DiabTB

FRAMEWORK

• Context: Long-term collaboration dating from 2015

• Duration: Dec 2020 – Dec 2025.

• Status: Completed.

• Role: Main collaborator and adviser.

• Funding: None.

• Collaboration: Mexican Social Security Institute (IMSS)

  • Country: Mexico

  • Partner Unit: Unidad de Investigación Biomédica de Zacatecas

  • Partner Team: Dr. Bruno Rivas-Santiago and Dr. Carmen J. Serrano

  • Key Personnel: 

    • Mónica Alejandra Valtierra-Alvarado, PhD graduate (2018-2022)

    • Dr. Carmen J. Serrano

A. Metabolic Control of Type 2 Diabetes Shapes the Phenotype of Human Monocytes and Macrophages

• Student: Mónica Alejandra Valtierra-Alvarado, PhD graduate (2018-2022)

• Supervisors: Carmen J. Serrano (Mexico) and Geanncarlo Lugo-Villarino (France)

SUMMARY: Type 2 diabetes mellitus (T2DM) is a major risk factor for tuberculosis and other infectious diseases, yet the cellular mechanisms linking metabolic dysregulation to impaired immunity remain incompletely understood. In this study, we examined how metabolic control in patients with T2DM influences the phenotype of circulating monocytes and monocyte-derived macrophages. Analyses of peripheral blood cells from diabetic patients revealed that poor glycemic control is associated with significant alterations in monocyte activation and differentiation programs. In particular, hyperglycemia was linked to reduced expression of antigen presentation markers and altered macrophage polarization profiles, suggesting a diminished capacity of these cells to mount effective antimicrobial responses. These results highlighted how systemic metabolic disturbances can reshape innate immune cell function and potentially contribute to the increased susceptibility of diabetic individuals to tuberculosis and other infections.

SIGNIFICANCE: This work provided one of the first mechanistic links between metabolic control in diabetes and the functional programming of monocyte-macrophage lineages, establishing a foundation for subsequent studies investigating how diabetes alters host responses to Mtb. These results were published in the Journal of Diabetes Complications in 2020, with Mónica as the first author, and my role is acknowledged as a co-author (Valtierra-Alvarado et al., J Diabetes Complications, 2020).

B. Diabetes Alters Macrophage-Mediated Crosstalk During Mtb Infection

• Student: Mónica Alejandra Valtierra-Alvarado, PhD graduate (2018-2022)

• Supervisors: Carmen J. Serrano (Mexico) and Geanncarlo Lugo-Villarino (France)

SUMMARY: Building on the previous publication (Valtierra-Alvarado et al., J Diabetes Complications, 2020), this study explored how macrophages from patients with T2DM respond to Mtb infection and influence surrounding immune cells. Using in vitro infection models, we demonstrated that macrophages derived from individuals with diabetes exhibit an altered capacity to regulate monocyte differentiation via paracrine signaling. Specifically, macrophages exposed to Mtb released soluble factors that modified the differentiation trajectory of neighboring monocytes, suggesting a “bystander effect” that amplifies immune dysregulation under diabetic conditions. These findings indicate that metabolic disease not only affects macrophage intrinsic functions but also disrupts immune communication networks during infection.

SIGNIFICANCE: This work revealed a previously underappreciated mechanism by which diabetes reshapes host–pathogen interactions by altering macrophage-driven communication within the monocyte–macrophage compartment, thereby potentially contributing to the increased severity of tuberculosis in diabetic patients. These results were published in Immunology Cell Biology in 2021, with Mónica as the first author, and my role is acknowledged as a co-author (Valtierra-Alvarado et al., Immunol Cell Biol., 2021).

C. Expansion of Immunosuppressive CD14⁺HLA-DR⁻/low Monocytes in Type 2 Diabetes

• Student: Mónica Alejandra Valtierra-Alvarado, PhD graduate (2018-2022)

• Supervisors: Carmen J. Serrano (Mexico) and Geanncarlo Lugo-Villarino (France)

SUMMARY:  Further investigating immune alterations in T2DM, this study focused on the expansion of immunosuppressive monocyte populations. Flow cytometry analyses of peripheral blood samples revealed a significant increase in CD14⁺HLA-DR⁻/low monocyte cells associated with myeloid-derived suppressor cell–like activity in patients with T2DM compared with healthy individuals. Importantly, the frequency of these cells was highest in patients with poor glycemic control and positively correlated with disease duration, age, and a composite glycemic index. These findings suggest that chronic hyperglycemia promotes the expansion of monocytes with immunosuppressive features, which may contribute to impaired immune surveillance and increased susceptibility to infections. 

SIGNIFICANCE:  This study identifies an immunosuppressive myeloid cell population associated with chronic hyperglycemia in T2DM, providing new insights into how metabolic disease may compromise immune competence and exacerbate infectious diseases such as TB. These results were published in Human Immunology in 2022, with Mónica as the first author, and my role is acknowledged as a co-author (Valtierra-Alvarado et al., Hum Immunol., 2022).

Connection Between Studies A, B, and C. 

The DiabTB project investigated how T2DM alters innate immune responses that are critical for controlling Mtb. Within this collaborative program, I contributed to studies examining how chronic hyperglycemia reshapes the phenotype and function of human monocytes and macrophages. My role is primarily at the intellectual level, providing strategic advice and supervising our PhD candidate, now Dr. Valtierra-Alvarado. These works collectively showed that poor glycemic control is associated with altered activation and differentiation of monocyte–macrophage populations, impaired macrophage communication with surrounding immune cells during Mtb infection, and the expansion of CD14⁺HLA-DR⁻/low immunosuppressive monocytes linked to chronic hyperglycemia. Together, these findings provide mechanistic insights into how metabolic dysregulation compromises innate immunity and may contribute to the increased susceptibility and severity of TB observed in diabetic patients.