• Apremilast
• TNF-α
• immunomodulation
• psoriasis
• tuberculosis

• Adult tuberculosis
• BCG prime-boost strategy
• BCG revaccination
• IL-10 inhibition
• Memory CD4+ T cell
• Primary Mycobacterium tuberculosis infection

• Animals
• Interleukin-10/metabolism
• Mice, Inbred C57BL
• BCG Vaccine/immunology
• Lung/immunology
• Th1 Cells/immunology
• Immunization, Secondary
• Tuberculosis/prevention & control
• Tuberculosis/immunology
• Mycobacterium tuberculosis/immunology
• Female
• CD4-Positive T-Lymphocytes/immunology
• Vaccination
• Mice
• Receptors, Interleukin-10/immunology

• No. 81971909 Innovative Research Group Project of the National Natural Science Foundation of China
• 2022YFA1303503 Key Technologies Research and Development Program

• vaccines
• tuberculosis

• 82171739 National Natural Science Foundation of China (National Science Foundation of China)
• 32394014 National Natural Science Foundation of China (National Science Foundation of China)
• 82171815 National Natural Science Foundation of China (National Science Foundation of China)
• National Key Research and Development Program of China(2021YFC2301503)
• National Key Research and Development Program of China(2022YFC2302900)

• Foxp3 T cells
• IL-4Rα
• listeriosis
• mice
• tuberculosis

• Animals
• Mice
• Disease Models, Animal
• Forkhead Transcription Factors/metabolism
• Listeria monocytogenes/immunology
• Listeriosis/immunology
• Listeriosis/microbiology
• Mice, Inbred BALB C
• Mice, Knockout
• Mycobacterium tuberculosis/immunology
• Signal Transduction
• T-Lymphocytes, Regulatory/immunology
• Tuberculosis/immunology
• Tuberculosis/microbiology

• Wellcome Trust

• Adjuvant
• Bacillus Calmette-Guerin
• Immunity
• Subunit vaccine
• Tuberculosis
• cationic pH-sensitive liposome

• Animals
• Liposomes
• Tuberculosis Vaccines/administration & dosage
• Tuberculosis Vaccines/immunology
• Mycobacterium tuberculosis/immunology
• Mice
• Vaccines, Subunit/immunology
• Vaccines, Subunit/administration & dosage
• Humans
• Female
• Adjuvants, Immunologic/administration & dosage
• Adjuvants, Immunologic/pharmacology
• Hydrogen-Ion Concentration
• Tuberculosis/prevention & control
• Tuberculosis/immunology
• Mice, Inbred C57BL
• Dendritic Cells/immunology
• Cations
• Antigens, Bacterial/immunology
• Antigens, Bacterial/administration & dosage
• Cytokines/metabolism
• CD8-Positive T-Lymphocytes/immunology
• Lung/immunology
• Lung/microbiology
• CD4-Positive T-Lymphocytes/immunology
• Bacterial Load

• Interleukin-17/metabolism
• Interleukin-17/immunology
• Animals
• Mycobacterium bovis/pathogenicity
• Mycobacterium bovis/immunology
• Tuberculosis, Pulmonary/immunology
• Tuberculosis, Pulmonary/microbiology
• Tuberculosis, Pulmonary/pathology
• Mice
• Mice, Inbred BALB C
• Virulence
• Lung/microbiology
• Lung/pathology
• Lung/immunology
• Female
• Cattle

• Consejo Nacional de Ciencia y Tecnología

• IL-17
• IL-1β
• Mycobacterium abscessus
• NLRP3 inflammasome
• Pulmonary inflammation

• Animals
• Mice
• Inflammasomes/metabolism
• Inflammasomes/immunology
• Interleukin-17/metabolism
• Interleukin-17/immunology
• Interleukin-1beta/metabolism
• Lung/pathology
• Lung/microbiology
• Lung/immunology
• Macrophages/immunology
• Macrophages/metabolism
• Mice, Inbred C57BL
• Mice, Knockout
• Mycobacterium abscessus/immunology
• Mycobacterium Infections, Nontuberculous/immunology
• Mycobacterium Infections, Nontuberculous/microbiology
• Mycobacterium Infections, Nontuberculous/pathology
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics

• BCG
• CD4 T cells
• IFN-γ
• antigen85B
• intracellular M. tuberculosis killing
• tuberculosis

• Animals
• Mice
• Acyltransferases/immunology
• Antigens, Bacterial/immunology
• Bacterial Proteins/immunology
• BCG Vaccine/immunology
• CD4-Positive T-Lymphocytes/immunology
• Cytokines/metabolism
• Mice, Inbred C57BL
• Microbial Viability
• Mycobacterium tuberculosis/immunology
• Tuberculosis/immunology
• Tuberculosis/microbiology

• RF-2019-12371111 Italian Ministry of Health
• RF-ISS-2009-1304225 Italian Ministry of Health-Istituto Superiore di Sanità AIDS Program ISS-2009

• Animals
• Mice
• Salmonella typhimurium
• Tryptophan/metabolism
• Salmonella Infections
• Microbiota
• Gastrointestinal Microbiome
• Receptors, Aryl Hydrocarbon/genetics
• Receptors, Aryl Hydrocarbon/metabolism

• tuberculosis
• lymphocyte activation

• R01 AI147948 NIAID NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
• Conacyt-I2T2-Contex James W. McLaughlin Predoctoral Fellowship

• P20 GM121176 NIGMS NIH HHS
• R01 AI111935 NIAID NIH HHS
• R37 AI042999 NIAID NIH HHS

• Chagas disease
• Immunogenicity

• Multicomponent protein
• Mycobacterium tuberculosis
• T-cell epitope-rich protein
• TB vaccine
• Vaccines

• Adjuvants
• Tuberculosis
• Vaccines

• Humans
• Tuberculosis/prevention & control
• Tuberculosis Vaccines
• Vaccines, Subunit
• Vaccine Development
• Adjuvants, Vaccine

• B cell
• Mycobacterium tuberculosis
• T cell
• tuberculosis
• vaccine

• Host Directed Therapy
• Mycobacterium tuberculosis
• Pulmonary TB
• tissue damage
• tuberculosis

• Th17
• immunopathology
• pathogens

• BCG
• Mycobacterium tuberculosis
• SARS-CoV-2
• pathogenesis
• superinfection
• virulence

• Mice
• Animals
• Mycobacterium tuberculosis
• Mycobacterium bovis
• Interleukin-17
• SARS-CoV-2
• BCG Vaccine
• Superinfection
• COVID-19
• Tuberculosis, Lymph Node
• Cytokines

• U.S. Department of Agriculture (USDA)
• United States Agency for International Development (USAID)

Neutrophils are implicated in the pathogenesis of many diseases involving inflammation. Neutrophils are also critical to host defence and have a key role in the innate immune response to infection. Despite their efficiencies against a wide range of pathogens however, their ability to contain and combat Mycobacterium tuberculosis (Mtb) in the lung remains uncertain and contentious. The host response to Mtb infection is very complex, involving the secretion of various cytokines and chemokines from a wide variety of immune cells, including neutrophils, macrophages, monocytes, T cells, B cells, NK cells and dendritic cells. Considering the contributing role neutrophils play in the advancement of many diseases, understanding how an inflammatory microenvironment affects neutrophils, and how neutrophils interact with other immune cells, particularly in the context of the infected lung, may aid the design of immunomodulatory therapies. In the current review, we provide a brief overview of the mechanisms that underpin pathogen clearance by neutrophils and discuss their role in the context of Mtb and non-Mtb infection. Next, we examine the current evidence demonstrating how neutrophils interact with a range of human and non-human immune cells and how these interactions can differentially prime, activate and alter a repertoire of neutrophil effector functions. Furthermore, we discuss the metabolic pathways employed by neutrophils in modulating their response to activation, pathogen stimulation and infection. To conclude, we highlight knowledge gaps in the field and discuss plausible novel drug treatments that target host neutrophil metabolism and function which could hold therapeutic potential for people suffering from respiratory infections.

• Chemokines/metabolism
• Cytokines/metabolism
• Humans
• Lung/metabolism
• Neutrophils
• Tuberculosis

• Irish Research Council
• Health Research Board

In the Investigation of the Management of Pericarditis (IMPI) randomized control, 2x2 factorial trial, Mycobacterium indicus pranii (MIP) immunotherapy, adjunctive corticosteroids or MIP combined with corticosteroids was compared to standard tuberculosis (TB) therapy for tuberculous pericarditis (TBP). While MIP and/or the combination of MIP and corticosteroids had no impact on all-cause mortality or pericarditis related outcomes, corticosteroids reduced the incidence of constrictive pericarditis at 12 months. Data suggests that both adjunctive therapies modulate the immune and inflammatory responses to pulmonary TB. Whether they affect systemic antigen-specific T cell responses, key immune mediators of Mycobacterium tuberculosis control, in patients with TBP is unknown.

Participants with definite or probable TBP were randomly assigned to receive five injections of MIP or placebo at 2-week intervals and either 6 weeks of oral prednisolone or placebo. Frequencies of CD4 and CD8 T cells expressing IFN-γ, IL-2 or TNF in response to MIP or purified protein derivative stimulation were measured by intracellular cytokine staining and flow cytometry up to 24 weeks post treatment.

Immunotherapy with MIP did not significantly modulate frequencies of Th1 CD4 and CD8 T cells compared to placebo. Adjunctive prednisolone also did not change mycobacteria-specific CD4 or CD8 T cell responses. By contrast, combinatorial therapy with MIP and prednisolone was associated with a modest increase in frequencies of multifunctional and single cytokine-expressing CD4 T cell responses at 6 and 24 weeks post treatment.

Consistent with the lack of a significant clinical effect in the IMPI trial, MIP immunotherapy did not significantly modulate mycobacteria-specific T cell responses. Despite the positive effect of prednisolone on hospitalizations and constrictive pericarditis in the IMPI trial, prednisolone did not significantly reduce pro-inflammatory T cell responses in this sub-study. The modest improvement of mycobacteria-specific T cell upon combinatorial therapy with MIP and prednisolone requires further investigation.

• Adjunctive corticosteroid
• Mycobacteriumindicus pranii immunotherapy
• T cell responses
• Tuberculous pericarditis

• CP: Immunology
• CP: Microbiology
• Mycobacterium tuberculosis
• lymphocytes
• single-cell RNA sequencing
• type I IFN

Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils.

• Adaptor Proteins, Signal Transducing/metabolism
• Adjuvants, Immunologic/chemistry
• Glycolipids
• Humans
• Immunization
• Monocytes
• Myeloid Differentiation Factor 88/metabolism
• Neutrophils
• Receptors, Interleukin-1/metabolism
• Th17 Cells
• Vaccination

• Deutsche Forschungsgemeinschaft

Early Th₁₇ responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th₁₇ polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th₁₇ responses. However, the molecular mechanisms that contributed to Th₁₇ polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th₁₇ polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th₁₇ responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th₁₇ polarization in vitro and in vivo. In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th₁₇ responses and identify the CD40-DLL4 pathways as targets for developing new Th₁₇-inducing vaccines and adjuvants for tuberculosis.

•

Mtb restricts Th₁₇ responses by impairing CD40 signaling on dendritic cells

• P30 CA008748 NCI NIH HHS
• P51 OD011132 NIH HHS
• R01 AI134244 NIAID NIH HHS
• R56 AI083366 NIAID NIH HHS

Delays in diagnosis and treatment of pulmonary tuberculosis (TB) can lead to more severe disease and increased transmission. Contact investigation among household contacts (HHCs) of TB patients is crucial to ensure optimal outcomes. In the context of a prospective cohort study in Palamaner, Southern India, this study attempted to assess the potential of 27 different soluble immune markers to accurately assign HHCs for appropriate treatment. A multiplex bead assay was applied on QuantiFERON (QFT)-nil supernatants collected from 89 HHCs grouped by longitudinal QFT status; M. tuberculosis (Mtb) infected (QFT positive at baseline and follow-up, n = 30), recent QFT converters (QFT-negative at baseline, n = 27) and converted to QFT-positivity within 6 months of exposure (at follow-up, n = 24) and QFT consistent negatives (n = 32). The 29 TB index cases represented Active TB. Active TB cases and HHCs with Mtb infection produced significantly different levels of both pro-inflammatory (IFNγ, IL17, IL8, IP10, MIP-1α, MIP1β, and VEGF) and anti-inflammatory (IL9 and IL1RA) cytokines. We identified a 4-protein signature (bFGF, IFNγ, IL9, and IP10) that correctly classified HHCs with Mtb infection vs. Active TB with a specificity of 92.6%, suggesting that this 4-protein signature has the potential to assign HHCs for either full-length TB treatment or preventive TB treatment. We further identified a 4-protein signature (bFGF, GCSF, IFNγ, and IL1RA) that differentiated HHCs with Mtb infection from QFT consistent negatives with a specificity of 62.5%, but not satisfactory to safely assign HHCs to no preventive TB treatment. QFT conversion, reflecting new Mtb infection, induced an elevated median concentration in nearly two-thirds (19/27) of the analyzed soluble markers compared to the levels measured at baseline. Validation in other studies is warranted in order to establish the potential of the immune biosignatures for optimized TB case detection and assignment to therapeutic and preventive treatment of Mtb infected individuals.

• Biomarkers/analysis
• Cytokines/analysis
• Humans
• Mycobacterium tuberculosis
• Prospective Studies
• Tuberculin Test
• Tuberculosis/diagnosis
• Tuberculosis/drug therapy
• Tuberculosis/prevention & control

• PLGA nanospheres
• chitosan
• mucosal and cell-mediated responses
• nasal delivery
• trimethyl chitosan

Cytokines are key mediators of cellular communication and regulators of biological advents. The timing, quantity and localization of cytokines are key features in producing specific biological outcomes, and thus have been thoroughly studied and reviewed while continuing to be a focus of the cytokine biology community. Due to the complexity of cellular signaling and multitude of factors that can affect signaling outcomes, systemic level studies of cytokines are ongoing. Despite their small size, cytokines can exhibit structurally promiscuous and dynamic behavior that plays an equally important role in biological activity. In this review using case studies, we highlight the recent insight gained from observing cytokines through a molecular lens and how this may complement a system-level understanding of cytokine biology, explain diversity of downstream signaling events, and inform therapeutic and experimental development.

• allostery
• cytokine
• immunology
• protein dynamics
• spectroscopy

Tuberculosis (TB) remains one of the leading causes of death worldwide due to a single infectious disease agent. BCG, the only licensed vaccine against TB, offers limited protection against pulmonary disease in children and adults. TB vaccine research has recently been reinvigorated by new data suggesting alternative administration of BCG induces protection and a subunit/adjuvant vaccine that provides close to 50% protection. These results demonstrate the need for generating adjuvants in order to develop the next generation of TB vaccines. However, development of TB-targeted adjuvants is lacking. To help meet this need, NIAID convened a workshop in 2020 titled “Advancing Vaccine Adjuvants for Mycobacterium tuberculosis Therapeutics”. In this review, we present the four areas identified in the workshop as necessary for advancing TB adjuvants: 1) correlates of protective immunity, 2) targeting specific immune cells, 3) immune evasion mechanisms, and 4) animal models. We will discuss each of these four areas in detail and summarize what is known and what we can advance on in order to help develop more efficacious TB vaccines.

• BCG
• CD4+ T cells
• M72
• TLR
• Th17
• adjuvants
• tuberculosis
• vaccines

• Paracoccidioides brasiliensis
• Dectine-1
• TLR2
• TLR4
• inflammatory response
• mesenchymal stem cells

• ESAT-6/CFP-10
• IFN-γ
• LTBI
• T cell responses
• TNF-α

• Animals
• Bacterial Load
• Disease Models, Animal
• Macaca mulatta
• Mycobacterium tuberculosis/immunology
• T-Lymphocytes/immunology
• Tuberculosis, Pulmonary/immunology

• U19 AI111211 NIAID NIH HHS
• P51 OD011132 NIH HHS
• R01 AI111914 NIAID NIH HHS
• R01 AI123047 NIAID NIH HHS
• R01 AI111943 NIAID NIH HHS
• R01 AI138587 NIAID NIH HHS
• R01 AI134240 NIAID NIH HHS
• P51 OD011133 NIH HHS
• P30 AI050409 NIAID NIH HHS
• K01 OD031898 NIH HHS
• U42 OD010442 NIH HHS

• Hematopoietic cells
• Lymphoid cells
• Mycobacterium tuberculosis
• Myeloid cells
• Tuberculosis

Host immune responses at the site of Mycobacterium tuberculosis (Mtb) infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modelled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin (IL)-17A and Th17 responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident in both circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote Th17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.

Tuberculosis vaccines capable of reducing disease worldwide have proven difficult to develop. BCG is effective in limiting childhood disease, but adult TB is still a major public health issue. Development of new vaccines requires identification of antigens that are both spatially and temporally available throughout infection, and immune responses to which reduce bacterial burden without increasing pathologic outcomes. Subunit vaccines containing antigen require adjuvants to drive appropriate long-lived responses. We generated a triple-antigen fusion containing the virulence-associated EsxN (Rv1793), the PPE42 (Rv2608), and the latency associated Rv2628 to investigate the balance between bacterial reduction and weight loss in an animal model of aerosol infection. We found that in both a low pattern recognition receptor (PRR) engaging adjuvant and a high PRR-engaging adjuvant (MPL/TDM/DDA) the triple-antigen fusion could reduce the bacterial burden, but also induced weight loss in the mice upon aerosol infection. The weight loss was associated with an imbalance between TNFα and IL-17 transcription in the lung upon challenge. These data indicate the need to assess both protective and pathogenic responses when investigating subunit vaccine activity.

• antigen
• tuberculosis
• vaccine
• weight loss

• MR/P011136/1 Medical Research Council
• BB/P001513/1 Biotechnology and Biological Sciences Research Council

• BCG
• TB
• adaptive
• innate
• revaccination
• trained immunity
• vaccination

• ESAT-6
• IL-1β
• Inflammasome
• Macrophages
• SAA3
• Tuberculosis

Chronic inflammatory pulmonary diseases are characterized by recurrent and persistent inflammation of the airways, commonly associated with poor clinical outcomes. Although their etiologies vary tremendously, airway neutrophilia is a common feature of these diseases. Neutrophils, as vital regulators linking innate and adaptive immune systems, are a double-edged sword in the immune response of the lung involving mechanisms such as phagocytosis, degranulation, neutrophil extracellular trap formation, exosome secretion, release of cytokines and chemokines, and autophagy. Although neutrophils serve as strong defenders against extracellular pathogens, neutrophils and their components can trigger various cascades leading to inflammation and fibrogenesis. Here, we review current studies to elucidate the versatile roles of neutrophils in chronic pulmonary inflammatory diseases and describe the common pathogenesis of these diseases. This may provide new insights into therapeutic strategies for chronic lung diseases.

• asthma
• chronic obstructive pulmonary disease
• cystic fibrosis
• fibrogenesis
• fibrosis
• idiopathic pulmonary fibrosis
• neutrophils

• NK cells
• granulomas
• immune protection
• lung
• pDCs
• single cell technologies
• tuberculosis
• type I IFNs

• Animals
• Dendritic Cells/immunology
• Humans
• Killer Cells, Natural/immunology
• Latent Tuberculosis/immunology
• Lung/cytology
• Lung/immunology
• Macaca mulatta
• Macrophages/immunology
• Mycobacterium tuberculosis/immunology
• Tuberculosis, Pulmonary/immunology
• Tuberculosis, Pulmonary/pathology

• R01 AI123780 NIAID NIH HHS
• R01 AI134236 NIAID NIH HHS
• R01 AI111914 NIAID NIH HHS
• R01 AI155024 NIAID NIH HHS
• R01 HL105427 NHLBI NIH HHS
• P01 AG051428 NIA NIH HHS
• R01 AI134240 NIAID NIH HHS
• P51 OD011133 NIH HHS
• U19 AI091036 NIAID NIH HHS
• S10 OD028732 NIH HHS
• U42 OD010442 NIH HHS
• R01 AI111943 NIAID NIH HHS
• P51 OD011104 NIH HHS

• Mycobacterium tuberculosis
• Rv0580c
• apoptosis
• cell wall
• cytokines

Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.

GM-CSF is involved in control over M. tuberculosis infection. Here the authors show that GM-CSF reduces type 1 interferon driven neutrophil recruitment, NETosis and bacterial growth in the lungs of infected mice, and provide evidence that this NETosis occurs in infected humans who are not responsive to antibiotic therapy.

• Listeria ivanovii
• Listeria monocytogenes
• Mycobacterium tuberculosis
• multistage
• vaccine