A half-century of research on tuberculosis: Successes and challenges.

Great progress has been made over the past half-century, but TB remains a formidable global health problem, particularly in low- and middle-income countries. Understanding the mechanisms of pathogenesis and necessary and sufficient conditions for protection are critical. The need for inexpensive and sensitive point-of-care diagnostic tests for earlier detection of infection and disease, shorter and less-toxic drug regimens for drug-sensitive and -resistant TB, and a more effective vaccine than BCG is immense. New and better tools, greater support for international research, collaborations, and training will be required to dramatically reduce the burden of this devastating disease which still kills 1.6 million people annually.

IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide.

Introduction: The COVID-19 pandemic has highlighted the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such mediator is interferon-g (IFN-γ), which, when administered to infected patients, is reported to result in viral clearance and resolution of pulmonary symptoms. IFN-γ treatment of a human lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the mechanism for this antiviral response was not identified. Methods: Given that IFN-γ has been shown to trigger antiviral activity via the generation of nitric oxide (NO), we investigated whether IFN-γ induction of antiviral activity against SARS-CoV-2 infection is dependent upon the generation of NO in human pulmonary epithelial cells. We treated the simian epithelial cell line Vero E6 and human pulmonary epithelial cell lines, including A549-ACE2, and Calu-3, with IFN-γ and observed the resulting induction of NO and its effects on SARS-CoV-2 replication. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) was employed to assess the dependency on NO production. Additionally, the study examined the effect of interleukin-1b (IL-1ß) on the IFN-g-induced NO production and its antiviral efficacy. Results: Treatment of Vero E6 cells with IFN-γ resulted in a dose-responsive induction of NO and an inhibitory effect on SARS-CoV-2 replication. This antiviral activity was blocked by pharmacologic inhibition of iNOS. IFN-γ also triggered a NO-mediated antiviral activity in SARS-CoV-2 infected human lung epithelial cell lines A549-ACE2 and Calu-3. IL-1ß enhanced IFN-γ induction of NO, but it had little effect on antiviral activity. Discussion: Given that IFN-g has been shown to be produced by CD8+ T cells in the early response to SARS-CoV-2, our findings in human lung epithelial cell lines, of an IFN-γ-triggered, NO-dependent, links the adaptive immune response to an innate antiviral pathway in host defense against SARS-CoV-2. These results underscore the importance of IFN-γ and NO in the antiviral response and provide insights into potential therapeutic strategies for COVID-19.

TREM2 macrophages induced by human lipids drive inflammation in acne lesions.

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.

The cellular architecture of the antimicrobial response network in human leprosy granulomas.

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.

BACKGROUND: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. METHODS: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. RESULTS: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499.

Development of Parenteral Nutrition-Associated Liver Disease and Other Adverse Effects in Neonates Receiving SMOFlipid or Intralipid.

BACKGROUND: Intravenous lipid emulsions (ILEs) are a risk factor for parenteral nutrition-associated liver disease (PNALD) in the neonatal population. Current literature supports the use of SMOFlipid (4-oil ILE), a fish oil-containing lipid emulsion, for the reversal of PNALD. However, there is little information about the use of 4-oil ILEs for preventing PNALD. The purpose of this study is to examine the safety of a 4-oil ILE in neonates and its effectiveness in preventing PNALD among neonates compared with Intralipid (a soybean-oil, SO-ILE). METHODS: This is an observational, cohort, comparative safety study, conducted in a level III neonatal intensive care unit. Participants include neonates who received a 4-oil ILE in their parenteral nutrition (PN) formula, who were matched with historical data of patients who received an SO-ILE, in a 1:3 fashion (4-oil ILE:SO-ILE). The primary outcome of this study is the presence of PNALD (defined as direct bilirubin > 2 mg/dL) after initiation of PN. RESULTS: A total of 1332 participants (333 4-oil ILE vs 999 SO-ILE) were included in the data analysis, and PNALD was found to occur in 1.8% of patients in the 4-oil ILE group and 3.6% of patients in the SO-ILE group (Relative risk (RR) 0.5; 95% CI, 0.21-1.18). CONCLUSION: The decrease in the incidence of PNALD among the 4-oil ILE group compared with the SO-ILE group indicates a 4-oil ILE may have a hepatoprotective effect.

The public health crisis of underimmunisation: a global plan of action.

Vaccination is one of public health's greatest achievements, responsible for saving billions of lives. Yet, 20% of children worldwide are not fully protected, leading to 1·5 million child deaths annually from vaccine-preventable diseases. Millions more people have severe disabling illnesses, cancers, and disabilities stemming from underimmunisation. Reasons for falling vaccination rates globally include low public trust in vaccines, constraints on affordability or access, and insufficient governmental vaccine investments. Consequently, an emerging crisis in vaccine hesitancy ranges from hyperlocal to national and worldwide. Outbreaks often originate in small, insular communities with low immunisation rates. Local outbreaks can spread rapidly, however, transcending borders. Following an assessment of underlying determinants of low vaccination rates, we offer an action based on scientific evidence, ethics, and human rights that spans multiple governments, organisations, disciplines, and sectors.

The Salzburg Statement on Vaccination Acceptance.

Immunization represents one of the greatest public health achievements. Vaccines save lives, make communities more productive and strengthen health systems. They are critical to attaining the UN Sustainable Development Goals. Vaccination also represents value for investment in public health. It is undisputedly one of the most cost-effective ways of avoiding disease, each year preventing 2-3 million deaths globally. We the concerned scientists, public health professionals, physicians, and child health advocates issue this Salzburg Statement along with the International Working Group on Vaccination and Public Health Solutions, proclaiming our unwavering commitment to universal childhood vaccination, and our pledge to support the development, testing, implementation, and evaluation of new, effective, and fact-based communication programs. Our goal is to explain vaccinations to parents or caregivers, answer their questions, address their concerns, and maintain public confidence in the personal, family and community protection that childhood vaccines provide. Every effort will also be made to communicate the dangers associated with these childhood illnesses to parents and communities since this information seems to have been lost in the present-day narrative. While vaccine misinformation has led to serious declines in community vaccination rates that require immediate attention, in other communities, particularly in low-income countries, issues such as lack of access. and unstable supply of vaccines need to be addressed.

IL-1ß Induces the Rapid Secretion of the Antimicrobial Protein IL-26 from Th17 Cells.

Th17 cells play a critical role in the adaptive immune response against extracellular bacteria, and the possible mechanisms by which they can protect against infection are of particular interest. In this study, we describe, to our knowledge, a novel IL-1ß dependent pathway for secretion of the antimicrobial peptide IL-26 from human Th17 cells that is independent of and more rapid than classical TCR activation. We find that IL-26 is secreted 3 hours after treating PBMCs with Mycobacterium leprae as compared with 48 hours for IFN-γ and IL-17A. IL-1ß was required for microbial ligand induction of IL-26 and was sufficient to stimulate IL-26 release from Th17 cells. Only IL-1RI+ Th17 cells responded to IL-1ß, inducing an NF-κB-regulated transcriptome. Finally, supernatants from IL-1ß-treated memory T cells killed Escherichia coli in an IL-26-dependent manner. These results identify a mechanism by which human IL-1RI+ "antimicrobial Th17 cells" can be rapidly activated by IL-1ß as part of the innate immune response to produce IL-26 to kill extracellular bacteria.

IL-26 contributes to host defense against intracellular bacteria.

IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Furthermore, IL-26, when added to human monocyte-derived macrophages infected with M. leprae, entered the infected cell, colocalized with the bacterium, and reduced bacteria viability. In addition, IL-26 induced autophagy via the cytoplasmic DNA receptor stimulator of IFN genes (STING), as well as fusion of phagosomes containing bacilli with lysosomal compartments. Altogether, our data suggest that the Th17 cytokine IL-26 contributes to host defense against intracellular bacteria.