Immunological aspectsReduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control
Introduction
The current pandemic of type 2 diabetes mellitus (DM) is accelerating in a world where approximately one third of the population is latently infected with Mycobacterium tuberculosis.1, 2 Adults with DM have at least a 3-fold higher risk of developing tuberculosis (TB).3, 4 In order to develop strategies to prevent TB among DM patients, we must understand the mechanism(s) by which DM increases the risk for TB.
The risk of TB can be stratified into (1) the risk of becoming infected with M. tuberculosis and (2) the risk of progression to active TB disease, but the impact of DM on the natural history of TB is unknown.5 The higher susceptibility of DM patients to TB may occur at both stages based on very limited data. In the present study we explored the impact of type 2 DM on the initial encounter between M. tuberculosis and the host innate immune system, based on indirect support from studies in humans6, 7 and mice.8, 9 Furthermore, studies in type 1 and 2 DM patients unrelated to TB also suggest compromised phagocyte immunity, including abnormalities in chemotaxis, phagocytosis, respiratory burst and altered expression of cytokines, adhesins and receptors (e.g. complement receptor 3, toll-like receptors).10, 11, 12, 13, 14, 15, 16, 17, 18 However, studies to date have varied in their findings, likely as a result of differences in study design and difficulty in controlling for a variety of associated factors.
M. tuberculosis is an intracellular bacterium that has adapted to the human host and evolved the ability to survive in mononuclear phagocytes. These cells can also limit intracellular M. tuberculosis growth under certain conditions. The ability of M. tuberculosis to survive inside phagocytes may depend on the strategy used by the bacterium to enter the host cell, i.e. receptor–ligand interactions that mediate phagocytosis.19 In the present study we focused on the initial interaction between M. tuberculosis and the host phagocyte to begin elucidating alterations in DM patients. We specifically evaluated the impact of DM on M. tuberculosis association (attachment and ingestion) with blood monocytes where entry is largely dependent on two processes. The first is the opsonization of M. tuberculosis by serum components, with the two most common being the C3b complement protein (and its breakdown product iC3b)20, 21 and natural antibodies to mycobacteria.22 The second is the binding of these opsonins to complement receptors (mainly CR1 and CR321) or, in the setting of immune serum, Fcγ receptors (FcγRI, FcγRII, FcγRIII) on the monocyte, which is followed by phagocytosis.19
Based on the current literature regarding TB patients and mice with DM, we hypothesized that the initial encounter between M. tuberculosis and the monocyte would be altered in DM patients with no previous exposure to the bacterium. There were two possible outcomes: the first would be that the higher susceptibility of DM patients to TB would be reflected by a higher rate of M. tuberculosis association with monocytes, which could lead directly to enhanced intracellular replication. The second possible outcome would be that M. tuberculosis association with monocytes is reduced, as has been reported in studies with other bacteria.10, 15, 23 This result would suggest that host cell recognition is altered, with the potential to induce a dysfunctional response that facilitates replication of ingested bacteria. In the present study we conducted experiments to explore which of these possibilities occurs in DM patients.
Section snippets
Participant enrollment and characterization
Healthy volunteers from South Texas (Hidalgo and Cameron counties) between the ages of 25 and 61 years (range 27–61 in DM and 25–56 in no DM) were identified in the community or at the Joslin Diabetes Center affiliated with Doctors Hospital at Renaissance. Those with no history of TB or knowledge of a positive tuberculin skin test (TST) were invited to participate according to a protocol approved by Committee for the Protection of Human subjects of UTHealth. Individuals were interviewed to
Lower association of M. tuberculosis with monocytes from DM patients
To determine if there is a difference in opsonin-dependent association of M. tuberculosis with monocytes from DM versus non-DM participants, we assayed for M. tuberculosis association with monocytes under low serum concentrations (5%) where classical complement activation is more prominent, versus high serum concentrations (20%) where the alternative pathway predominates.27 We evaluated the monocytes and autologous serum from eight participants without DM and nine with DM (four DMb and five
Discussion
We conducted the first in vitro studies aimed at identifying alterations in the initial interaction between human monocytes from DM patients and M. tuberculosis. Our findings provide evidence for reduced association of M. tuberculosis with monocytes from DM patients. This observation was strongest under higher serum concentrations (20% versus 5%), and appeared to involve heat-labile serum components, most likely complement. Together, these findings suggest a difference in the mechanism by which
Acknowledgments
We are grateful to Ms. Damaris Garcia and Ms. Izelda Zarate for field and laboratory support and to the staff at the Joslin-Doctors Hospital at Renaissance for assistance with participant enrollment.
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