Nagajyothi Lab Research
Our laboratory has focused on investigating: (i) the role that adipocytes play in the immune system and (ii) the effect of dysfunctional adipocytes in the pathogenesis, progression and severity of various infectious and non-infectious diseases. Adipocytes are the major regulator of whole-body energy and immune homeostasis. We have demonstrated that adipocytes themselves are a source of inflammatory mediators (IL-6, IL-10, IL1β, IFN-γ, TNF-α, CCL2, CCL5, CXCL10, leptin, and adiponectin). Many factors including infections, diseases, diet, and exercise influence adipocyte physiology, while the pathology of adipocytes influences the outcome of diseases. Our laboratory is currently examining the crosstalk between the pathogenic adipocytes and the outcome of diseases in the research areas described below.
Impact of the loss of adipocytes on progression and severity of acute and chronic infectious diseases
We are using two models of acute and chronic infectious diseases, Chagas cardiomyopathy and pulmonary tuberculosis (TB), caused by a parasite Trypanosoma cruzi and bacterium Mycobacterium tuberculosis, respectively, to examine the impact of gain of body fat and loss of fat cells on the outcome of the disease. Our earlier studies demonstrated a correlation between increased body fat mass and increased survival during acute infection and loss in fat mass and increased progression and severity during chronic stage of infection. We recently discovered that adipocyte released adipomes, which are specific to the pathogenic conditions, regulate other cells including immune cells. Currently, our studies are focused on investigating disease associated immune-metabolic pathways, which are regulated by pathogenic adipocytes/adiponectin/adipomes, to identify specific drug targets to prevent the progression of Chagas cardiomyopathy and activation/reactivation of TB disease.
Role of pathogenic adipocytes in increasing the risk of metastatic breast cancer
Obesity is a known risk factor for the development of breast cancer and in promoting metastasis. Clinical studies have shown that women with Type 2 Diabetes Mellitus (T2DM) have a higher risk of developing a highly aggressive form of breast cancer compared to women without diabetes. Dysfunctional adipocytes are part of the pathogenic conditions of obesity and T2DM. The female breast is mostly made up of adipose tissue containing mainly mature adipocytes, preadipocytes, and adipose tissue derived stem cells (ASC). The breast tumor progression also depends on the crosstalk between tumor epithelial cells and the surrounding adipocytes. Our lab is studying the role of pathogenic adipocytes in regulating the tumor associated macrophages in promoting tumor cell growth and metastasis. We are collaborating with Dr. Olivier Loudig to investigate the regulatory role of adipocyte-derived factors on the tumor microenvironment in inducing distant metastasis and therapeutic resistance.
Influence of diet on overactivated immune system during acute infections
The physiology of each organ depends on its metabolic status, and the metabolic requirements of the heart, lung, brain, adipose tissue, muscle, kidney, and liver are strikingly different. Most of the localized acute infections affect the metabolic status of both the systemic and infected organ. The activity of immune cells is regulated by the metabolic environment. Our recent studies demonstrated that a high-fat diet reduces the levels of pro-inflammatory signaling in the infected area, whereas a carbohydrate-rich diet increases the levels of pro-inflammatory mediators in murine models of acute Chagas and TB diseases. We are currently investigating the effect of diets on the pathophysiology of adipocytes in regulating the activity of localized and systemic immune cells.
Effect of metabolic syndromes on infectious diseases and vice versa
The metabolic syndrome describes a group of risk factors for the development of diabetes and cardiovascular disease. In the present-day world, the epidemic of metabolic syndromes is increasing while the number of cases of old infectious diseases are decreasing due to the available drugs and vaccines. However, recent clinical and research data demonstrated that subjects with metabolic syndromes are vulnerable to acute and chronic diseases. Our lab investigates the role of adipocytes in the progression of metabolic syndromes and its effect on the clinical outcome of infectious diseases such as Chagas and TB diseases. Currently we are aiming to investigate the role of pathogenic adipocytes in the severity of COVID-19 patients with metabolic syndromes, T2DM and cardiovascular diseases. In addition, our laboratory is also investigating whether the infectious diseases contribute to the pathogenesis of metabolic syndromes. Our data show a strong link between asymptomatic infections, anti-TB drug treatments, and the development of insulin resistance. We are investigating the effect of the presence of infectious pathogens in AT and the effects of antibiotic treatment on adipocyte physiology (acute and chronic exposure) in the pathogenesis of metabolic syndromes and diseases.
The long-term vision of our research is to demonstrate that adipocyte-derived adipokines and adipomes could serve as therapeutic targets for various infectious and non-infectious diseases.