Alcohol enhances type 1 interferon-α production and mortality in young mice infected with Mycobacterium tuberculosis.

In the current study, we used a mouse model and human blood samples to determine the effects of chronic alcohol consumption on immune responses during Mycobacterium tuberculosis (Mtb) infection. Alcohol increased the mortality of young mice but not old mice with Mtb infection. CD11b+Ly6G+ cells are the major source of IFN-α in the lungs of Mtb-infected alcohol-fed young mice, and IFN-α enhances macrophage necroptosis in the lungs. Treatment with an anti-IFNAR-1 antibody enhanced the survival of Mtb-infected alcohol-fed young mice. In response to Mtb, peripheral blood mononuclear cells (PBMCs) from alcoholic young healthy individuals with latent tuberculosis infection (LTBI) produced significantly higher amounts of IFN-α than those from non-alcoholic young healthy LTBI+ individuals and alcoholic and non-alcoholic old healthy LTBI+ individuals. Our study demonstrates that alcohol enhances IFN-α production by CD11b+Ly6G+ cells in the lungs of young Mtb-infected mice, which leads to macrophage necroptosis and increased mortality. Our findings also suggest that young alcoholic LTBI+ individuals have a higher risk of developing active TB infection.

IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice.

In this study, we determined the role of IL-21R signaling in Mycobacterium tuberculosis infection, using IL-21R knockout (KO) mice. A total of 50% of M. tuberculosis H37Rv-infected IL-21R KO mice died in 6 mo compared with no deaths in infected wild type (WT) mice. M. tuberculosis-infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of Ag-specific T cells in lungs compared with M. tuberculosis-infected WT mice. Ag-specific T cells from the lungs of M. tuberculosis-infected IL-21R KO mice had increased expression of T cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less, and produced less IFN- γ, compared with Ag-specific T cells from the lungs of M. tuberculosis-infected WT mice. T cells from M. tuberculosis-infected IL-21R KO mice were unable to induce optimal macrophage responses to M. tuberculosis. This may be due to a decrease in the Ag-specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin and enhanced functional capacity of Ag-specific T cells of M. tuberculosis-infected mice. The sum of our findings suggests that IL-21R signaling is essential for the optimal control of M. tuberculosis infection.

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection.

In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.

Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection.

Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.

A rho GDP dissociation inhibitor produced by apoptotic T-cells inhibits growth of Mycobacterium tuberculosis.

In this study, we found that a subpopulation of CD4(+)CD25(+) (85% Foxp3(+)) cells from persons with latent tuberculosis infection (LTBI) inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4(+)CD25(+) (85% Foxp3(+)) cells is responsible for this inhibition of M. tb growth in human macrophages and in mice. M. tb-expanded CD4(+C)D25(+)Foxp3(+)D4GDI(+) cells do not produce IL-10, TGF-ß and IFN-γ. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1ß, TNF-α and ROS, and by increasing apoptosis of M. tb-infected MDMs. D4GDI was concentrated at the site of disease in tuberculosis patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from tuberculosis patients produced less D4GDI than PBMC from persons with LTBI. M. tb-expanded CD4+CD25+ (85% Foxp3(+)) cells and D4GDI induced intracellular M. tb to express the dormancy survival regulator DosR and DosR-dependent genes, suggesting that D4GDI induces a non-replicating state in the pathogen. Our study provides the first evidence that a subpopulation of CD4(+)CD25(+) (85% Foxp3+) cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.

Antimicrobial Treatment Options for Difficult-to-Treat Resistant Gram-Negative Bacteria Causing Cystitis, Pyelonephritis, and Prostatitis: A Narrative Review.

Urinary tract infections, including cystitis, acute pyelonephritis, and prostatitis, are among the most common diagnoses prompting antibiotic prescribing. The rise in antimicrobial resistance over the past decades has led to the increasing challenge of urinary tract infections because of multidrug-resistant and "difficult-to-treat resistance" among Gram-negative bacteria. Recent advances in pharmacotherapy and medical microbiology are modernizing how these urinary tract infections are treated. Advances in pharmacotherapy have included not only the development and approval of novel antibiotics, such as ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, ceftolozane/tazobactam, cefiderocol, plazomicin, and glycylcyclines, but also the re-examination of the potential role of legacy antibiotics, including older aminoglycosides and tetracyclines. Recent advances in medical microbiology allow phenotypic and molecular mechanism of resistance testing, and thus antibiotic prescribing can be tailored to the mechanism of resistance in the infecting pathogen. Here, we provide a narrative review on the clinical and pre-clinical studies of drugs that can be used for difficult-to-treat resistant Gram-negative bacteria, with a particular focus on data relevant to the urinary tract. We also offer a pragmatic framework for antibiotic selection when encountering urinary tract infections due to difficult-to-treat resistant Gram-negative bacteria based on the organism and its mechanism of resistance.

Implementation of a Virtual Huddle to Support Patient Care During the COVID-19 Pandemic.

Background: During a surge of COVID-19 cases, the volume of acute care patients with hypoxemic respiratory failure placed a high burden of responsibility on internal medicine, pulmonary and critical care medicine, and clinical pharmacy services. Observations: We describe the COVID-19 Tele-Huddle Program, a novel approach to communication between key stakeholders in COVID-19 patient care through a daily video conferencing huddle. The program was implemented during a 4-week surge in COVID-19 cases at a large, academic medical center in Houston, Texas. Data collected during the COVID-19 Tele-Huddle Program included the type and number of interventions implemented, number of patients discussed, and COVID-19 therapies provided. In addition, hospital medicine team members completed a user-experience survey. Conclusions: A multidisciplinary consultation service using video conferencing can support the care of patients with high disease severity without overwhelming existing inpatient medical, intensive care, and pharmacy services.

Retrospective Review on the Safety and Efficacy of Nitrofurantoin for the Treatment of Cystitis in the Veteran Population With or Without Renal Insufficiency.

BACKGROUND: The emergence of antimicrobial resistance in uropathogens has generated interest in the use of nitrofurantoin in controversial populations, such as in males and those with renal dysfunction. The purpose of this study was to compare the efficacy and safety of nitrofurantoin for the treatment of cystitis in males and females with variable degrees of renal dysfunction. METHODS: A retrospective chart review was conducted in adult patients who received nitrofurantoin for acute cystitis in the outpatient setting. The primary outcome was clinical cure compared between males and females and across various renal function groups (creatinine clearances [CrCl] >60 mL/min, 30-60 mL/min, and <30 mL/min) following nitrofurantoin treatment. The secondary outcome was adverse events. RESULTS: A total of 446 patients were included, with 278 females and 168 males. The overall clinical cure rate was 86.5% (95% CI, 83.0%-89.4%; n = 386). The clinical cure rate did not vary between genders (odds ratio [OR], 0.6; 95% CI 0.35-1.04; P = .085) or between patients with a CrCl >60 mL/min compared with those with CrCl 30-60 mL/min (OR, 1.01; 95% CI, 0.40-2.44; P = 1). The 1 patient with a CrCl <30 mL/min was not included in the analysis. A history of benign prostatic hyperplasia (OR, 0.5; 95% CI, 0.26-0.99; P = .045) or cirrhosis (OR, 0.21; 95% CI, 0.06-0.82; P = .025) was associated with decreased odds of clinical cure. Adverse events occurred in 2% (n = 9) of patients. CONCLUSIONS: There was no statistically significant difference in clinical cure with nitrofurantoin between genders or various renal functions.

c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice.

CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1-/- but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1-/- Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1-/- Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1-/- Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1-/- but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.

A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice.

Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1+ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1+ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1+ cells in islet allograft-transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3-NK1.1+ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1+ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma.