Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques

Abstract

Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating the closest possible modelling of human TB. To establish a predictive peripheral biomarker profile based on a larger cohort of rhesus macaques (RM), we analyzed results pertaining to peripheral blood serum chemistry and cell counts from RMs that were experimentally exposed to Mtb in our prior studies and characterized as having either developed active TB (ATB) disease or latent TB infection (LTBI). We compared lung CFU burdens and quantitative pathologies with a number of measurables in the peripheral blood. Based on our results, the investigations were then extended to the study of specific molecules and cells in the lung compartments of a subset of these animals and their immune responses. In addition to the elevated serum C-reactive protein (CRP) levels, frequently used to discern the level of Mtb infection in model systems, reduced serum albumin-to-globulin (A/G) ratios were also predictive of active TB disease. Furthermore, higher peripheral myeloid cell levels, particularly those of neutrophils, kynurenine-to-tryptophan ratio, an indicator of induced expression of the immunosuppressive molecule indoleamine dioxygenase, and an influx of myeloid cell populations could also efficiently discriminate between ATB and LTBI in experimentally infected macaques. These quantifiable correlates of disease were then used in conjunction with a regression-based analysis to predict bacterial load. Our results suggest a potential biomarker profile of TB disease in rhesus macaques, that could inform future NHP–TB research. Our results thus suggest that specific biomarkers may be developed from the myeloid subset of peripheral blood or plasma with the ability to discriminate between active and latent Mtb infection.

System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection

“…The ATB and Mtb /SIV groups exhibited strong, positive correlations to their respective bacterial loads ( Table 2 ). These results support CRP at peak and endpoint as a correlate of more severe Mtb infection, with previous studies also suggesting that serum A/G ratio may be a viable biomarker of ATB ( 24 ), but similar to CRP, other confounding factors could interfere ( 37 ) and convolute the interpretation of results.…”

“…Bacterial burden, viral load, and immunologic response were determinants for classification to either active (ATB, n=16), latent (LTBI, n=11), Mtb /SIV co-infected ( Mtb /SIV, n=8), and naïve control (CTRL, n=6) groups. Through the use of serum chemistry, CRP values, and Albumin/Globulin (A/G) ratios were obtained ( 24 ). Blood cell percentages for monocytes, lymphocytes, and neutrophils were also quantified.…”

Testing pulmonary physiology in ventilated non‐human primates

“…[33][34][35] The degree to which vaccines or anti-viral therapeutics might protect the lung from viral injury in an NHP model could be assessed using this pulmonary physiology testing protocol. In addition, many other fields of pulmonary research using NHP or other animal models may benefit from this protocol including research in the fields of tuberculosis, 36 asthma, 37 and inhaled pollutants. 10…”

Kynurenine Pathway in Respiratory Diseases

“… 125 Since this study, several other groups have confirmed the link between IDO activity and tuberculosis diagnosis or severity. 106 , 107 , 109 , 110 , 126 In addition, IDO1 may have diagnostic value in the early identification of multidrug-resistant (MDR) TB patients, as IDO1 has been positively correlated with cavitary lung lesions in TB patients, potentially indicating a more severe infectious state and a higher risk of developing MDR-TB. 111 These studies were also validated by metabolomics analysis, which showed that increased IDO activity helps to distinguish TB patients from healthy individuals.…”