time, and it cannot reduce 28-day mortality.

Herpes Simplex Virus Entry by a Nonconventional Endocytic Pathway.

Herpes simplex virus 1 (HSV-1) causes significant morbidity and mortality in humans worldwide. HSV-1 enters epithelial cells via an endocytosis mechanism that is low-pH dependent. However, the precise intracellular pathway has not been identified, including the compartment where fusion occurs. In this study, we utilized a combination of molecular and pharmacological approaches to better characterize HSV entry by endocytosis. HSV-1 entry was unaltered in both cells treated with small interfering RNA (siRNA) to Rab5 or Rab7 and cells expressing dominant negative forms of these GTPases, suggesting entry is independent of the conventional endo-lysosomal network. The fungal metabolite brefeldin A (BFA) and the quinoline compound Golgicide A (GCA) inhibited HSV-1 entry via beta-galactosidase reporter assay and impaired incoming virus transport to the nuclear periphery, suggesting a role for trans-Golgi network (TGN) functions and retrograde transport in HSV entry. Silencing of Rab9 or Rab11 GTPases, which are involved in the retrograde transport pathway, resulted in only a slight reduction in HSV infection. Together, these results suggest that HSV enters host cells by an intracellular route independent of the lysosome-terminal endocytic pathway.IMPORTANCE Herpes simplex virus 1 (HSV-1), the prototype alphaherpesvirus, is ubiquitous in the human population and causes lifelong infection that can be fatal in neonatal and immunocompromised individuals. HSV enters many cell types by endocytosis, including epithelial cells, the site of primary infection in the host. The intracellular itinerary for HSV entry remains unclear. We probed the potential involvement of several Rab GTPases in HSV-1 entry and suggest that endocytic entry of HSV-1 is independent of the canonical lysosome-terminal pathway. A nontraditional endocytic route may be employed, such as one that intersects with the trans-Golgi network (TGN). These results may lead to novel targets for intervention.

Acute descending necrotizing mediastinitis as a complication of the retropharyngeal abscess caused by anaerobes

Descending necrotizing mediastinitis (DNM) is a rare, life-threatening form of mediastinitis caused by odontogenic, pharyngeal, or cervical infections. The retropharyngeal space is the most common primary site of infection. Given the fulminant course and high mortality rate, early diagnosis and prompt treatment are important predictors of survival in patients with DNM. Appropriate empirical antibiotic treatment, prompt surgical intervention, and proper management of patients in the intensive care unit can be of vital importance. We present the case of a previously healthy 20-year-old male patient who was successfully cured and discharged from the Clinical Center University of Sarajevo after suffering from a severe form of mediastinitis as a complication of the retropharyngeal abscess caused by anaerobes.

An individualized administration model of vancomycin in elderly patients with sepsis and factors influencing augmented renal clearance.

Vancomycin efficacy is dependent on appropriate dosing, which should aim to achieve a target serum trough level. The purpose of this study was to determine the variables that predicted vancomycin serum trough concentrations in elderly patients with sepsis. This retrospective cohort study, which was conducted in the medical ICU of a university-affiliated teaching hospital in China, included 87 medical patients with sepsis who were enrolled from January 2014 to December 2017. All the patients were at least 60years old (mean age=74.8±8.2years), and 51.7% (n=45) of them were male. The most common primary site of infection was the lungs (67.8%), followed by the abdomen (12.6%). Patients with septic shock accounted for 21.8% (n=19) of the cases. The proportion of patients with vancomycin serum trough concentrations reaching target concentrations (≥15mg/L) was 47.1% (41 cases). Multivariate linear regression showed that the creatinine clearance rate (CCR) and the daily dosage of vancomycin were independent predictors of vancomycin serum trough concentrations (both p's<0.05), and the model for predicting vancomycin trough concentrations should be: serum trough concentration (mg/L)=15.942-0.101×CCR (mL/min)+0.347×vancomycin daily doses (mg/kg/d). Augmented renal clearance (ARC) was present in 13 patients (14.9%), and logistic regression revealed body mass index (OR=1.420, p=.002) and serum creatinine level (OR=0.883, p=.002) were independent predictors of ARC. The CCR and daily dosage of vancomycin were significantly correlated with vancomycin serum trough concentrations in elderly patients with sepsis, and the individualized administration model should be verified through further clinical trials. BMI and serum creatinine level were identified to be independent predictors of ARC in elderly patients.

Control of Cytokines in Latent Cytomegalovirus Infection.

Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny virions, occurs in differentiated cell types, while undifferentiated myeloid precursor cells are the primary site of latent infection. The outcome of HCMV infection depends partly on the cell type and differentiation state but is also influenced by the composition of the immune environment. In this review, we discuss the role of early interactions between HCMV and the host immune system, particularly cytokine and chemokine networks, that facilitate the establishment of lifelong latent infection. A better understanding of these cytokine signaling pathways could lead to novel therapeutic targets that might prevent latency or eradicate latently infected cells.

Transcriptional and proteomic insights into the host response in fatal COVID-19 cases

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome.

Mitochondria, are undoubtedly critical organelle of a eukaryotic cell, which provide energy and offer a platform for most of the cellular signaling pathways that decide cell fate. The role of mitochondria in immune-metabolism is now emerging as a crucial process governing several pathological states, including infection, cancer, and diabetes. Mitochondria have therefore been a vulnerable target for several bacterial and viral pathogens to control host machinery for their survival, replication, and dissemination. Mycobacterium tuberculosis, a highly successful human pathogen, persists inside alveolar macrophages at the primary infection site, applying several strategies to circumvent macrophage defenses, including control of host mitochondria. The infection perse and specific mycobacterial factors that enter the host mitochondrial milieu perturb mitochondrial dynamics and function by disturbing mitochondrial membrane potential, shifting bioenergetics parameters such as ATP and ROS, orienting the host cell fate and thereby infection outcome. In the present review, we attempt to integrate the available information and emerging dogmas to get a holistic view of Mycobacterium tuberculosis infection vis-a-vis mycobacterial factors that target host mitochondria and changes therein in terms of morphology, dynamics, proteomic, and bioenergetic alterations that lead to a differential cell fate and immune response determining the disease outcome. We also discuss critical host factors and processes that are overturned by Mycobacterium tuberculosis, such as cAMP-mediated signaling, redox homeostasis, and lipid droplet formation. Further, we also present alternate dogmas as well as the gaps and limitations in understanding some of the present research areas, which can be further explored by understanding some critical processes during Mycobacterium tuberculosis infection and the reasons thereof. Toward the end, we propose to have a set of guidelines for pursuing investigations to maintain uniformity in terms of early and late phase, MOI of infection, infection duration and incubation periods, the strain of mycobacteria, passage numbers, and so on, which all work as probable variables toward different readouts. Such a setup would, therefore, help in the smooth integration of information across laboratories toward a better understanding of the disease and possibilities of host-directed therapy.

Circular RNA PRKCI and microRNA-545 relate to sepsis risk, disease severity and 28-day mortality

This study aimed to explore the clinical values of circular RNA protein kinase C iota (circ-PRKCI) and its target microRNA-545 (miR-545) in sepsis patients. Plasma samples of 121 sepsis patients and 60 healthy controls (HCs) were collected, then circ-PRKCI and miR-545 expressions were detected using RT-qPCR. Sepsis patients’ demographics, biochemical indexes, medical histories, infection information were recorded. Besides, comprehensive disease scores (APACHE II score and SOFA score) were assessed within 24 h after admission. According to the survival status, 28-day mortality was calculated. Decreased circ-PRKCI expression and increased miR-545 expression were observed in sepsis patients compared to HCs, both of which had close correlations with sepsis risk. Besides, circ-PRKCI was negatively correlated with miR-545 in sepsis patients and HCs, respectively. Circ-PRKCI was negatively correlated with serum creatinine, white blood cell, C-reactive protein, APACHE II score, SOFA score, but positively correlated with albumin, which also related to blood stream infection (as primary infection site) and anaerobes infection in sepsis patients. Whereas the miR-545 showed a roughly opposite tendency. Decreased circ-PRKCI and increased miR-545 expressions were discovered in deaths compared to survivors, and both of them had values for predicting 28-day mortality risk in sepsis patients, which were slightly lower than the predictive values of APACHE II score and SOFA score for predicting 28-day mortality risk. Multivariate logistic analyses displayed circ-PRKCI as an independent factor predicting decreased 28-day mortality risk. In conclusion, circ-PRCKI insufficiency and miR-545 sufficiency were related to sepsis risk, clinical disease severity and 28-day mortality risk.

Abstract S01-01: Therapeutic targeting of TMPRSS2 and ACE2 as a potential strategy to combat COVID-19

Abstract The novel SARS-CoV-2 infection responsible for the COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm associated oncogenic signaling. A better understanding of the host cell factors and their regulators will help identify potential therapies to block SARS-CoV-2 infection at an early stage and thereby prevent cancer progression. Host cell infection by SARS-CoV-2 requires the binding of the viral spike S protein to ACE2 receptor and priming by the serine protease TMPRSS2—encoded by a well-known androgen response gene and highly expressed in patients diagnosed with prostate cancer. Epidemiologic data showing increased severity and mortality of SARS-CoV-2 disease in men suggest a possible role for androgen in the transcriptional activation of ACE2 and TMPRSS2 in the lungs and other primary infection sites. Here, by performing in vivo castration in mice, RT-PCR, immunoblotting, Co-IP, and pseudovirus infection assays in multiple cell lines, we present evidence for the transcriptional regulation of TMPRSS2 and ACE2 by androgen, their endogenous interaction, as well as a novel combination of drugs in blocking viral infection. In adult male mice, castration led to a significant loss in the expression of ACE2 and TMPRSS2 at the transcript and protein levels in the lung, heart, and small intestine. Intriguingly, castrated mice displayed a substantial increase in ACE2 in the kidney, which could potentially be due to the low blood pressure resulting from androgen deprivation. Endogenous TMPRSS2 and ACE2 were found to be physically interacting, as observed by reciprocal immunoprecipitation followed by immunoblotting. Importantly, along with full-length zymogen form, a prominent novel small isoform of TMPRSS2 was found to be associated with ACE2 in lung and prostate cells. In an overexpression system, camostat—a serine protease inhibitor specific to TMPRSS2—inhibited the cleavage of spike S, suggesting a direct role of this serine protease in priming the viral spike S protein, a prerequisite for an active infection. Furthermore, a combination of camostat, antiandrogen, and epigenetic drugs at sublethal concentrations blocked SARS-CoV-2 pseudovirus infection in multiple cell types. Together, our preclinical data provide a strong rationale for clinical evaluation of TMRPSS2 inhibitors, antiandrogens, and epigenetic drug combinations along with antiviral drug remdesivir as early as clinically possible to prevent progression to pneumonia and multiorgan failure as a result of hyperinflammatory responses in COVID-19 patients. Citation Format: Qu Deng, Reyaz Ur Rasool, Ramakrishnan Natesan, Irfan A. Asangani. Therapeutic targeting of TMPRSS2 and ACE2 as a potential strategy to combat COVID-19 [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S01-01.

Digital droplet PCR for the detection and quantification of circulating bovine Deltapapillomavirus.

In this study, the digital droplet polymerase chain reaction (ddPCR) was used to quantify circulating bovine papillomavirus (BPV; genus: Deltapapillomavirus) DNA levels in blood samples from 25 clinically normal cows and 15 cows with chronic enzootic haematuria due to papillomavirus-associated bladder tumours. ddPCR detected BPV DNA in 95% of all the samples (i.e. in 24 of the clinically normal cows and 14 of the diseased animals), whereas quantitative real-time PCR (qPCR) detected it in only 57.5% of the same blood samples, with percentage differences between ddPCR and qPCR being statistically significant (p-value≤.05), according to chi-squared test. Furthermore, ddPCR detected BPV infections by a single genotype and by multiple genotypes in 37% and 63% of the cows, whereas qPCR detected these in 16% and 16%. Of the two assays, ddPCR was the more sensitive and accurate clinical diagnostic tool, allowing the detection of otherwise undetectable BPV genotypes, and consequently, a higher number of BPV co-infections. qPCR failed to detect many BPV co-infections by multiple genotypes. Therefore, ddPCR may be an essential tool for improving diagnostic procedures, allowing the identification of the genotypic distribution of BPV and a better understanding about the territorial divergence, if any, of the BPV prevalence in different areas. No significant differences in the blood viral load estimations were observed between the two animal groups, suggesting that the bloodstream could be a site of primary infection. Finally, as BPV DNA was detected in cows affected by non-invasive urothelial tumours, including papilloma and papillary urothelial neoplasms of low malignant potential, the circulating BPVs appeared to be independent of the status of urothelial neoplasms. Therefore, unlike in humans, circulating BPVs cannot be an actual prognostic marker of urothelial tumours in cows.

Identification of a Novel LysR-Type Transcriptional Regulator in Staphylococcus aureus That Is Crucial for Secondary Tissue Colonization during Metastatic Bloodstream Infection.

Staphylococcus aureus is a common cause of bacteremia that can lead to severe complications once the bacteria exit the bloodstream and establish infection in secondary organs. Despite its clinical relevance, little is known about the bacterial factors facilitating the development of these metastatic infections. Here, we used an S. aureus transposon mutant library coupled to transposon insertion sequencing (Tn-Seq) to identify genes that are critical for efficient bacterial colonization of secondary organs in a murine model of metastatic bloodstream infection. Our transposon screen identified a LysR-type transcriptional regulator (LTTR), which was required for efficient colonization of secondary organs such as the kidneys in infected mice. The critical role of LTTR in secondary organ colonization was confirmed using an isogenic mutant deficient in the expression of LTTR. To identify the set of genes controlled by LTTR, we used an S. aureus strain carrying the LTTR gene in an inducible expression plasmid. Gene expression analysis upon induction of LTTR showed increased transcription of genes involved in branched-chain amino acid biosynthesis, a methionine sulfoxide reductase, and a copper transporter as well as decreased transcription of genes coding for urease and components of pyrimidine nucleotides. Furthermore, we show that transcription of LTTR is repressed by glucose, is induced under microaerobic conditions, and required trace amounts of copper ions. Our data thus pinpoints LTTR as an important element that enables a rapid adaptation of S. aureus to the changing host microenvironment.IMPORTANCEStaphylococcus aureus is an important pathogen that can disseminate via the bloodstream and establish metastatic infections in distant organs. To achieve a better understanding of the bacterial factors facilitating the development of these metastatic infections, we used in this study a Staphylococcus aureus transposon mutant library in a murine model of intravenous infection, where bacteria first colonize the liver as the primary infection site and subsequently progress to secondary sites such as the kidney and bones. We identified a novel LysR-type transcriptional regulator (LTTR), which was specifically required by S. aureus for efficient colonization of secondary organs. We also determined the transcriptional activation as well as the regulon of LTTR, which suggests that this regulator is involved in the metabolic adaptation of S. aureus to the host microenvironment found in secondary infection sites.

Murine Skin-resident γδT Cells Impair the Immune Response to HSV in Skin.

HSV is an important cause of brain infection. Virus entry is often through breeches in the skin. γδT cells play an immunoprotective role in mice after corneal, genital or footpad (subcutaneous) HSV infection. Here we report that the presence of γδT cells in murine skin is associated with increased severity of herpetic disease, reduced protective cytokine responses and increased viral spread from the skin to the sensory ganglia in the zosteriform model. γδT cell-deficient (TCR δ -/-) mice displayed significantly decreased herpetic lesion severity after flank HSV infection compared to WT C57BL/6 controls at both primary and secondary skin infection sites. Viral titer at the primary skin site was similar to WT mice in γδT cell-deficient mice, but was significantly decreased in the ganglia and secondary skin site. γδT cell-deficient mice showed increased Th1 responses by both T cells and non-T cells at the primary site, and decreased T-cell Th17 responses and immune infiltration at the secondary site. Cytokine responses of epidermal and dermal γδT cells to HSV also differed in WT mice (Th1 in epidermis, and Th17 in the dermis), suggesting a functional dichotomy between these two subsets. Our data suggest that in contrast to other mouse models of HSV infection, skinresident γδT cells promote the pathogenesis of HSV in skin.

Multimodality Imaging in the Diagnostic Work-Up of Endocarditis and Cardiac Implantable Electronic Device (CIED) Infection.

Infective endocarditis (IE) is a serious cardiac condition, which includes a wide range of clinical presentations, with varying degrees of severity. The diagnosis is multifactorial and a proper characterization of disease requires the identification of the primary site of infection (usually the cardiac valve) and the search of secondary systemic complications. Early depiction of local complications or distant embolization has a great impact on patient management and prognosis, as it may induce to aggressive antibiotic treatment or, in more advanced cases, cardiac surgery. In this setting, the multimodality imaging has assumed a pivotal role in the clinical decision making and it requires the physician to be aware of the advantages and disadvantages of each imaging technique. Echocardiography is the first imaging test, but it has several limitations. Therefore, the integration with other imaging modalities (computed tomography, magnetic resonance imaging, nuclear imaging) becomes often necessary. Different strategies should be applied depending on whether the infection is suspected or already ascertained, whether located in native or prosthetic valves, in the left or right chambers, or if it involves an implanted cardiac device. In addition, detection of extracardiac IE-related lesions is crucial for a correct management and treatment. The aim of this review is to illustrate strengths and weaknesses of the various methods in the most common clinical scenarios.

Interdigital Tinea: The Forerunner of Infectious Eczematoid Dermatitis

Infectious eczematoid dermatitis (IED) is defined as an acute, eczematous eruption that occurs secondary to autosensitization to purulent drainage from a primary infected site. The condition is believed to develop when bacterial products, most often the result of Staphylococcal or Streptococcal species, act as haptens and stimulate an immune response. IED typically manifests as a plaque with associated vesicles and pustules surrounding drainage from a central infectious source, or as oozing, erythema, crusting, and scaling spreading peripherally from a central infectious source. Management of IED includes both targeting the causative primary infection and suppressing the immune response producing a hypersensitivity reaction. This report details two cases. Case 1 describes a common presentation of tinea pedis. Case 2 is that of a 28 year-old-male who presented with an acute onset tender, pruritic, weeping rash after wearing boots for two straight days, and who was subsequently diagnosed and treated for IED.

C-Type Lectin Receptors in Host Defense Against Bacterial Pathogens.

Antigen-presenting cells (APCs) are present throughout the human body—in tissues, at barrier sites and in the circulation. They are critical for processing external signals to instruct both local and systemic responses toward immune tolerance or immune defense. APCs express an extensive repertoire of pattern-recognition receptors (PRRs) to detect and transduce these signals. C-type lectin receptors (CLRs) comprise a subfamily of PRRs dedicated to sensing glycans, including those expressed by commensal and pathogenic bacteria. This review summarizes recent findings on the recognition of and responses to bacteria by membrane-expressed CLRs on different APC subsets, which are discussed according to the primary site of infection. Many CLR-bacterial interactions promote bacterial clearance, whereas other interactions are exploited by bacteria to enhance their pathogenic potential. The discrimination between protective and virulence-enhancing interactions is essential to understand which interactions to target with new prophylactic or treatment strategies. CLRs are also densely concentrated at APC dendrites that sample the environment across intact barrier sites. This suggests an–as yet–underappreciated role for CLR-mediated recognition of microbiota-produced glycans in maintaining tolerance at barrier sites. In addition to providing a concise overview of identified CLR-bacteria interactions, we discuss the main challenges and potential solutions for the identification of new CLR-bacterial interactions, including those with commensal bacteria, and for in-depth structure-function studies on CLR-bacterial glycan interactions. Finally, we highlight the necessity for more relevant tissue-specific in vitro, in vivo and ex vivo models to develop therapeutic applications in this area.

Fatty acids as novel treatment options for Pseudomonad and Staphylococcal infection

Pseudomonas aeruginosa and Staphylococcus aureus are bacteria pathogens that cause a myriad of infections affecting various sites in the body including the eyes, ears, lungs, skin, heart, bones, and blood amongst others. These bacteria can be disseminated via the blood to other parts of the body away from the primary site of infection and consequences vary from mild to severe with death occurring in certain instances. Both bacterial infections can occur individually, as well as in co-infection resulting in even worse outcomes. P. aeruginosa and S. aureus exhibit multidrug resistance against current antibiotic treatment regimens, which accentuates the challenge in managing the infections caused by these bacteria. To prevent the looming era of untreatable bacterial infections, alternative treatment regimens that are cost effective and accessible are needed. To explore novel treatment options, twenty-five organic compounds comprising fatty acids and their derivatives were screened for antibacterial activity in broth microdilution assay to determine the minimum inhibitory concentration and minimum bactericidal concentration against both P. aeruginosa and S. aureus. Five candidates (N–nonanoic acid, butyric acid, heptanoic acid, palmitoleic acid, and isopropyl myristate) were effective against P. aeruginosa. Seven candidates (N–nonanoic acid, palmitoleic acid, tridecanoic acid, sebaic acid, undecanoic acid, monolaurin, and monocaprin) were effective against S. aureus. Candidates such as N–nonanoic acid and palmitoleic acid were effective against both P. aeruginosa and S. aureus, demonstrating that the same fatty acids show potential to be used against both Gram negative and Gram positive bacterial infections.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n=24) and orthopaedic limitations (n=19). Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.