Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series

Abstract

Background There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. Methods Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. Results Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. Conclusions Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.

Morphoproteomic-Guided Host-Directed Therapy for Tuberculosis

“…Our group has taken the approach that in order to understand TB pathology we must study lung samples taken from untreated or under-treated TB individuals. Successful antibiotic treatment is known to significantly alter pathology ( 26 – 30 ). As MTB is killed by the antibiotic, the antigens that stimulate the host immune responses that generate the lung pathology are cleared.…”

Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection

“…Higher abundances in the progressor group (Weiner et al, 2018) Glutamine, histidine Lower abundances in the progressor group BK and DABK Serum of 13 HIV-negative adults with microbiologically confirmed active TB TB treatment response Elevated BK and DABK levels after treatment completion (Qian et al, 2016) 12(R)-HETE, 12R-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid; Ac1PIM1, acylphosphatidylinositol mannoside; ADA, adenosine deaminase; BK, bradykinin; DABK, DesArg 9 -bradykinin; CAP, community-acquired pneumonia; GC6-74, the grand challenges in global health GC6-74 project; HIV, human immunodeficiency virus; LAM, lipoarabinomannan; LPI, lysophosphatidylinositol; LTBI, latent tuberculosis infection; MAs, mycolic acids; MPE, malignancy pleural effusion; PG, phosphatidylglycerol; TB, tuberculosis; TPE, tuberculous pleural effusion.…”

Kinins and Their Receptors in Infectious Diseases

“…Instead, the serum contents of des-Arg 9 -BK were reduced during the consolidation phase of treatment. Thus, kinin levels might represent useful biological markers to predict the outcomes of TB treatment [ 20 ]. By using an in vivo model of M. tuberculosis infection, it was demonstrated that splenomegaly increased in B 2 receptor knockout mice, whereas B 1 /B 2 double knockouts presented a reduction of spleen weight [ 73 ].…”

“…Additionally, the therapeutic benefits of ACE inhibitors, such as captopril, also rely on the modulation of kinins and their biological effects [ 16 ]. Over the last four decades, the role of either kinin receptor and other components of the kinin system has been described in a series of infectious conditions, such as sepsis, schistosomiasis, leishmaniosis, Chagas Disease, candidiasis, tuberculosis, malaria, and it has been recently correlated with Covid-19 infection [ 17 , 18 , 19 , 20 , 21 , 22 ]. Considering the abovementioned evidence, the present review article aims to discuss the relevance of the kinin system, mainly of kinin receptors, as pharmacological targets for management of infectious diseases, attempting to cover the implication of kinins in the progression of infection-related illnesses in humans.…”