Successful treatment of invasive mycobacterium infection with interferon beta in a patient with Interferon-Gamma Receptor 1 deficiency.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by approximately 21 genetic defects, including a mutation in Interferon-Gamma Receptor 1 (IFNGR1). IFNGR1 deficiency leads to a loss of cellular responsiveness to type II Interferon (IFN-γ), which plays a significant role in controlling intracellular bacteria. This study explored the response of IFN-ß therapy in a patient with partial IFNGR1 deficiency to treat invasive mycobacterial infection. The biological therapy was used successfully as an adjuvant to anti-mycobacterial medications to treat a 17-year-old girl with partial IFNGR1 deficiency who presented with a recurrent mycobacterial infection that extended to her central nervous system, which resulted in clinical and radiological improvement. This report suggests that activation of type I IFN through Signal Transducers and Activators of Transcription1 (STAT1) could bypass the early IFN-γ signaling defects and activate IFN-γ production. For that reason, IFN-ß might be used as a beneficial adjuvant therapy for managing extensive central nervous system mycobacterial infection, especially in patients with IFNGR1 deficiency.

Disseminated mycobacterium avium complex spinal osteomyelitis in a patient with interferon gamma receptor deficiency: A case report.

Disseminated mycobacterium avium complex (MAC) infection is rare and is classically associated with immunodeficient states. Osteomyelitis is a rare manifestation of disseminated MAC infection. The overwhelming majority of MAC infections occur in patients with human immunodeficiency virus (HIV). Disseminated MAC infection has been described in interferon gamma receptor deficiency, an immunodeficiency mechanistically linked to mycobacterial infection. We present a case of disseminated MAC vertebral osteomyelitis in a patient with interferon gamma receptor deficiency.

Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib.

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients.

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10-4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12-7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

Identification, functional characterization and expression pattern of interferon-gamma (IFN-γ) and interferon-gamma receptor 1 (IFNGR1) in Nibea albiflora.

Interferon-gamma (IFN-γ) is an inflammatory cytokine that plays a crucial role in regulating both innate and cell-mediated immune responses by binding to a receptor complex made up of IFNGR1 and IFNGR2. In this study, the complete cDNA of IFN-γ and IFNGR1 from Nibea albiflora were cloned and functionally characterized (named NaIFN-γ and NaIFNGR1), whose complete cDNA sequences were 1593 bp and 2792 bp, encoding 201 and 399 amino acids, respectively. Multiple sequence alignment and phylogenetic analysis showed that the concluded amino acids sequences of NaIFN-γ and NaIFNGR1 shared high identity with their teleost orthologues including the IFN-γ signature and nuclear localization signal (NLS) motif in NaIFN-γ and FN Ⅲ domain in NaIFNGR1. Real-time PCR showed that NaIFN-γ and NaIFNGR1 constitutively expressed in all tested tissues, such as the head-kidney, spleen, liver, kidney, gill, muscle, blood, and intestine with the highest expression of NaIFN-γ and NaIFNGR1 appearing in the liver and gill, respectively. After experiencing stimulation with Polyinosinic-polycytidylic acid (Poly (I:C)), Vibrio alginolyticus (V. alginolyticus) or Vibrio parahaemolyticus (V. parahaemolyticus), NaIFN-γ and NaIFNGR1 mRNA were up-regulated with the time-dependent model. Due to the presence of a nuclear localization signal (NLS), the subcellular localization revealed that NaIFN-γ dispersed throughout the cytoplasm and nucleus. NaIFNGR1, as a member of Cytokine receptor family B, was primarily expressed on the cell membrane. When NaIFN-γ and NaIFNGR1 were co-transfected, their fluorescence signals overlapped on the membrane of HEK 293T cells indicating the potential interaction between IFN-γ and IFNGR1. The GST-pull-down results further showed that NaIFN-γ could directly interact with the extracellular region of NaIFNGR1, further confirming the affinity between IFN-γ and IFNGR1. Taken together, the results firstly demonstrated that the NaIFN-γ ligand-receptor system existed in N.albiflora and played a pivotal part in N.albiflora's immune response against pathogenic bacterial infections, which contributed to the better understanding of the role of IFN-γ in the immunomodulatory mechanisms of teleost.

Mycobacterium avium Complex Infections: Detailed Phenotypic and Functional Immunological Work-Up Is Required despite Genetic Analyses.

INTRODUCTION: Cervical scrofulous lymphadenitis due to Mycobacterium avium complex (MAC) in immunocompetent adults is a rare disease. The presence of MAC infections demands meticulous clinical evaluation of patients along with detailed phenotypic and functional evaluation of their immune system including next-generation sequencing (NGS) analyses of target genes. METHODS: Exact clinical histories of the index patients both suffering from retromandibular/cervical scrofulous lymphadenitis were obtained along with phenotypic and functional immunological evaluations of leukocyte populations followed by targeted NGS-based sequencing of candidate genes. RESULTS: Immunological investigations showed normal serum immunoglobulin and complement levels, but lymphopenia, which was caused by significantly reduced CD3+CD4+CD45RO+ memory T-cell and CD19+ B-cell numbers. Despite normal T-cell proliferation to a number of accessory cell-dependent and -independent stimuli, the PBMC of both patients elaborated clearly reduced levels of a number of cytokines, including IFN-γ, IL-10, IL-12p70, IL-1α, IL-1ß, and TNF-α upon TCR-dependent T-cell stimulation with CD3-coated beads but also superantigens. The IFN-γ production deficiency was confirmed for CD3+CD4+ helper and CD4+CD8+ cytotoxic T cells on the single-cell level by multiparametric flow cytometry irrespective of whether PMA/ionomycin-stimulated whole blood cells or gradient-purified PBMC was analyzed. In the female patient L1, targeted NGS-based sequencing revealed a homozygous c.110T>C mutation in the interferon-γ receptor type 1 (IFNGR1) leading to significantly reduced receptor expression on both CD14+ monocytes and CD3+ T cells. Patient S2 presented with normal IFNGR1 expression on CD14+ monocytes but significantly reduced IFNGR1 expression on CD3+ T cells, despite the absence of detectable homozygous mutations in the IFNGR1 itself or disease-related target genes. Exogenous addition of increasing doses of IFN-γ resulted in proper upregulation of high-affinity FcγRI (CD64) on monocytes from patient S2, whereas monocytes from patient L1 showed only partial induction of CD64 expression after incubation with high doses of IFN-γ. CONCLUSION: A detailed phenotypic and functional immunological examination is urgently required to determine the cause of a clinically relevant immunodeficiency, despite detailed genetic analyses.

Investigation of the relationship between interferon-gamma receptor 1-56C/T gene polymorphism and genetic susceptibility to lung sarcoidosis: A cross-sectional study.

Objectives: This study aims to investigate the relationship between the interferon-gamma receptor 1 (IFNGR1) polymorphism and susceptibility to lung sarcoidosis. Patients and methods: The study included a total of 55 patients (13 males, 42 females; mean age: 46.5±9.1 years; range, 22 to 66 years) with lung sarcoidosis and 28 healthy controls (6 males, 22 females; mean age: 43.9±5.9 years; range 22 to 60 years) selected from the Turkish population. The polymerase chain reaction was used for genotyping of participants to determine single-nucleotide polymorphisms. Hardy-Weinberg equilibrium, which is considered an important tool for detecting genotyping errors, was tested. Allele and genotype frequencies of patients and controls were compared using logistic regression analysis. Results: The analyses showed no correlation between the tested IFNGR1 single-nucleotide polymorphism (rs2234711) and lung sarcoidosis (p>0.05). The categorization analysis according to the clinical features, laboratory, and radiographic characteristics showed no correlation between the tested polymorphism of IFNGR1 (rs2234711) and these characteristics (p>0.05). Conclusion: The results of the study showed that the tested gene polymorphism (rs2234711) of IFNGR1 was not associated with lung sarcoidosis. More comprehensive studies are needed to verify our results.

Association between IFNGR1 gene polymorphisms and tuberculosis susceptibility: A meta-analysis.

The association of IFN-γ receptor 1 (IFNGR1) gene polymorphisms with tuberculosis (TB) susceptibility has not been systematically studied. We therefore conducted a meta-analysis to assess their association. Literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library. Odds ratio (OR) and 95% confidence interval (CI) was pooled by the random-effect model. Statistical analyses were performed using STATA 12.0 software. Fourteen studies involved 7,699 TB cases and 8,289 controls were included in this meta-analysis. A significant association was found between the IFNGR1 rs2234711 polymorphism and TB susceptibility among Africans in dominant model (OR = 1.24, 95%CI:1.01-1.52), and among Asians in allele model (OR = 0.89, 95%CI: 0.79-0.99), homozygote model (OR = 0.82, 95%CI: 0.70-0.98) and additive model (OR = 0.90, 95%CI: 0.83-0.97). In addition, a significant association was observed between the IFNGR1 rs7749390 polymorphism and TB susceptibility among Africans in allele model (OR = 0.89, 95%CI: 0.82-0.98). No significant association was found between the IFNGR1 rs1327474 polymorphism and TB susceptibility. In summary, IFNGR1 rs2234711 polymorphism was associated with increased TB susceptibility in Africans and decreased TB susceptibility in Asians, while IFNGR1 rs7749390 polymorphism was associated with decreased TB susceptibility in Africans.

Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1.

Human interferon-gamma (hIFNγ) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFNγ to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFNγ-hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

The role of interferon-gamma and interferon-gamma receptor in tuberculosis and nontuberculous mycobacterial infections.

Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM) remain the leading causes of lung disease and mortality worldwide. Interferon-gamma (IFN-γ) and its receptor (IFN-γR) play a key role in mediating immunity against Mtb and NTM. This study was conducted as a systematic review; all information was collected from databases such as: PubMed, Scopus, Medline, SID, and medical databases. Finally, all the collected data were reviewed, and all content was categorized briefly. There is growing evidence that IFN-γ plays an important role in host defense against these two intracellular pathogens by activating macrophages. In addition, IFN-γ has been shown to be an integral part of various antibacterial methods such as granuloma formation and phagosome-lysosome fusion, both of which lead to the death of intracellular Mycobacterium. As a result, its absence is associated with overgrowth of intracellular pathogens and disease caused by Mtb or Mycobacterium nontuberculosis. We also look at the role of IFN-γR in Mtb or NTM because IFN-γ acts through IFN-γR. Finally, we introduce new approaches to the treatment of M. tuberculosis complex (MTC) and NTM disease, such as cell and gene-based therapies that work by modulating IFN-γ and IFN-γR.

Predictive Value of Interferon γ Receptor Gene Polymorphisms for Hepatocellular Carcinoma Susceptibility.

BACKGROUND: Recent reports suggested relation between Interferon Gamma (IFN-γ) gene polymorphism and the risk of development of HCC on top of hepatic cirrhosis. The aim of this study was to address the predictive value of Interferon Gamma gene receptor (IFN-γR) polymorphisms for the occurrence of hepatocellular carcinoma on top of liver cirrhosis. PATIENTS AND METHODS: This is a case control study performed on patients selected from the outpatient hepatology clinic, specialized medical hospital, Mansoura University, Egypt, from August 2017 to February 2019. The included patients were categorized into two groups; 60 patients with HCC on top of cirrhosis and 20 patients with hepatic cirrhosis. For all patients IFN-γR polymorphism was identified by RFLP. RESULTS: Our study showed that HCC patients had male predominance. Additionally, diabetes mellitus (DM) was found in 28.3% of total HCC patients. Half of HCC patients in this study were from rural areas (50%). The frequency of AA at position -611 in the IFN-γR (-611 IFN-γR) was significantly higher in the HCC group as compared to cirrhotic group (P=0.021). Moreover; the frequency of CC and CT genotypes of IFN-γR -56 was not significantly different in HCC group as compared to control group (P>0.05). The IFN-γR (-611 IFN-γ) AA genotype significantly increased risk of HCC (OR= 0.78, 95% CI= 0.10-6.39; P= 0.042). CONCLUSION: The analysis of IFN-γR -611 single nucleotide gene polymorphism could be a valuable marker for predicting subgroup of cirrhotic patients with high risk of developing HCC.  Cirrhotic patients have AA genotype of IFN-γR-611 recommended to be under close follow up.

Paraspeckle Promotes Hepatocellular Carcinoma Immune Escape by Sequestering IFNGR1 mRNA.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the most common type of hepatic malignancies, with poor prognosis and low survival rate. Paraspeckles, which are unique subnuclear structures, are recently found to be involved in the development of various tumors, including HCC, and are related to induction in chemoresistance of HCC. This study aimed to investigate the possibility of paraspeckle in HCC cells participating in immune escape and its underlying mechanism in vitro and in vivo. METHODS: Expression of NEAT1_2, the framework of paraspeckle, in HCC cells and tissues was detected by qRT-PCR and RNA-FISH. mRNAs interacted with NEAT1_2 were pull-downed and sequenced in C-terminal S1-aptamer-tagged NEAT1_2 endogenously expressed HCC cells constructed using CRISPR-CAS9 knock-in technology. The effects of paraspeckle on HCC sensitivity to T-cell-mediated cytolysis were detected by T-cell mediated tumor cell killing assay. The roles of NEAT1_2 or NONO on IFNGR1 expression and IFN-γ signaling by applying gene function loss analysis in HCC cells were detected by qRT-PCR, RNA immunoprecipitation, Western blotting, and ELISA. The role of paraspeckle during adoptive T-cell transfer therapy for HCC in vivo was performed with a subcutaneous xenograft mouse. RESULTS: Paraspeckle in HCC cells is negatively related to T-cell-mediated cytolysis. Destruction of paraspeckle in HCC cells by knockdown of NEAT1_2 or NONO significantly improved the sensibility of resistant HCC cells to T-cell killing effects. Furthermore, IFNGR1 mRNA, which is sequestered by NEAT1_2 and NONO, is abundant in paraspeckle of T-cell killing-resistant HCC cells. Incapable IFN-γ-IFNGR1 signaling accounts for paraspeckle mediated-adoptive T-cell therapy resistance. Moreover, NEAT1_2 expression negatively correlates with IFNGR1 expression in clinical HCC tissues. CONCLUSIONS: Paraspeckle in HCC cells helps tumor cells escape from immunosurveillance through sequestering IFNGR1 mRNA to inhibiting IFN-γ-IFNGR1 signaling, thereby avoiding T-cell killing effects. Collectively, our results hint that NEAT1_2 highly expressed HCC patient is more resistant to T-cell therapy in clinic, and NEAT1_2 may be potential target for HCC immunotherapy.

Overview of nontuberculous mycobacterial disease in children.

Nontuberculous mycobacteria (NTM) are ubiquitous organisms in our surrounding environment. Four distinct clinical syndromes associated with NTM infection have been described: skin and soft tissue disease, lymphadenitis, disseminated disease and pulmonary disease. In children, lymphadenitis is the most common NTM clinical entity, particularly affecting those aged 1-5 years who have no known risk factors for disease. Optimal management of NTM lymphadenitis is not entirely clear, although surgical intervention is likely a definitive therapy. Disseminated NTM disease is uncommon and only seen in the setting of immunocompromise. In previously well children, this presentation should always lead to consideration of an underlying immune defect, such as Mendelian susceptibility to mycobacterial disease. Identification of the underlying cause enables more targeted therapy and better prognostic understanding. Pulmonary NTM disease is fundamentally different to the other clinical syndromes, presenting in different hosts, who have different comorbidities, and follow a different clinical course.

Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways.

Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.

Successful Matched Related Bone Marrow Transplantation in a Patient with Autosomal Dominant Interferon Gamma Receptor 1 Deficiency.

This is a report of a successful bone marrow transplant in an IFN-γR1 patient with progressive mycobacterial infection. PURPOSE: Hematopoietic cell transplant in patients with interferon gamma receptor deficiencies has been fraught with challenges, not the least of which is failure of engraftment and infectious complications. METHODS: This is a report of a successful hematopoietic cell transplant in an actively infected patient of advanced age. RESULTS: This case report shows successful engraftment and resolution of infection posttransplant using a matched related donor in a single institution. CONCLUSION: A successful curative HCT despite persistent, disseminated, nontuberculous mycobacterial infection in a patient with AD-IFNγR1 suggests that this approach, while difficult, may be useful in other patients with otherwise refractory disease.

Mouse Models for Use in Cryptosporidium Infection Studies and Quantification of Parasite Burden Using Flow Cytometry, qPCR, and Histopathology.

Cryptosporidiosis threatens life of young children in developing countries and newborn calves around the world. No vaccine or therapy can prevent or cure this diarrhea-inducing enteric disease caused by Cryptosporidium spp. protozoan parasites. There is an essential need to discover new therapeutic drugs efficient in reducing parasite burden in infected individuals. Research therefore relies on reliable small animal models of cryptosporidiosis. Here, we present excellent mouse models which can efficiently mimic pathogenesis of human and bovine cryptosporidiosis. We also describe methods to purify C. parvum oocysts from stool and intestine of infected mice to facilitate oocyst quantification. Moreover, we present protocols using flow cytometry, quantitative polymerase chain reaction, and histopathology to accurately quantify parasite burden in stool or intestine samples.

JAK2 V617F -Mediated Clonal Hematopoiesis Accelerates Pathological Remodeling in Murine Heart Failure.

Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2 V617F ) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted JAK2 V617F expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that JAK2 V617F mutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells.

Polymorphisms in Promoter Region of the Interferon-Gamma Receptor-1 Gene and its Relation with Susceptibility to Brucellosis.

BACKGROUND & OBJECTIVE: Brucellosis is one of the most prevalent bacterial zoonotic diseases which afflicts both humans and animals. Genetic factors play an important role in susceptibility to brucellosis. One of these factors is interferon-gamma (IFN-), which is vital in the defense mechanism against infectious diseases such as brucellosis. The purpose of this study was to evaluate the relationship between two single nucleotide polymorphisms (SNPs) at positions -611 and -56 within the promoter region of interferon-gamma receptor-1 gene (IFN- R1) and brucellosis. METHODS: In this research, the genomic DNA was collected from 60 peripheral blood samples infected with brucellosis and 68 healthy volunteers. DNA was extracted by salting out method. Then, DNA genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). RESULTS: The results showed that there is a significant difference in -611 SNP frequencies between control and patient groups. At position -611, CC genotype was related to patient group (P=0.024) and TT genotype was related to the control group. According to the results, males had a higher frequency of Brucella infection. CONCLUSION: The presence of C allele in position -611 in IFNγ R1 gene promoter was related to a higher risk of disease and susceptibility to brucellosis. Moreover, the presence of T allele in position γ.