Research progress and clinical application of the new target IP-10 for tuberculosis infection

Tuberculosis, as a global infectious disease that seriously threatens human health, the situation of prevention and control is still grim. According to statistics from the World Health Organization (WHO), there were approximately 9.87 million new cases and 1.28 million deaths of active tuberculosis (ATB) worldwide in 2020.

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Recent Advances

Research Progress and Clinical Application of IP-10 as a New Target for Tuberculosis Infection

Tuberculosis, as a serious infectious disease threatening human health worldwide, still faces severe challenges in prevention and control. Statistics from the World Health Organization (WHO) show that in 2020, there were approximately 9.87 million new cases of active tuberculosis (ATB) globally, with about 1.28 million deaths due to tuberculosis. In China, there were 842,000 new cases in the same year, accounting for 8.5% of the global new cases, ranking second among the 30 high-burden tuberculosis countries[1]. These figures highlight the urgency of tuberculosis prevention and control, especially the urgent need for innovation in diagnostic technologies. In recent years, interferon gamma-induced protein 10 (IP-10) has emerged as a new biomarker for tuberculosis infection, showing promising application prospects in the field of tuberculosis diagnosis and providing new solutions to overcome the limitations of traditional diagnostic methods.

I. Current Status and Challenges in Tuberculosis Diagnosis

Pathogenic detection, as the "gold standard" for tuberculosis diagnosis, provides intuitive and confirmatory results. However, in clinical practice, the low positive rate of pathogenic detection severely hinders timely diagnosis. In 2018, the pathogenic positive rate among pulmonary tuberculosis patients in China was less than 40%, meaning that over half of suspected tuberculosis patients require comprehensive diagnosis based on clinical manifestations, immunological tests, and imaging examinations. This reliance on indirect evidence prolongs the diagnostic cycle and increases the risk of misdiagnosis and missed diagnosis, which is extremely unfavorable for the early control of tuberculosis.

Interferon Gamma Release Assays (IGRAs) are mature immunological detection technologies developed in recent years and have become important tools for diagnosing Mycobacterium tuberculosis infection[2]. The core principle is to use tuberculosis-specific antigens to stimulate tuberculosis-specific T cells in peripheral blood, and determine the infection status by detecting the level of interferon-gamma (IFN-γ) released after activation or counting the number of T cells secreting IFN-γ. This method has the advantage of distinguishing Mycobacterium tuberculosis infection from BCG vaccination and most non-tuberculous mycobacterial infections, with relatively high specificity.

Currently, there are two main types of IGRAs widely used in clinical practice: one is QuantiFERON-TB Gold In-Tube (QFT-GIT), which uses enzyme-linked immunosorbent assay (ELISA) to quantitatively detect IFN-γ levels released by sensitized T cells in whole blood samples after antigen stimulation; the other is T-SPOT.TB test, which counts the number of T cells releasing IFN-γ through enzyme-linked immunospot assay (ELISPOT). Although IGRAs play an important role in tuberculosis diagnosis, they have obvious limitations: the operation process is relatively cumbersome, with a reporting cycle usually exceeding 2 days; the detection rate is low in immunocompromised populations; uncertain results are prone to occur in cases of high inflammatory background or low lymphocyte count, increasing the difficulty of clinical judgment.

II. Biological Characteristics of IP-10 as a New Target for Tuberculosis Infection

In studies on early diagnostic markers for active tuberculosis, it was found that interferon gamma-induced protein 10 (IP-10) is highly expressed in the peripheral blood of tuberculosis patients[3]. IP-10 is a chemokine, also known as CXCL10, belonging to the CXC chemokine family. Its encoding gene is located in the human chromosome 4q21 region, sharing homology and relevance in gene structure and function with other members of the family.

IP-10 expression has a wide range of cellular sources and strict regulatory mechanisms. Under physiological conditions, its basal expression level is low. After stimulation by inflammatory signals such as IFN-γ, various cells can initiate IP-10 expression and secretion, including activated T cells, neutrophils, spleen cells, keratinocytes, endothelial cells, and mononuclear macrophages. This inducible expression pattern enables IP-10 to respond rapidly to infection or inflammatory stimuli and participate in immune regulation processes.

The biological function of IP-10 is mainly achieved through binding to specific receptors. It has been confirmed that CXCR3 is the main functional receptor of IP-10 and also the common receptor of another CXC chemokine MIG (CXCL9). CXCR3 is highly expressed on IL-2-activated T cells, especially specifically expressed on Th1-type helper T cells, and also expressed on eosinophils. When IP-10 binds to CXCR3, it can induce directional migration of immune cells by activating downstream signaling pathways, promote the aggregation of T cells to inflammatory sites, and enhance local immune responses. During Mycobacterium tuberculosis infection, as an important chemokine, IP-10 can recruit tuberculosis-specific T cells to the infection site, participate in pathogen clearance and immune regulation, which provides a solid biological basis for its use as a diagnostic target for tuberculosis infection.

III. Application Value of IP-10 in Tuberculosis Diagnosis

A large number of studies have shown that IP-10, as a new type of tuberculosis infection biomarker, has significant advantages in tuberculosis diagnosis. Studies have shown that in the QFT-Plus test, the IP-10 level in peripheral blood of active tuberculosis patients after stimulation with TB1 and TB2 antigens is significantly increased, and its diagnostic efficacy is higher than that of traditional IFN-γ detection[4]. More importantly, the expression level of IP-10 is less affected by the body's immune status, and can maintain relatively stable expression even in the case of T cell function exhaustion, making IP-10 a more reliable tuberculosis infection biomarker.

In 2022, a multi-center prospective study was conducted in Beijing Chest Hospital Affiliated to Capital Medical University, Henan Provincial Infectious Diseases Hospital, and Shenzhen Third People's Hospital. This study simultaneously performed IP-10 detection and T-SPOT.TB detection on suspected tuberculosis patients, and systematically evaluated the diagnostic performance and result consistency of the two methods through comparison and analysis with the final diagnosis results[5]. A total of 1307 suspected tuberculosis patients and 172 healthy controls were recruited in the study. After strict inclusion and exclusion criteria screening, 352 confirmed tuberculosis patients and 153 healthy controls were finally included in the statistical analysis. The results showed that the proportion of uncertain results in IP-10 detection was 0.39%, lower than 1.39% in T-SPOT.TB test (P=0.094), indicating that IP-10 detection has better stability. The total coincidence rate of the two detection methods reached 95.0%, with a positive coincidence rate of 96.3% and a negative coincidence rate of 92.4%. The kappa value of consistency test was 0.89 (P<0.001), suggesting a high degree of consistency between IP-10 detection and traditional T-SPOT.TB test. Correlation analysis results showed that CXCL10 mRNA expression level was moderately positively correlated with IFN-γ release (r=0.6761, P<0.0001), which further confirmed the close association between IP-10 and Mycobacterium tuberculosis-specific immune responses.

IV. Advantages of IP-10 in Tuberculosis Diagnosis in Special Populations

Patients with abnormal immune function are a difficult group in tuberculosis diagnosis, especially in HIV-infected individuals. Due to severe impairment of the immune system, the proportion of uncertain results in traditional IGRAs detection is significantly higher, and diagnostic sensitivity is obviously insufficient. In 2023, a prospective multi-center study was conducted to explore this issue in depth. The study was carried out in 5 research centers including Shanghai Public Health Clinical Center, Beijing Chest Hospital Affiliated to Capital Medical University, Beijing You'an Hospital Affiliated to Capital Medical University, Lanzhou Pulmonary Hospital, and Xinjiang No.8 People's Hospital. The diagnostic performance of IP-10 detection and QFT-GIT detection was compared in a cohort of suspected tuberculosis patients with HIV co-infection[6]. A total of 200 eligible patients were included in the analysis. The results showed that there were 13 uncertain results in IP-10 detection, while QFT-GIT detection had 42 uncertain results. The uncertain result rate of IP-10 detection was significantly lower than that of QFT-GIT detection (P=0.000026), fully demonstrating the superiority of IP-10 in the application of immunocompromised populations.

Further stratified analysis found that when the CD4⁺T cell count was <200 cells/μL, the uncertain proportion of IP-10 detection results was significantly lower than that of QFT-GIT detection, and there was no significant difference in the uncertain result rate of IP-10 detection among patients with different CD4⁺T cell count levels, indicating that IP-10 detection is less affected by immune function status. When the CD4⁺T cell count was <350 cells/μL, the positive rate of IP-10 detection in each subgroup was significantly higher than that of QFT-GIT detection, which can more effectively identify tuberculosis infection in immunocompromised patients and reduce missed diagnoses. These research results provide strong evidence for the application of IP-10 in the diagnosis of immunocompromised populations.

V. Clinical Significance of Mycobacterium Tuberculosis-Specific Cellular Immune IP-10 Detection

Mycobacterium tuberculosis-specific cellular immune IP-10 detection has extensive clinical application value and can provide diagnostic basis for various clinical scenarios. In terms of assisting "bacteriologically negative" tuberculosis diagnosis, it can help identify tuberculosis infection in patients with unexplained fever of unknown origin; assist in the differential diagnosis of pulmonary shadows, distinguish pulmonary tuberculosis from other lung diseases, especially in cases with atypical symptoms, improving diagnostic accuracy; provide objective immunological evidence to reduce the risk of misdiagnosis between pulmonary tuberculosis and other lung diseases.

In the auxiliary diagnosis of extrapulmonary tuberculosis, IP-10 detection plays an important role. Extrapulmonary tuberculosis has complex clinical manifestations and difficult pathogenic detection. IP-10 can assist in the diagnosis of tuberculous meningitis, bone tuberculosis, tuberculous pleurisy, peritonitis, and lymph node tuberculosis, providing references for the formulation of treatment plans.

In the screening of tuberculosis infection in high-risk populations, IP-10 detection has significant advantages. Close contacts of smear-positive pulmonary tuberculosis patients are high-risk groups for tuberculosis infection. IP-10 can detect latent infections early and facilitate timely intervention; in hematopoietic stem cell and solid organ transplantation, it is used for patient screening and donor selection to reduce the risk of post-transplantation morbidity; for populations using immunosuppressants or with immunocompromise and immunodeficiency, such as patients with rheumatoid arthritis receiving biological agent therapy and systemic lupus erythematosus patients, it can more accurately assess the infection status; for susceptible populations such as patients with diabetes, silicosis, renal insufficiency, malnutrition, and the elderly, IP-10 can be used as a routine screening tool to achieve early detection and early diagnosis and treatment.

In summary, as a new type of tuberculosis infection biomarker, IP-10 has high diagnostic sensitivity, specificity, and stability, especially showing obvious advantages in immunocompromised populations, providing new technical support and research directions for the early diagnosis and precise prevention and control of tuberculosis. With the deepening of research and the improvement of technology, IP-10 detection is expected to play a more important role in tuberculosis prevention and control work.

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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【1】World Health Organization.Global tuberculosis report 2020. Geneva: World Health Organization, 2020.

【2】Gao L, Lu W, Bai L, et al. Latent tuberculosis infection in rural china: Baseline results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis.

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