• Diabetes
• coronavirus disease-19
• human immunodeficiency virus
• mycobacteria
• sarcoidosis
• systemic lupus erythematosus.

• Humans
• Insulin Resistance
• Interferons
• Up-Regulation
• Diabetes Mellitus, Type 2
• COVID-19/immunology
• SARS-CoV-2

• biomarker
• immunology
• latent tuberculosis infection (LTBI)
• tuberculosis
• vaccine

• Humans
• Latent Tuberculosis/immunology
• Homeostasis/immunology
• Mycobacterium tuberculosis/immunology
• Tuberculosis Vaccines/immunology
• Animals

• 22Y11920500 Shanghai "Science and Technology Innovation Action Plan" Medical Innovation Research Special Project
• 82372263 National Natural Science Foundation of China

• HIV
• Hepatitis C
• Mortality

• Humans
• HIV Infections/complications
• Brazil/epidemiology
• Coinfection
• Retrospective Studies
• Blood Donors
• Survival Analysis
• Liver Diseases
• Neoplasms
• Hepatitis C/complications

• HBV
• Hepatitis B virus
• Northeastern Iran
• OBI
• Occult hepatitis B virus infection
• Qualitative real-time PCR
• TB
• Tuberculosis
• qPCR

• interferons
• interleukins
• mycobacteria
• tuberculosis
• tumor necrosis factor

• Humans
• Mycobacterium tuberculosis/metabolism
• Interferon Type I/metabolism
• Virulence
• COVID-19
• Tuberculosis
• Immunity, Innate
• Interferons/metabolism

• R15 HL143545 NHLBI NIH HHS

• cohort
• hepatitis C
• tuberculosis

• Adult
• Humans
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/epidemiology
• Incidence
• Cohort Studies
• Tuberculosis/epidemiology
• Tuberculosis/complications
• Risk Factors
• Hepatitis C/epidemiology
• Latent Tuberculosis/complications
• Hepacivirus

• D43 TW007124 FIC NIH HHS
• CC999999 Intramural CDC HHS
• U19 AI111211 NIAID NIH HHS
• P30 AI050409 NIAID NIH HHS
• P30 AI168386 NIAID NIH HHS
• K24 AI114444 NIAID NIH HHS
• National Institutes of Health
• Fogarty International Center
• National Institute of Allergy and Infectious Diseases
• Emory/Georgia TB Research Advancement Center
• Emory University Center for AIDS Research
• TB Research Unit ASTRa

• Infection
• Myelofibrosis
• Reactivation
• Ruxolitinib
• TBC
• Tuberculosis

It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.

Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosismmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation.

• MmsA (Rv0753c)
• Mycobacterium tuberculosis
• STING
• p62
• selective autophagy
• type I IFN

• Drug-induced hepatitis
• Ethiopia
• Hepatitis B
• Hepatitis C
• Tuberculosis

• Adult
• Antitubercular Agents/adverse effects
• Chemical and Drug Induced Liver Injury/epidemiology
• Coinfection/epidemiology
• Coinfection/microbiology
• Coinfection/virology
• Female
• Hepatitis B/epidemiology
• Hepatitis C/epidemiology
• Humans
• Incidence
• Liver/drug effects
• Liver/pathology
• Liver/virology
• Male
• Middle Aged
• Prevalence
• Proportional Hazards Models
• Prospective Studies
• Tuberculosis/complications
• Tuberculosis/drug therapy
• Tuberculosis/virology
• Young Adult

Hepatitis C virus (HCV) infection is a major health problem associated with considerable risk of mortality in different regions of the world. The purpose of this study was to investigate the contribution of HCV infection on all-cause and liver-related mortality, in a large cohort of blood donors in Brazil.

This is a retrospective cohort study of blood donors from 1994 to 2013, at Fundação Pró-Sangue—Hemocentro de São Paulo (FPS). This cohort included 2,892 and 5,784 HCV antibody seropositive and seronegative donors, respectively. Records from the FPS database and the Mortality Information System (SIM: a national database in Brazil) were linked through a probabilistic record linkage (RL). Mortality outcomes were defined based on ICD-10 (10th International Statistical Classification of Diseases and Related Health Problems) codes listed as the cause of death on the death certificate. Hazard ratios (HRs) were estimated for outcomes using Cox multiple regression models.

When all causes of death were considered, RL identified 209 deaths (7.2%) among seropositive blood donors and 190 (3.3%) among seronegative blood donors. Donors seropositive for HCV infection had a 2.5 times higher risk of death due to all causes (95% CI: 1.76–2.62; p<0.001). When only liver-related causes of death were considered, RL identified 73 deaths among seropositive blood donors and only 6 among seronegative blood donors. Donors seropositive for HCV infection had a 23.4 times higher risk of death due to liver related causes (95% CI: 10.2–53.9; p<0.001). Donors seropositive for HCV had a 29.5 (95%CI: 3.9–221.7), 2.8 (95% CI: 1.4–5.5) and a 1.9 (95% CI: 1.2–3.0) times higher risk of death due to hepatocellular carcinoma, infection or trauma, respectively, compared to seronegative donors.

All-cause and liver-related mortality rate was increased among blood donors seropositive for HCV compared with the mortality rate among seronegative blood donors. Our data confirms HCV as a relevant cause of death in Brazil and also suggest that interventions directed at following patients even after access to specific drug treatment are urgent and necessary.

• Adolescent
• Adult
• Blood Donors/statistics & numerical data
• Brazil
• Cohort Studies
• Female
• Hepatitis C/blood
• Hepatitis C/immunology
• Hepatitis C/mortality
• Hepatitis C Antibodies/blood
• Humans
• Liver/virology
• Male
• Middle Aged
• Retrospective Studies
• Young Adult

• Alleles
• Animals
• Cytokines/immunology
• Disease Models, Animal
• Female
• Genetic Predisposition to Disease
• Interferon Type I/genetics
• Interferon Type I/immunology
• Interleukin 1 Receptor Antagonist Protein/genetics
• Interleukin 1 Receptor Antagonist Protein/immunology
• Lung/immunology
• Lung/microbiology
• Macrophages/immunology
• Macrophages/microbiology
• Male
• Mice
• Mice, Congenic
• Receptors, Somatostatin/genetics
• Specific Pathogen-Free Organisms
• Tuberculosis/genetics
• Tuberculosis/immunology

• R01 HL126066 NHLBI NIH HHS
• R37 AI075039 NIAID NIH HHS
• R01 AI075039 NIAID NIH HHS
• P01 AI063302 NIAID NIH HHS
• R01 HL133190 NHLBI NIH HHS

• Rheumatoid arthritis
• direct-acting antivirals
• hepatitis C
• immune reconstitution
• tuberculosis

To describe the incidence of active tuberculosis and the occurrence of adverse events after isoniazid treatment in patients with latent tuberculosis infection (LTBI) who also had chronic inflammatory diseases and were treated with immunobiologic agents in an endemic area in Brazil.

The diagnosis of LTBI was based on anamnesis, clinical examination, chest X-ray, and a tuberculin skin test (TST). Patients received prophylactic treatment (isoniazid for six months) in accordance with the Brazilian guidelines.

A total of 101 patients were evaluated between July of 2011 and July of 2015. Of those, 55 (54.46%) were women (mean age, 53.16 ± 1.76 years) and 46 (45.54%) were men (mean age, 45.39 ± 2.13 years). A total of 79 patients (78.22%) were being treated with immunobiologic agents and 22 (21.78%) were being treated with immunomodulatory or immunosuppressive agents. In the screening for LTBI, 53 patients (52.48%) had a TST induration ≥ 10 mm. Chest X-ray findings consistent with LTBI were observed in 36 patients (35.64%). Isoniazid preventive therapy was effective in 96 (95.05%) of the 101 patients evaluated. It is of note that 84 (83.17%) of the patients experienced no adverse effects from the use of isoniazid and that 83 (98.81%) of those patients completed the prophylactic treatment (p = 0.002). Active tuberculosis was diagnosed in 5 (6.33%) of the 79 patients treated with immunobiologic agents and in 1 (4.55%) of the 22 patients treated with other immunomodulators/immunosuppressants.

A six-month course of isoniazid proved to be safe and effective in the treatment of LTBI, which is essential to reducing the risk of developing active tuberculosis.

• Animals
• Disease Models, Animal
• Humans
• Immunity
• Interferon Type I/metabolism
• Models, Biological
• Tuberculosis/immunology
• Tuberculosis/metabolism
• Tuberculosis/pathology

• Wellcome Trust
• FC001126 Arthritis Research UK
• MC_U117565642 Medical Research Council
• Cancer Research UK
• The Francis Crick Institute
• National Institutes of Allergy and Infectious Diseases

Mycobacteria Bovis osteomyelitis is a rare adverse effect after Bacillus Calmette-Guerin (BCG) intravesical therapy. A 62-year-old male presented with acute spinal cord compression three months after completing his second course of therapy for bladder cancer. The first course with intravesical BCG was complicated with an episode of hematuria. He reported intermittent subjective fever for 3 weeks thereafter which resolved with Tylenol. Interferon-α2 B was added to the second cycle of intravesical BCG with the indication here being residual tumor, and was tolerated well. His complete blood count and liver function tests were unremarkable on admission. MRI showed features of osteomyelitis with cord compression at T4/T5. Biopsy of the affected bone showed caseating granuloma which was positive for acid fact bacilli, later confirmed to be Mycobacterium Bovis by PCR and pyrazinamide resistance. He was started on intravenous steroids and underwent spinal cord decompression. Rifampin, Isoniazid, and Ethambutol were then commenced. His weakness improved and after two months of therapy he was asymptomatic and back to his baseline function. Osteomyelitis is a rare but serious complication. Early diagnosis and treatment is important as the outcomes are good.

• Intravesical BCG
• Mycobacteria bovis
• Spinal osteomyelitis

Chronic hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipasvir/sofosbuvir with or without concomitant weight-based ribavirin was approved with a very significant increase in the sustained virological response. However, new side effects have been associated. We report the first case of an HCV infected patient treated for 12 wk with the combination of sofosbuvir/ledipasvir plus ribavirin who developed a miliary tuberculosis (TB) infection while on therapy. The patient was a 65-year-old woman, who referred malaise, asthenia, hyporexia, 7 kg weight loss, productive cough, evening fever and night sweats, right after finishing the treatment. The chest computed tomography-scan revealed a superior mediastinal widening secondary to numerous lymphadenopathies with extensive necrosis and bilateral diffuse lung miliary pattern with little subsequent bilateral pleural effusion, highly suggestive of lymph node tuberculosis with lung miliary spread. A bronchoscopy was performed and bronchial suction showed more than 50 acid-alcohol resistant bacillus per line. A Mycobacterium tuberculosis DNA was detected in blood by polymerase chain reaction, which confirmed the diagnosis of miliary tuberculosis. Some cases of TB infection have been identified with α-interferon-based therapy and with the triple therapy of pegylated interferon, ribavirin and boceprevir or telaprevir. However, significant infection has not been reported with sofosbuvir/ledipasvir plus ribavirin. We believe that the case is relevant to increase awareness of opportunistic infections and particularly TB infection. Although the international guidelines offer no recommendation regarding TB screening, we wonder whether it would be advisable to screen for opportunistic infections prior to the introduction of HCV therapy.

• Tuberculosis
• Ledipasvir
• Ribavirin
• Sofosbuvir
• Hepatitis C