ERS International Congress 2023: highlights from the Basic and Translational Sciences Assembly.

Early career members of Assembly 3 (Basic and Translational Sciences) of the European Respiratory Society (ERS) summarise the key messages discussed during six selected sessions that took place at the ERS International Congress 2023 in Milan, Italy. Aligned with the theme of the congress, the first session covered is "Micro- and macro-environments and respiratory health", which is followed by a summary of the "Scientific year in review" session. Next, recent advances in experimental methodologies and new technologies are discussed from the "Tissue modelling and remodelling" session and a summary provided of the translational science session, "What did you always want to know about omics analyses for clinical practice?", which was organised as part of the ERS Translational Science initiative's aims. The "Lost in translation: new insights into cell-to-cell crosstalk in lung disease" session highlighted how next-generation sequencing can be integrated with laboratory methods, and a final summary of studies is presented from the "From the transcriptome landscape to innovative preclinical models in lung diseases" session, which links the transcriptome landscape with innovative preclinical models. The wide range of topics covered in the selected sessions and the high quality of the research discussed demonstrate the strength of the basic and translational science being presented at the international respiratory conference organised by the ERS.

Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy.

Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8+ T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.

Impact of COVID-19 on long-term lung function in lung transplant recipients: A single-center retrospective cohort study.

Available data are limited concerning long-term lung function (LF) evolution after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant (LT) recipients. The aim of this study is to determine the effect of first SARS-CoV-2 infection on long-term LF in LT recipients. We analyzed spirometry results of LT recipients followed at our institution (March 2020 to July 2022) at 3, 6, and 12 months after first SARS-CoV-2 infection. Overall, 42 LT patients of our cohort (70%) with COVID-19 were included for long-term LF analysis. Forced expiratory volume in 1 s (FEV1 ) declined significantly at 3 months (-4.5%, -97 mL, 95% CI [-163; -31], p < .01), but not at 6 and 12 months (-3.9%, -65 mL, 95% CI [-168; +39], p = .21). Results were quite similar for the forced vital capacity. Spirometry values declined significantly at 3 months after COVID-19 in LT recipients, presented a mixed decline at 6 months, and no significant decline at 12 months.

ERS International Congress 2022: highlights from the Basic and Translational Science Assembly.

In this review, the Basic and Translational Science Assembly of the European Respiratory Society provides an overview of the 2022 International Congress highlights. We discuss the consequences of respiratory events from birth until old age regarding climate change related alterations in air quality due to pollution caused by increased ozone, pollen, wildfires and fuel combustion as well as the increasing presence of microplastic and microfibres. Early life events such as the effect of hyperoxia in the context of bronchopulmonary dysplasia and crucial effects of the intrauterine environment in the context of pre-eclampsia were discussed. The Human Lung Cell Atlas (HLCA) was put forward as a new point of reference for healthy human lungs. The combination of single-cell RNA sequencing and spatial data in the HLCA has enabled the discovery of new cell types/states and niches, and served as a platform that facilitates further investigation of mechanistic perturbations. The role of cell death modalities in regulating the onset and progression of chronic lung diseases and its potential as a therapeutic target was also discussed. Translational studies identified novel therapeutic targets and immunoregulatory mechanisms in asthma. Lastly, it was highlighted that the choice of regenerative therapy depends on disease severity, ranging from transplantation to cell therapies and regenerative pharmacology.

Personalized predictions of adverse side effects of the COVID-19 vaccines.

Background: Misconceptions about adverse side effects are thought to influence public acceptance of the Coronavirus disease 2019 (COVID-19) vaccines negatively. To address such perceived disadvantages of vaccines, a novel machine learning (ML) approach was designed to generate personalized predictions of the most common adverse side effects following injection of six different COVID-19 vaccines based on personal and health-related characteristics. Methods: Prospective data of adverse side effects following COVID-19 vaccination in 19943 participants from Iran and Switzerland was utilized. Six vaccines were studied: The AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2, and the mRNA-1273 vaccine. The eight side effects were considered as the model output: fever, fatigue, headache, nausea, chills, joint pain, muscle pain, and injection site reactions. The total input parameters for the first and second dose predictions were 46 and 54 features, respectively, including age, gender, lifestyle variables, and medical history. The performances of multiple ML models were compared using Area Under the Receiver Operating Characteristic Curve (ROC-AUC). Results: The total number of people receiving the first dose of the AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2, and mRNA-1273 were 6022, 7290, 5279, 802, 277, and 273, respectively. For the second dose, the numbers were 2851, 5587, 3841, 599, 242 and 228. The Logistic Regression model for predicting different side effects of the first dose achieved ROC-AUCs of 0.620-0.686, 0.685-0.716, 0.632-0.727, 0.527-0.598, 0.548-0.655, 0.545-0.712 for the AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2 and mRNA-1273 vaccines, respectively. The second dose models yielded ROC-AUCs of 0.777-0.867, 0.795-0.848, 0.857-0.906, 0.788-0.875, 0.683-0.850, and 0.486-0.680, respectively. Conclusions: Using a large cohort of recipients vaccinated with COVID-19 vaccines, a novel and personalized strategy was established to predict the occurrence of the most common adverse side effects with high accuracy. This technique can serve as a tool to inform COVID-19 vaccine selection and generate personalized factsheets to curb concerns about adverse side effects.

Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.

Major histocompatibility complex class I (MHC-I) deficiency, also known as bare lymphocyte syndrome type 1 (BLS-1), is a rare autosomal recessively inherited immunodeficiency disorder with remarkable clinical and biological heterogeneity. Transporter associated with antigen processing (TAP) is a member of the ATP-binding cassette superfamily of transporters and consists of two subunits, TAP1 or TAP2. Any defect resulting from a mutation or deletion of these two subunits may adversely affect the peptide translocation in the endoplasmic reticulum, which is an important process for properly assembling MHC-I molecules. To date, only 12 TAP2-deficient patients were reported in the literature. Herein, we described two Iranian cases with 2 and 3 decades of delayed diagnosis of chronic necrotizing granulomatous skin lesions due to TAP2 deficiency without pulmonary involvement. Segregation analysis in family members identified 3 additional homozygous asymptomatic carriers. In both asymptomatic and symptomatic carriers, HLA-I expression was only 4-15% of the one observed in healthy controls. We performed the first deep immunophenotyping in TAP2-deficient patients. While total CD8 T cell counts were normal as previously reported, the patients showed strongly impaired naïve CD8 T cell counts. Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cell counts were increased.

[Pulmonary fibrosis and lung cancer: between complementarities and specificities]. / Fibrose pulmonaire et cancer pulmonaire : entre complémentarités et spécificités.

Lung cancer is the leading cause of cancer mortality in the developed world. Diffuse fibrosing interstitial lung disease (ILD) consist of a heterogeneous group that includes idiopathic pulmonary fibrosis (IPF). Diffuse ILD is a risk factor for the development of lung cancer which on its own is associated with an increased risk of morbidity and mortality. Despite common mechanisms between fibrogenesis and carcinogenesis, the underlying pathogenesis of lung cancer and fibrosis overlap is poorly understood. The clinical management of these patients remains a medical challenge requiring a multidisciplinary approach, particularly in view of the risk of acute exacerbation of fibrosing ILD following most lung cancer treatments, leading to a considerable negative outcome on overall prognosis.

Le carcinome bronchopulmonaire (CBP) est la première cause de mortalité par cancer dans les pays développés. Les pneumopathies interstitielles diffuses fibrosantes (PIDf) sont un groupe hétérogène comprenant, entre autres, la fibrose pulmonaire idiopathique. Les PIDf sont un facteur de risque de développement du CBP et sont associées à un risque accru de morbi-mortalité. Malgré des mécanismes communs entre la fibrogenèse et la carcinogenèse, la pathogenèse sous-jacente de l'association CBP et PIDf est mal comprise. La gestion clinique de ces patients est un défi médical nécessitant une prise en charge multidisciplinaire, en particulier devant les risques d'exacerbation aiguë de la PIDf grevant le pronostic.

Longevity of immunity following COVID-19 vaccination: a comprehensive review of the currently approved vaccines.

It is unknown how long the immunity following COVID-19 vaccination lasts. The current systematic review provides a perspective on the persistence of various antibodies for available vaccines.Both the BNT162b2 and the mRNA-1273 induce the production of IgA antibodies, reflecting the possible prevention of the asymptomatic spread. The mRNA-1273 vaccine's antibodies were detectable until 6 months, followed by the AZD1222, 3 months, the Ad26.COV2.S and the BNT162b2 vaccines within 2 months.The BNT162b2 produced anti-spike IgGs 11 days after the first dose and peaked at day 21, whereas the AZD1222 induced a neutralizing effect 22 days after the first dose.These vaccines induce T-cell mediated immune responses too. Each one of the AZD1222, Ad26.COV2.S, mRNA-1273 mediates T-cell response immunity at days 14-22, 15, and 43 after the first dose, respectively. Whereas for the BNT162b1 and BNT162b2 vaccines, T-cell immunity is induced 7 days and 12 weeks after the booster dose, respectively.

Symptom Prediction and Mortality Risk Calculation for COVID-19 Using Machine Learning.

Background: Early prediction of symptoms and mortality risks for COVID-19 patients would improve healthcare outcomes, allow for the appropriate distribution of healthcare resources, reduce healthcare costs, aid in vaccine prioritization and self-isolation strategies, and thus reduce the prevalence of the disease. Such publicly accessible prediction models are lacking, however. Methods: Based on a comprehensive evaluation of existing machine learning (ML) methods, we created two models based solely on the age, gender, and medical histories of 23,749 hospital-confirmed COVID-19 patients from February to September 2020: a symptom prediction model (SPM) and a mortality prediction model (MPM). The SPM predicts 12 symptom groups for each patient: respiratory distress, consciousness disorders, chest pain, paresis or paralysis, cough, fever or chill, gastrointestinal symptoms, sore throat, headache, vertigo, loss of smell or taste, and muscular pain or fatigue. The MPM predicts the death of COVID-19-positive individuals. Results: The SPM yielded ROC-AUCs of 0.53-0.78 for symptoms. The most accurate prediction was for consciousness disorders at a sensitivity of 74% and a specificity of 70%. 2,440 deaths were observed in the study population. MPM had a ROC-AUC of 0.79 and could predict mortality with a sensitivity of 75% and a specificity of 70%. About 90% of deaths occurred in the top 21 percentile of risk groups. To allow patients and clinicians to use these models easily, we created a freely accessible online interface at www.aicovid.net. Conclusion: The ML models predict COVID-19-related symptoms and mortality using information that is readily available to patients as well as clinicians. Thus, both can rapidly estimate the severity of the disease, allowing shared and better healthcare decisions with regard to hospitalization, self-isolation strategy, and COVID-19 vaccine prioritization in the coming months.

Using Machine Learning to Predict Mortality for COVID-19 Patients on Day 0 in the ICU.

Rationale: Given the expanding number of COVID-19 cases and the potential for new waves of infection, there is an urgent need for early prediction of the severity of the disease in intensive care unit (ICU) patients to optimize treatment strategies. Objectives: Early prediction of mortality using machine learning based on typical laboratory results and clinical data registered on the day of ICU admission. Methods: We retrospectively studied 797 patients diagnosed with COVID-19 in Iran and the United Kingdom (U.K.). To find parameters with the highest predictive values, Kolmogorov-Smirnov and Pearson chi-squared tests were used. Several machine learning algorithms, including Random Forest (RF), logistic regression, gradient boosting classifier, support vector machine classifier, and artificial neural network algorithms were utilized to build classification models. The impact of each marker on the RF model predictions was studied by implementing the local interpretable model-agnostic explanation technique (LIME-SP). Results: Among 66 documented parameters, 15 factors with the highest predictive values were identified as follows: gender, age, blood urea nitrogen (BUN), creatinine, international normalized ratio (INR), albumin, mean corpuscular volume (MCV), white blood cell count, segmented neutrophil count, lymphocyte count, red cell distribution width (RDW), and mean cell hemoglobin (MCH) along with a history of neurological, cardiovascular, and respiratory disorders. Our RF model can predict patient outcomes with a sensitivity of 70% and a specificity of 75%. The performance of the models was confirmed by blindly testing the models in an external dataset. Conclusions: Using two independent patient datasets, we designed a machine-learning-based model that could predict the risk of mortality from severe COVID-19 with high accuracy. The most decisive variables in our model were increased levels of BUN, lowered albumin levels, increased creatinine, INR, and RDW, along with gender and age. Considering the importance of early triage decisions, this model can be a useful tool in COVID-19 ICU decision-making.

Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature.

We describe the case of a 42 year old, healthy patient with Covid-19 who despite improvement in his respiratory symptoms developed a mild to moderate cytokine release syndrome (CRS) and an associated monoarticular gout flare. Since the patient refused admission to the hospital and had stable vital signs, we chose to treat him with a safe anti-inflammatory and non-immunosuppressive therapy. To hit two birds with one stone, we considered colchicine, as it has systemic anti-inflammatory effects and is also effective in gout flare. Unexpectedly, 48 hours after treatment, not only did his ongoing fever and toe pain disappear, he also had significant improvements in his general state of health and all his inflammatory markers including fibrinogen, ferritin, D-dimer, and IL-6 levels normalized. To our knowledge, the use of colchicine in Covid-19 and CRS has not been reported. This observation merits the consideration of colchicine as a safe, inexpensive and oral medication for the treatment of mild to moderate CRS in Covid-19 patients. More importantly, in Covid-19 patients with early lung involvement colchicine may be an appropriate candidate to prevent CRS in adjunction with routine antiviral agents. Indeed, multicenter, randomized controlled studies are required to evaluate the benefits of this therapy.

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

BACKGROUND: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. METHODS: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. RESULTS: We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. CONCLUSIONS: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).

Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes.

Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of idiopathic pulmonary fibrosis (IPF). The aim of this study was to test the therapeutic effects of extracellular vesicles produced by human BM MSCs (MEx) in a bleomycin-induced pulmonary fibrosis model and investigate mechanisms of action. Adult C57BL/6 mice were challenged with endotracheal instillation of bleomycin and treated with MEx concurrently, or for reversal models, at day 7 or 21. Experimental groups were assessed at day 7, 14, or 28. Bleomycin-challenged mice presented with severe septal thickening and prominent fibrosis, and this was effectively prevented or reversed by MEx treatment. MEx modulated lung macrophage phenotypes, shifting the proportions of lung proinflammatory/classical and nonclassical monocytes and alveolar macrophages toward the monocyte/macrophage profiles of control mice. A parallel immunomodulatory effect was demonstrated in the BM. Notably, transplantation of MEx-preconditioned BM-derived monocytes alleviated core features of pulmonary fibrosis and lung inflammation. Proteomic analysis revealed that MEx therapy promotes an immunoregulatory, antiinflammatory monocyte phenotype. We conclude that MEx prevent and revert core features of bleomycin-induced pulmonary fibrosis and that the beneficial actions of MEx may be mediated via systemic modulation of monocyte phenotypes.

Oscillatory stimuli differentiate adapting circuit topologies.

Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.

ISG15 deficiency and increased viral resistance in humans but not mice.

ISG15 is an interferon (IFN)-α/ß-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/ß signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.

Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection.

BACKGROUND: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. METHODS: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. RESULTS: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. CONCLUSIONS: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Human intracellular ISG15 prevents interferon-α/ß over-amplification and auto-inflammation.

Intracellular ISG15 is an interferon (IFN)-α/ß-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/ß-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/ß immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-α/ß signalling, resulting in the enhancement and amplification of IFN-α/ß responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/ß immunity. In humans, intracellular ISG15 is IFN-α/ß-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-α/ß and prevention of IFN-α/ß-dependent autoinflammation.

Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency.

ISG15 is an interferon (IFN)-α/ß-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.