Publications by authors named "Thomas R Hawn"

86 Publications

HDAC3 inhibitor RGFP966 controls bacterial growth and modulates macrophage signaling during Mycobacterium tuberculosis infection.

Tuberculosis (Edinb) 2021 Feb 18;127:102062. Epub 2021 Feb 18.

Department of Medicine, University of Washington, Seattle, WA, USA.

Rationale: Host-directed therapeutics for Mycobacterium tuberculosis (Mtb) offer potential strategies for combatting antibiotic resistance and for killing non-replicating bacilli. Phenylbutyrate, a partially selective histone-deacetylase (HDAC) inhibitor, was previously shown to control Mtb growth and alter macrophage inflammatory pathways at 2-4 mM concentrations.

Objective: To identify a more potent and selective HDAC inhibitor that modulates macrophage responses to mycobacteria and has direct antibacterial effects against Mtb.

Methods: We used cellular approaches to characterize the role of pharmacologic inhibition of HDAC3 on Mtb growth and Mtb-induced peripheral and alveolar macrophage immune functions.

Measurements And Main Results: RGFP966, an HDAC3 inhibitor, controlled Mtb, BCG and M. avium growth directly in broth culture and in human peripheral blood monocyte-derived and alveolar macrophages with an MIC50 of approximately 5-10 μM. In contrast, RGFP966 did not inhibit growth of several other intracellular and extracellular bacteria. We also found that RGFP966 modulated macrophage pro-inflammatory cytokine secretion in response to Mtb infection with decreased IL6 and TNF secretion.

Conclusions: We identified a potent and selective small molecule inhibitor of HDAC3 with direct antimicrobial activity against Mtb and modulation of macrophage signaling pathways.
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http://dx.doi.org/10.1016/j.tube.2021.102062DOI Listing
February 2021

Latent Tuberculosis Infection and Subclinical Coronary Atherosclerosis in Peru and Uganda.

Clin Infect Dis 2021 01 3. Epub 2021 Jan 3.

Harrington Heart & Vascular Institute, Case Western Reserve University School of Medicine, Ohio, United States of America.

Background: Tuberculosis has been linked to an increased risk of atherosclerotic cardiovascular disease (ASCVD). We assessed whether latent tuberculosis infection (LTBI) is associated with subclinical coronary atherosclerosis in two TB-prevalent areas.

Methods: We analyzed cross-sectional data from studies conducted in Lima, Peru, and Kampala, Uganda. Individuals ≥40 years old were included. We excluded persons with known history of ASCVD events or active TB. Participants underwent QuantiFERON®-TB (QFT) testing to define LTBI, and computed tomography angiography to examine coronary atherosclerosis. A Coronary Artery Disease-Reporting Data System (CAD-RADS) score ≥3 defined obstructive CAD (plaque causing ≥50% stenosis).

Results: 113 persons with LTBI and 91 persons without LTBI were included. There were no significant differences between LTBI and non-LTBI participants in terms of age (median [interquartile range]; 56 [51-62] vs. 55 [49-64], p=0.829), male sex (38% vs. 42%; p=0.519), or 10-year ASCVD risk scores (7.1 [3.2-11.7] vs. 6.1 [2.8-10.8]; p=0.533). CAD prevalence (any plaque) was similar between groups (29% vs. 24%; p=0.421). Obstructive CAD was present in 9% of LTBI and 3% of non-LTBI individuals; p=0.095. LTBI was associated with obstructive CAD after adjusting for ASCVD risk score, HIV status, and study site (adjusted odds ratio, 4.96, 95% CI 1.05-23.44; p=0.043). Quantitative QFT TB antigen minus nil interferon-gamma responses were associated with obstructive CAD (adjusted odds ratio, 1.2, 95% CI 1.03-1.41; p=0.022).

Conclusions: LTBI was independently associated with an increased likelihood of subclinical obstructive CAD. Our data indicates that LTBI is a non-traditional correlate of ASCVD risk.
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http://dx.doi.org/10.1093/cid/ciaa1934DOI Listing
January 2021

Genetic Variation in Toll-Like Receptor 5 and Colonization with Flagellated Bacterial Vaginosis-Associated Bacteria.

Infect Immun 2021 Feb 16;89(3). Epub 2021 Feb 16.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Bacterial vaginosis (BV) is a vaginal dysbiotic condition linked to negative gynecological and reproductive sequelae. Flagellated bacteria have been identified in women with BV, including spp. and BV-associated bacterium-1 (BVAB1), an uncultivated, putatively flagellated species. The host response to flagellin mediated through Toll-like receptor 5 (TLR5) has not been explored in BV. Using independent discovery and validation cohorts, we examined the hypothesis that TLR5 deficiency-defined by a dominant negative stop codon polymorphism, rs5744168-is associated with an increased risk for BV and increased colonization with flagellated bacteria associated with BV (BVAB1, , and ). TLR5 deficiency was not associated with BV status, and TLR5-deficient women had decreased colonization with BVAB1 in both cohorts. We stimulated HEK-hTLR5-overexpressing NF-κB reporter cells with whole, heat-killed or and with partially purified flagellin from these species; as BVAB1 is uncultivated, we used cervicovaginal lavage (CVL) fluid supernatant from women colonized with BVAB1 for stimulation. While heat-killed and CVL fluid from women colonized with BVAB1 stimulate a TLR5-mediated response, heat-killed did not. In contrast, partially purified flagellin from both species stimulated a TLR5-mediated response We observed no correlation between vaginal interleukin 8 (IL-8) and flagellated BVAB concentrations among TLR5-sufficient women. Interspecies variation in accessibility of flagellin recognition domains may be responsible for these observations, as reflected in the potentially novel flagellin products encoded by species versus those encoded by BVAB1.
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http://dx.doi.org/10.1128/IAI.00060-20DOI Listing
February 2021

A randomized controlled trial of isoniazid to prevent Mycobacterium tuberculosis infection in Kenyan HIV-exposed uninfected infants.

Clin Infect Dis 2020 Jun 21. Epub 2020 Jun 21.

Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.

Background: HIV-exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary M. tuberculosis infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection.

Methods: We conducted a randomized non-blinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months daily INH (10 mg/kg) vs. no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit).

Results: Between August 15, 2016 and June 6, 2018, 416 infants were screened, with 300 (72%) randomized to INH or no INH (150 per arm); 2 were excluded due to HIV infection. Among 298 randomized HEU infants, 12-month retention was 96.3% (287/298) and 88.9% (265/298) had primary outcome data. Mtb infection prevalence at 12-months follow-up was 10.6% (28/265); 7.6% (10/132) in INH and 13.5% (18/133) in no INH arms (7.0 vs. 13.4 per 100PY, HR 0.53 [95%CI 0.24-1.14], p=0.11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH arms; RR 0.48 [95%CI 0.22-1.05], p=0.07). Frequency of severe adverse events was similar between arms (INH 14.0% [21/150] vs. no INH 10.7% [16/150], p=0.38), with no INH-related adverse events.

Conclusions: Further studies evaluating TB preventive therapy to prevent or delay primary Mtb infection in HEU and other high-risk infants are warranted.
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http://dx.doi.org/10.1093/cid/ciaa827DOI Listing
June 2020

Clinical Development of New TB Vaccines: Recent Advances and Next Steps.

Front Microbiol 2019 30;10:3154. Epub 2020 Jan 30.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, United States.

(Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01 provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01 with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01 and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will.
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http://dx.doi.org/10.3389/fmicb.2019.03154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002896PMC
January 2020

Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent infection in HIV-exposed uninfected children.

BMJ Open 2020 01 21;10(1):e034308. Epub 2020 Jan 21.

Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.

Introduction: HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population.

Methods And Analysis: We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ~10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry.

Ethics And Dissemination: An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants.

Trial Registration Number: NCT02613169; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-034308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045242PMC
January 2020

Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil.

Int J Infect Dis 2020 Mar 13;92:21-28. Epub 2019 Dec 13.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Bahia, Brazil; Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, Bahia, Brazil; Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Bahia, Brazil; Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil. Electronic address:

Background: Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection.

Methods: We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models.

Results: Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95%CI=1.15-12.0; p=0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR=24.84; 95%CI=2.26-272.95; p=0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p=0.029).

Conclusions: Polymorphisms in PYHIN1-IFI16-AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort.
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http://dx.doi.org/10.1016/j.ijid.2019.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197195PMC
March 2020

Nicotinamide Limits Replication of Mycobacterium tuberculosis and Bacille Calmette-Guérin Within Macrophages.

J Infect Dis 2020 03;221(6):989-999

TB Research & Training Center, Department of Medicine, University of Washington, Seattle, Washington, USA.

Novel antimicrobials for treatment of Mycobacterium tuberculosis are needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrict M. tuberculosis replication in addition to their direct antimicrobial properties. Both compounds had modest activity in 7H9 broth, but only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM and the related compound pyrazinamide restricted growth of bacille Calmette-Guérin but not wild-type Mycobacterium bovis, which both lack a functional nicotinamidase/pyrazinamidase (PncA) rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulent M. tuberculosis mutant encoding a deletion in pncA. We conclude that the differential activity of NAM and nicotinic acid on infected macrophages suggests host-specific NAM targets rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-type M. bovis or M. tuberculosis.
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http://dx.doi.org/10.1093/infdis/jiz541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050990PMC
March 2020

Importance of Study Design and Phenotype Definition in Ongoing Studies of Resistance to Latent Mycobacterium tuberculosis Infection.

J Infect Dis 2020 03;221(6):1025-1026

Divisinon of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1093/infdis/jiz539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050985PMC
March 2020

TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia.

Mucosal Immunol 2019 11 28;12(6):1382-1390. Epub 2019 Aug 28.

Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires' disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, Tollip mice demonstrated significantly fewer bacterial colony-forming unit and increased cytokine responses from BAL fluid. Tollip macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC ex vivo. This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16-0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies.
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http://dx.doi.org/10.1038/s41385-019-0196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824992PMC
November 2019

Publisher Correction: IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure.

Nat Med 2019 Jul;25(7):1175

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

In the version of this article originally published, there was an error in the abstract. The word disease should not have been included in the sentence "These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI". The sentence should have been "These individuals were highly exposed to Mtb but tested negative by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI." The error has been corrected in the HTML and PDF versions of this article.
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http://dx.doi.org/10.1038/s41591-019-0519-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609258PMC
July 2019

Nontuberculous Mycobacteria and Heterologous Immunity to Tuberculosis.

J Infect Dis 2019 08;220(7):1091-1098

Tuberculosis Research and Training Center, Department of Medicine, University of Washington, Seattle.

Development of an improved tuberculosis (TB) vaccine is a high worldwide public health priority. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, provides variable efficacy against adult pulmonary TB, but why this protection varies is unclear. Humans are regularly exposed to non-tuberculous mycobacteria (NTM) that live in soil and water reservoirs and vary in different geographic regions around the world. Immunologic cross-reactivity may explain disparate outcomes of BCG vaccination and susceptibility to TB disease. Evidence supporting this hypothesis is increasing but challenging to obtain due to a lack of reliable research tools. In this review, we describe the progress and bottlenecks in research on NTM epidemiology, immunology and heterologous immunity to Mtb. With ongoing efforts to develop new vaccines for TB, understanding the effect of NTM on vaccine efficacy may be a critical determinant of success.
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http://dx.doi.org/10.1093/infdis/jiz285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736075PMC
August 2019

IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure.

Nat Med 2019 06 20;25(6):977-987. Epub 2019 May 20.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.
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http://dx.doi.org/10.1038/s41591-019-0441-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559862PMC
June 2019

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.

Science 2019 03;363(6434)

Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by () in suppression of immunity against bacterial infection. Pf promote wound infection in mice and are associated with chronic human wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-β (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.
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http://dx.doi.org/10.1126/science.aat9691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656896PMC
March 2019

Remembering the Host in Tuberculosis Drug Development.

J Infect Dis 2019 04;219(10):1518-1524

Stop TB Partnership Working Group on New Drugs, New York, New York.

New therapeutics to augment current approaches and shorten treatment duration are of critical importance for combating tuberculosis (TB), especially those with novel mechanisms of action to counter the emergence of drug-resistant TB. Host-directed therapy (HDT) offers a novel strategy with mechanisms that include activating immune defense mechanisms or ameliorating tissue damage. These and related concepts will be discussed along with issues that emerged from the workshop organized by the Stop TB Working Group on New Drugs, held at the Gordon Research Conference for Tuberculosis Drug Development in Lucca, Italy in June 2017, titled "Strategic Discussion on Repurposing Drugs & Host Directed Therapies for TB." In this review, we will highlight recent data regarding drugs, pathways, and concepts that are important for successful development of HDTs for TB.
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http://dx.doi.org/10.1093/infdis/jiy712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562157PMC
April 2019

Toll-like receptor chaperone HSP90B1 and the immune response to Mycobacteria.

PLoS One 2018 14;13(12):e0208940. Epub 2018 Dec 14.

University of Washington, Seattle, WA, United States of America.

Rationale: HSP90B1, also known as gp96, is a chaperone for multiple Toll-like receptors (TLRs) and is necessary for TLR-mediated inflammatory responses in murine myeloid cells. The molecule is also expressed in T-cells though its specific role is unknown. We hypothesized that human HSP90B1 regulates monocyte and T-cell responses to Mycobacterium tuberculosis (Mtb) and bacilli Calmette-Guerin (BCG) and that its variants are associated with susceptibility to TB disease.

Methods: We screened 17 haplotype-tagging SNPs in the HSP90B1 gene region for association with BCG-induced T-cell cytokine responses using both an ex-vivo whole blood assay (N = 295) and an intracellular cytokine staining assay (N = 180) on samples collected 10 weeks after birth. Using a case-control study design, we evaluated the same SNPs for association with TB disease in a South African pediatric cohort (N = 217 cases, 604 controls). A subset of these SNPs was evaluated for association with HSP90B1 expression in human monocytes, monocyte-derived dendritic cells, and T-cells using RT-PCR. Lastly, we used CRISPR/Cas9 gene editing to knock down HSP90B1 expression in a human monocyte cell line (U937). Knockdown and control cell lines were tested for TLR surface expression and control of Mtb replication.

Results: We identified three SNPs, rs10507172, rs10507173 and rs1920413, that were associated with BCG-induced IL-2 secretion (p = 0.017 for rs10507172 and p = 0.03 for rs10507173 and rs1920413, Mann-Whitney, dominant model). SNPs rs10507172 and rs10507173 were associated with TB disease in an unadjusted analysis (p = 0.036 and 0.025, respectively, dominant model) that strengthened with sensitivity analysis of the definite TB cases, which included only those patients with microbiologically confirmed Mtb (p = 0.007 and 0.012, respectively). Knockdowns of HSP90B1 in monocyte cell lines with CRISPR did not alter TLR2 surface expression nor influence Mtb replication relative to controls.

Conclusion: Among infants, an HSP90B1 gene-region variant is associated with BCG-induced IL-2 production and may be associated with protection from TB disease. HSP90B1 knockdown in human monocyte-like cell lines did not influence TLR2 surface localization nor Mtb replication. Together, these data suggest that HSP90B1 regulates T-cell, but not monocyte, responses to mycobacteria in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294361PMC
May 2019

Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda.

Clin Infect Dis 2019 05;68(10):1705-1712

Tuberculosis Research Unit, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Background: Resistance to latent Mycobacterium tuberculosis (M.tb) infection, identified by persistently negative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA), after close contact with pulmonary tuberculosis (TB) patients has not been extensively characterized. Stability of this "resistance" beyond 2 years from exposure is unknown.

Methods: 407 of 657 eligible human immunodeficiency virus (HIV)-negative adults from a TB household contact study with persistently negative TST (PTST-) or with stable latent M.tb infection (LTBI) were retraced 9.5 years (standard deviation = 3.2) later. Asymptomatic retraced contacts underwent 3 IGRAs and follow-up TST, and their M.tb infection status classified as definite/possible/probable.

Results: Among PTST- with a definite classification, 82.7% were concordantly TST-/ quantiferon-TB Gold- (QFT-), and 16.3% converted to TST+/QFT+ LTBI. Among original LTBI contacts, 83.6% remained LTBI, and 3.9% reverted their TST and were QFT-. Although TST and QFT concordance was high (κ = 0.78), 1.0% of PTST and 12.5% of original LTBI contacts could not be classified due to discordant TST and QFT results. Epidemiological variables did not differ between retraced PTST- and LTBI contacts.

Conclusion: Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients living in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with 2 different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop "classic" LTBI.
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http://dx.doi.org/10.1093/cid/ciy751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495009PMC
May 2019

Fine-mapping analysis of a chromosome 2 region linked to resistance to Mycobacterium tuberculosis infection in Uganda reveals potential regulatory variants.

Genes Immun 2019 07 13;20(6):473-483. Epub 2018 Aug 13.

Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.

Tuberculosis (TB) is a major public health burden worldwide, and more effective treatment is sorely needed. Consequently, uncovering causes of resistance to Mycobacterium tuberculosis (Mtb) infection is of special importance for vaccine design. Resistance to Mtb infection can be defined by a persistently negative tuberculin skin test (PTST-) despite living in close and sustained exposure to an active TB case. While susceptibility to Mtb is, in part, genetically determined, relatively little work has been done to uncover genetic factors underlying resistance to Mtb infection. We examined a region on chromosome 2q previously implicated in our genomewide linkage scan by a targeted, high-density association scan for genetic variants enhancing PTST- in two independent Ugandan TB household cohorts (n = 747 and 471). We found association with SNPs in neighboring genes ZEB2 and GTDC1 (peak meta p = 1.9 × 10) supported by both samples. Bioinformatic analysis suggests these variants may affect PTST- by regulating the histone deacetylase (HDAC) pathway, supporting previous results from transcriptomic analyses. An apparent protective effect of PTST- against body-mass wasting suggests a link between resistance to Mtb infection and healthy body composition. Our results provide insight into how humans may escape latent Mtb infection despite heavy exposure.
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http://dx.doi.org/10.1038/s41435-018-0040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374218PMC
July 2019

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

Nat Rev Immunol 2018 09;18(9):575-589

Department of Medicine, University of Washington, Seattle, WA, USA.

Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.
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http://dx.doi.org/10.1038/s41577-018-0025-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278832PMC
September 2018

The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires' disease in humans.

PLoS Pathog 2018 01 3;14(1):e1006829. Epub 2018 Jan 3.

Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires' disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires' disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection.

Trial Registration: ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.
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http://dx.doi.org/10.1371/journal.ppat.1006829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770077PMC
January 2018

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

Am J Respir Crit Care Med 2017 08;196(4):502-511

1 University of Washington School of Medicine, Seattle, Washington.

Rationale: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood.

Objectives: To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.

Methods: We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection.

Measurements And Main Results: We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2 CD4 T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection.

Conclusions: TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.
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http://dx.doi.org/10.1164/rccm.201611-2346OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564674PMC
August 2017

The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes.

Tuberculosis (Edinb) 2017 05 21;104:38-45. Epub 2017 Feb 21.

Univ. of Washington, Seattle, WA, USA.

Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.
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http://dx.doi.org/10.1016/j.tube.2017.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289319PMC
May 2017

Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection.

PLoS One 2017 17;12(4):e0175844. Epub 2017 Apr 17.

Department of Medicine, University of Washington, Seattle, Washington, United States of America.

Rationale: Understanding mechanisms of resistance to M. tuberculosis (M.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases, such as HIV.

Objectives: To compare the early transcriptional response of M.tb-infected monocytes between Ugandan household contacts of tuberculosis patients who demonstrate clinical resistance to M.tb infection (cases) and matched controls with latent tuberculosis infection.

Methods: Cases (n = 10) and controls (n = 18) were selected from a long-term household contact study in which cases did not convert their tuberculin skin test (TST) or develop tuberculosis over two years of follow up. We obtained genome-wide transcriptional profiles of M.tb-infected peripheral blood monocytes and used Gene Set Enrichment Analysis and interaction networks to identify cellular processes associated with resistance to clinical M.tb infection.

Measurements And Main Results: We discovered gene sets associated with histone deacetylases that were differentially expressed when comparing resistant and susceptible subjects. We used small molecule inhibitors to demonstrate that histone deacetylase function is important for the pro-inflammatory response to in-vitro M.tb infection in human monocytes.

Conclusions: Monocytes from individuals who appear to resist clinical M.tb infection differentially activate pathways controlled by histone deacetylase in response to in-vitro M.tb infection when compared to those who are susceptible and develop latent tuberculosis. These data identify a potential cellular mechanism underlying the clinical phenomenon of resistance to M.tb infection despite known exposure to an infectious contact.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393882PMC
April 2017

Species-Specific Risk Factors, Treatment Decisions, and Clinical Outcomes for Laboratory Isolates of Less Common Nontuberculous Mycobacteria in Washington State.

Ann Am Thorac Soc 2017 Jul;14(7):1129-1138

1 Department of Medicine, School of Medicine and.

Rationale: Nontuberculous mycobacteria (NTM) are a diverse group of environmental organisms that infrequently cause human disease. Understanding of the epidemiologic and clinical characteristics associated with NTM disease is needed to refine diagnostic and treatment strategies, particularly among the less commonly isolated species.

Objectives: To improve knowledge of geographic variance of NTM species, to correlate detailed clinical information with isolation of specific NTM, and to examine the decision to treat and outcomes for specific NTM.

Methods: Mycobacterial cultures submitted to the University of Washington mycobacterial laboratory from 1998 to 2011 were examined. We report isolation frequency and demographic information from all samples with clinical variables. We also examined treatment decisions and outcomes in a subset of patients with Mycobacterium abscessus complex, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium lentiflavum, Mycobacterium porcinum, and Mycobacterium xenopi.

Results: Cultures of NTM were available from 3,470 patients, 937 of whom had clinical data available. When we compared patients born within or outside Washington State, we found that the mycobacterial species frequency varied. Among 168 patients with one of the studied environmental mycobacteria, 72% had major comorbid conditions. Bronchiectasis was common among patients with pulmonary isolation of any NTM, including those with nonpathogenic M. gordonae. Although mortality was high (37%), few deaths were directly attributable to mycobacterial infection. Among 56 patients who met American Thoracic Society criteria for NTM lung disease, 22 were treated, and 19 of those had M. abscessus complex and M. kansasii. The treatment regimens used tended to follow published guidelines.

Conclusions: Isolation of NTM varied by geographic region of origin and location within Washington State. Several clinical risk factors were specific to individual species. Comorbid conditions were common in patients with and without mycobacterial disease. Among patients with one of the studied organisms, there was a high mortality rate more frequently related to comorbid conditions than to mycobacterial disease.
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http://dx.doi.org/10.1513/AnnalsATS.201609-731OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566289PMC
July 2017

Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.

J Infect Dis 2016 10 2;214(8):1260-7. Epub 2016 Aug 2.

Department of Medicine, University of Washington School of Medicine.

Background: Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI.

Methods: We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication.

Results: In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy.

Conclusions: These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.
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http://dx.doi.org/10.1093/infdis/jiw347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034956PMC
October 2016

Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist.

J Infect Dis 2016 Apr 26;213(7):1189-97. Epub 2015 Nov 26.

University of Washington School of Medicine, Seattle, Washington.

Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-interacting protein (TOLLIP) regulates Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messenger RNA (mRNA) expression of candidate immune genes in skin biopsy specimens from 85 individuals with leprosy. TOLLIP mRNA was highly and specifically correlated with IL-1R antagonist (IL-1Ra). In a case-control gene-association study with 477 cases and 1021 controls in Nepal, TOLLIP single-nucleotide polymorphism rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, P = 1.4 × 10(-3)) and with increased skin expression of TOLLIP and IL-1Ra. Stimulation of TOLLIP-deficient monocytes with M. leprae produced significantly less IL-1Ra (P < .001), compared with control. These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism. Inhibition of TOLLIP may decrease an individual's susceptibility to leprosy and offer a novel therapeutic target for IL-1-dependent diseases.
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http://dx.doi.org/10.1093/infdis/jiv570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779304PMC
April 2016

T Cell Responses against Mycobacterial Lipids and Proteins Are Poorly Correlated in South African Adolescents.

J Immunol 2015 Nov 14;195(10):4595-603. Epub 2015 Oct 14.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109;

Human T cells are activated by both peptide and nonpeptide Ags produced by Mycobacterium tuberculosis. T cells recognize cell wall lipids bound to CD1 molecules, but effector functions of CD1-reactive T cells have not been systematically assessed in M. tuberculosis-infected humans. It is also not known how these features correlate with T cell responses to secreted protein Ags. We developed a flow cytometric assay to profile CD1-restricted T cells ex vivo and assessed T cell responses to five cell wall lipid Ags in a cross-sectional study of 19 M. tuberculosis-infected and 22 M. tuberculosis-uninfected South African adolescents. We analyzed six T cell functions using a recently developed computational approach for flow cytometry data in high dimensions. We compared these data with T cell responses to five protein Ags in the same cohort. We show that CD1b-restricted T cells producing antimycobacterial cytokines IFN-γ and TNF-α are detectable ex vivo in CD4(+), CD8(+), and CD4(-)CD8(-) T cell subsets. Glucose monomycolate was immunodominant among lipid Ags tested, and polyfunctional CD4 T cells specific for this lipid simultaneously expressed CD40L, IFN-γ, IL-2, and TNF-α. Lipid-reactive CD4(+) T cells were detectable at frequencies of 0.001-0.01%, and this did not differ by M. tuberculosis infection status. Finally, CD4 T cell responses to lipids were poorly correlated with CD4 T cell responses to proteins (Spearman rank correlation -0.01; p = 0.95). These results highlight the functional diversity of CD1-restricted T cells circulating in peripheral blood as well as the complementary nature of T cell responses to mycobacterial lipids and proteins. Our approach enables further population-based studies of lipid-specific T cell responses during natural infection and vaccination.
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http://dx.doi.org/10.4049/jimmunol.1501285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637215PMC
November 2015

Granulomatosis With Polyangiitis Presenting With an Intracardiac Mass and Complete Heart Block: Enhanced Images by 3-Dimensional Echocardiography.

Circulation 2015 Sep;132(10):961-4

From Division of Cardiology, Harborview Medical Center, Seattle, WA (T.T.); Department of Cardiology, Rocky Mountain Heart and Lung, Kalispell Regional Medical Center, Kalispell, MT (S.L.G.); Division of Radiology, Memorial Sloan-Kettering Cancer Center, New York (L.M.); Department of Cardiothoracic Surgery, Loma Linda Medical Center, CA (D.R.); Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington Medical Center, Seattle (T.R.H.); Departments of Pathology and Laboratory Medicine, University of Washington, Seattle (C.L.F.); Division of Nephrology, Department of Medicine, Harborview Medical Center/University of Washington, Seattle (F.C.); and Division of Cardiology, Harborview Medical Center/University of Washington Medical Center, Seattle (E.A.G.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.016851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976451PMC
September 2015

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Nat Biotechnol 2015 Jun 25;33(6):610-6. Epub 2015 May 25.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software.
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http://dx.doi.org/10.1038/nbt.3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569006PMC
June 2015

New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics.

Immunol Rev 2015 Mar;264(1):344-62

Department of Medicine, University of Washington, Seattle, WA, USA.

Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50 years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. One solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. Here, we discuss recent progress in so-called 'host-directed therapeutics' (HDTs), focusing on two general mechanistic strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii) immunomodulatory HDTs that facilitate protective immune responses that kill Mtb or reduce deleterious responses that exacerbate disease. HDTs hold significant promise as adjunctive therapies in that they are less likely to engender resistance, will likely have efficacy against antibiotic-resistant strains, and may have activity against non-replicating Mtb. However, TB is a complex and variegated disease, and human populations exhibit significant diversity in their immune responses to it, which presents a complicated landscape for HDTs to navigate. Nevertheless, we suggest that a detailed mechanistic understanding of drug action, together with careful selection of disease stage targets and dosing strategies may overcome such limitations and allow the development of HDTs as effective adjunctive treatment options for TB.
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http://dx.doi.org/10.1111/imr.12255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571192PMC
March 2015