Changes in Host Response to Mycobacterium tuberculosis Infection Associated With Type 2 Diabetes: Beyond Hyperglycemia

REVIEW published: 04 October 2019 doi: 10.3389/fcimb.2019.00342 Changes in Host Response to Mycobacterium tuberculosis Infection Associated With Type 2 Diabetes: Beyond Hyperglycemia Cristian Alfredo Segura-Cerda 1,2 , Wendy López-Romero 2 and Mario Alberto Flores-Valdez 2* 1 Doctorado en Farmacología, Universidad de Guadalajara, Guadalajara, Mexico, 2 Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico Edited by: Igor Kramnik, Boston University, United States Reviewed by: Kai Huang, University of Texas Medical Branch at Galveston, United States Robert Cody Sharp, University of Florida Health, United States *Correspondence: Mario Alberto Flores-Valdez ; Specialty section: This article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 03 July 2019 Accepted: 23 September 2019 Published: 04 October 2019 Citation: Segura-Cerda CA, López-Romero W and Flores-Valdez MA (2019) Changes in Host Response to Mycobacterium tuberculosis Infection Associated With Type 2 Diabetes: Beyond Hyperglycemia. Front. Cell. Infect. Microbiol. 9:342. doi: 10.3389/fcimb.2019.00342 Tuberculosis (TB) remains as the first cause of death among infectious diseases worldwide. Global incidence of tuberculosis is in part coincident with incidence of type 2 diabetes (T2D). Incidence of T2D is recognized as a high-risk factor that may contribute to tuberculosis dissemination. However, mechanisms which favor infection under T2D are just starting to emerge. Here, we first discuss the evidences that are available to support a metabolic connection between TB and T2D. Then, we analyze the evidences of metabolic changes which occur during T2D gathered thus far for its influence on susceptibility to M. tuberculosis infection and TB progression, such as hyperglycemia, increase of 1AC levels, increase of triglycerides levels, reduction of HDL-cholesterol levels, increased concentration of lipoproteins, and modification of the activity of some hormones related to the control of metabolic homeostasis. Finally, we recognize possible advantages of metabolic management of immunity to develop new strategies for treatment, diagnosis, and prevention of tuberculosis. Keywords: Mycobacterium tuberculosis infection, type 2 diabetes, hyperglycemia, diabetic dyslipidemia, hormones INTRODUCTION Infection with Mycobacterium tuberculosis, which in susceptible people leads to either active or latent tuberculosis (TB), remains as a high-burden health problem globally. It is calculated that in 2017, TB caused 1.3 millions deaths, and 10.0 million new cases were reported (WHO, 2018). Some disorders have been recognized as risk factors to develop pulmonary TB, such as HIV coinfection, malnutrition, tobacco smoking, and type 2 diabetes (T2D) (WHO, 2018). T2D is a chronic metabolic disorder that essentially affect the function of pancreatic β-cells, resulting in progressive development of insuline resistance and chronic inflammation (Defronzo et al., 2015). Several meta-analysis show that T2D is associated with a two- to four-fold increased risk of active TB, even multidrug-resistant TB (Amare et al., 2013; Al-Rifai et al., 2017; Liu et al., 2017; Hayashi and Chandramohan, 2018). As a risk factor for developing TB, T2D has attracted attention by its projected increase and its prevalente worldwide. In 2018, it was estimated that T2D affected one of each 10 individuals globally (425 million people around the world) and it is projected that the number of cases of T2D may increase by 40% in 2045 (IDF, 2017). Hence, an increase in the global burden of T2D poses a higher risk of TB spread worldwide in the upcoming years. Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 October 2019 | Volume 9 | Article 342 Segura-Cerda et al. Metabolic Changes and TB Susceptibility suggest that progression from prediabetes to T2D may influence the susceptibility to M. tuberculosis infection (Figure 1B). An study of household contacts of active TB patients (who had a higher risk to develop TB) showed that prediabetes is present in at least 27% of them (Shivakumar et al., 2018), while another study in western India that included 1,073 participants, revealed that more than one-half of newly diagnosed TB patients had T2D or pre-T2D (Mave et al., 2017). Prediabetes induces changes in cytokines production that are related to control of M. tuberculosis infection. A study in prediabetic-TB patients showed that they had higher circulating concentrations of IFN-γ, TNF-α, IL-12, IL-17, IL-1β, GMCSF (cytokines that favors Th1 response) and also had higher concentrations of IL-5, IL-10, and TGF-β (cytokines related to regulation of cytokine response) than TB patients without prediabetes (Kumar et al., 2014). This dysregulation of cytokines levels found in plasma may compromise the immune response against M. tuberculosis, and suggest that progressive changes in immune response related to T2D progression may influence the susceptibility to TB. Progression of T2D in obese patients produces changes that can be related to an increased TB susceptibility through modulation of adypocytokines such as the C1q tumor necrosis factor related protein-3 (C1qTNF3 or CTRP-3). C1qTNF3 is a cytokine produced by macrophages and adipocytes that reduces inflammation generated by adipocytes (Kopp et al., 2010; Schmid et al., 2014). A study in obese patients showed that T2D induces a reduction in the plasmatic concentrations of this cytokine as compared with non-T2D patients (Elsaid et al., 2019). A study conducted in South Africa and Gambia, showed that patients who progress from a Latent TB Infection (LTBI) to active TB (LTBI defined as TST+, Quantiferon TB assay+) have lower concentrations of C1qTNF3 in plasma than LTBI patients who did not progress to TB during a more than 1 year follow-up (Penn-Nicholson et al., 2019). These findings suggest that the reduction in C1qTNF3 might be a potential contributor to the increased risk for TB in people with T2D, and might be a factor worth evaluating in the clinic. In formally established T2D (as opposed to pre-T2D), some additional disorders in metabolism may occur, such as hyperglycemia, dyslipidemia, changes in lipoprotein concentrations, and changes in hormonal profiles (Olokoba et al., 2012; Carrera Boada and Martinez-Moreno, 2013). These alterations seem to be an adequate environment for M. tuberculosis infection to thrive in T2D subjects, likely improving persistence of mycobacteria and allowing them to consolidate the pulmonar infection and its effects (Figure 1C). Epidemiological data about comorbidity between TB and T2D show that there is a close relationship between both diseases. A recent meta-analysis showed that 16% of newly-diagnosed TB patients have T2D and up to 4.1% of T2D patients develop TB (Wilkinson et al., 2017). In 2017, close to (...truncated)