The Influence of Body Fat Dynamics on Pulmonary Immune Responses in Murine Tuberculosis: Unraveling Sex-Specific Insights.

The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis (Mtb) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb-HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8+ cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold (p ≤ 0.01) and 1.7-fold (p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8+ cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ (p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8+ T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8+ cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8+ cell activation.

Adipocyte-released adipomes in Chagas cardiomyopathy: Impact on cardiac metabolic and immune regulation.

Chronic Trypanosoma cruzi infection leads to Chagas cardiomyopathy (CCM), with varying manifestations such as inflammatory hypertrophic cardiomyopathy, arrhythmias, and dilated cardiomyopathy. The factors responsible for the increasing risk of progression to CCM are not fully understood. Previous studies link adipocyte loss to CCM progression, but the mechanism triggering CCM pathogenesis remains unexplored. Our study uncovers that T. cruzi infection triggers adipocyte apoptosis, leading to the release of extracellular vesicles named "adipomes". We developed an innovative method to isolate intact adipomes from infected mice's adipose tissue and plasma, showing they carry unique lipid cargoes. Large and Small adipomes, particularly plasma-derived infection-associated L-adipomes (P-ILA), regulate immunometabolic signaling and induce cardiomyopathy. P-ILA treatment induces hypertrophic cardiomyopathy in wild-type mice and worsens cardiomyopathy severity in post-acute-infected mice by regulating adipogenic/lipogenic and mitochondrial functions. These findings highlight adipomes' pivotal role in promoting inflammation and impairing myocardial function during cardiac remodeling in CD.

The Many Hosts of Mycobacteria 9 (MHM9): A conference report.

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.

Susceptibility of Fat Tissue to SARS-CoV-2 Infection in Female hACE2 Mouse Model.

The coronavirus disease (COVID-19) is a highly contagious viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 has had a catastrophic effect globally causing millions of deaths worldwide and causing long-lasting health complications in COVID-19 survivors. Recent studies including ours have highlighted that adipose tissue can act as a reservoir where SARS-CoV-2 can persist and cause long-term health problems. Here, we evaluated the effect of SARS-CoV-2 infection on adipose tissue physiology and the pathogenesis of fat loss in a murine COVID-19 model using humanized angiotensin-converting enzyme 2 (hACE2) mice. Since epidemiological studies reported a higher mortality rate of COVID-19 in males than in females, we examined hACE2 mice of both sexes and performed a comparative analysis. Our study revealed for the first time that: (a) viral loads in adipose tissue and the lungs differ between males and females in hACE2 mice; (b) an inverse relationship exists between the viral loads in the lungs and adipose tissue, and it differs between males and females; and (c) CoV-2 infection alters immune signaling and cell death signaling differently in SARS-CoV-2 infected male and female mice. Overall, our data suggest that adipose tissue and loss of fat cells could play important roles in determining susceptibility to CoV-2 infection in a sex-dependent manner.

Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model.

Breast cancer (BC) is the most diagnosed cancer type, accounting for one in eight cancer diagnoses worldwide. Epidemiological studies have shown that obesity is associated with increased risk of BC in post-menopausal women, whereas adiposity reduces the risk of BC in premenopausal women. The mechanistic link between obesity and BC has been examined by combining murine BC models with high-fat diet (HFD) induced obesity. However, the effect of adiposity (not obesity) induced by a short period of HFD consumption on BC pathogenesis is not well understood. In the current study, we examined the effects of different diet compositions on BC pathogenesis using a young E0771 syngeneic BC mouse model fed on either an HFD or regular diet (RD: a low-fat high-carbohydrate diet) for a short period (4 weeks) before implanting mammary tumors in mice. We analyzed the effect of diet composition on the onset of tumor growth, metastasis, and metabolic and immune status in the tumor microenvironment (TME) using various methods including in vivo bioluminescence imaging and immunoblotting analyses. We showed for the first time that a short-term HFD delays the onset of tumorigenesis by altering the immune and metabolic signaling and energy mechanism in the TME. However, RD may increase the risk of tumorigenesis and metastasis by increasing pro-inflammatory factors in the TME in young mice. Our data suggest that diet composition, adipogenesis, and loss of body fat likely regulate the pathogenesis of BC in a manner that differs between young and post-menopausal subjects.

Diets Differently Regulate Pulmonary Pathogenesis and Immune Signaling in Mice during Acute and Chronic Mycobacterium tuberculosis Infection.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection persists as a leading cause of mortality and morbidity globally, especially in developing and underdeveloped countries. The prevalence of TB-DM (diabetes mellitus) is higher in low- and middle-income countries where TB and DM are most prevalent. Epidemiological data suggest that slight obesity reduces the risk of TB, whereas DM increases the risk of pulmonary TB. Diets can alter the levels of body fat mass and body mass index by regulating systemic adiposity. Earlier, using a transgenic Mtb-infected murine model, we demonstrated that loss of body fat increased the risk of pulmonary bacterial load and pathology. In the present study, we investigated whether increased adiposity alters pulmonary pathology and bacterial load using C57BL/6 mice infected with HN878 Mtb strain and fed a medium-fat diet (MFD). We analyzed the effects of MFD on the lung during acute and chronic infections by comparing the results to those obtained with infected mice fed a regular diet (RD). Histological and biochemical analyses demonstrated that MFD reduces bacterial burden by increasing the activation of immune cells in the lungs during acute infection and reduces necrosis in the lungs during chronic infection by decreasing lipid accumulation. Our data suggest that slight adiposity likely protects the host during active TB infection by regulating immune and metabolic conditions in the lungs.

Sex Differences in Cardiac Pathology of SARS-CoV2 Infected and Trypanosoma cruzi Co-infected Mice.

Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survive COVID-19, post-COVID cardiac damage greatly increases the risk of cardiomyopathy and heart failure. Currently, the number of COVID-related cases are increasing in Latin America, where a major COVID comorbidity is Chagas' heart disease, which is caused by the parasite Trypanosoma cruzi. However, the interplay between indeterminate Chagas disease and COVID-19 is unknown. We investigated the effect of CoV2 infection on heart pathology in T. cruzi infected mice (coinfected with CoV2 during the indeterminate stage of T. cruzi infection). We used transgenic human angiotensin-converting enzyme 2 (huACE2/hACE2) mice infected with CoV2, T. cruzi, or coinfected with both in this study. We found that the viral load in the hearts of coinfected mice is lower compared to the hearts of mice infected with CoV2 alone. We demonstrated that CoV2 infection significantly alters cardiac immune and energy signaling via adiponectin (C-ApN) and AMP-activated protein kinase (AMPK) signaling. Our studies also showed that increased ß-adrenergic receptor (b-AR) and peroxisome proliferator-activated receptors (PPARs) play a major role in shifting the energy balance in the hearts of coinfected female mice from glycolysis to mitochondrial ß-oxidation. Our findings suggest that cardiac metabolic signaling may differently regulate the pathogenesis of Chagas cardiomyopathy (CCM) in coinfected mice. We conclude that the C-ApN/AMPK and b-AR/PPAR downstream signaling may play major roles in determining the progression, severity, and phenotype of CCM and heart failure in the context of COVID.

Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice.

Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and Mycobacterium tuberculosis (Mtb) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of Mtb infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that Mtb persists in adipose tissue and that Mtb infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during Mtb infection in adult mice. We also showed that Mtb infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of Mtb infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between Mtb infection and subsequent metabolic syndrome.

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease.

Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.

Inhibition of SREBP Improves Cardiac Lipidopathy, Improves Endoplasmic Reticulum Stress, and Modulates Chronic Chagas Cardiomyopathy.

Background Trypanosoma cruzi is an intracellular parasite that causes debilitating chronic Chagas cardiomyopathy (CCM), for which there is no effective drug or vaccine. Previously, we demonstrated increased cardiac lipid accumulation and endoplasmic reticulum stress in mice with CCM. Increased endoplasmic reticulum stress may lead to uncontrolled SREBP (sterol regulatory element-binding protein) activation and lipotoxicity in the myocardium during the intermediate stage of infection and result in progression to chronic CCM. Therefore, we investigated whether inhibiting SREBP activation modulates CCM progression in T cruzi-infected mice. Methods and Results T cruzi-infected cultured cardiomyocytes (3:1 multiplicity of infection; 24 hours postinfection) were incubated with betulin (3 µmol/L per mL), an SREBP inhibitor, for 24 hours. Quantitative polymerase chain reaction and Western blotting analyses demonstrated a significant reduction in SREBP activation, lipid biosynthesis, and endoplasmic reticulum stress in betulin-treated infected cells compared with untreated cells. T cruzi infected (103 trypomastigotes of the Brazil strain) Swiss mice were fed a customized diet containing betulin during the intermediate stage (40 days postinfection) until the chronic stage (120 DPI). Cardiac ultrasound imaging and histological and biochemical analyses demonstrated anatomical and functional improvements in betulin-treated, infected mice compared with untreated controls: we observed a significant reduction in cholesterol/fatty acid synthesis that may result in the observed cardiac reduction in cardiac lipid accumulation, mitochondrial and endoplasmic reticulum stress, and ventricular enlargement. Conclusions Our study (in vitro and vivo) demonstrates that inhibition of cardiac SREBP activation reduces cardiac damage during T cruzi infection and modulates CCM in a murine Chagas model.

Advances in understanding the role of adipose tissue and mitochondrial oxidative stress in Trypanosoma cruzi infection.

Trypanosoma cruzi, the etiologic agent of Chagas disease, causes a latent infection that results in cardiomyopathy. Infection with this pathogen is a major socio-economic burden in areas of endemic infection throughout Latin America. The development of chagasic cardiomyopathy is dependent on the persistence of this parasite in host tissues. Pathogenesis of this cardiomyopathy is multifactorial and research indicates that it includes microvascular dysfunction, immune responses to host and parasite antigens, and various vasoactive and lipid mediators produced by both the host and parasite. It has been demonstrated that T. cruzi persists in adipose tissue and uses fat as a nutritional niche in infected hosts. This chronic infection of adipose tissue plays an important role in the pathogenesis and persistence of this infection and involves mitochondrial stress responses as well as the production of various anti-inflammatory adipokines and pro-inflammatory cytokines by both white and brown adipose tissue. The changes in diet in endemic regions of infection have resulted in an epidemic of obesity that has significant implications for the pathogenesis of T. cruzi infection and the development of chagasic cardiomyopathy in infected humans.

Adipose Tissue Regulates Pulmonary Pathology during TB Infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, remains a major cause of mortality and morbidity worldwide. One-third of the world population is infected with M. tuberculosis, and about 15 million people with latent tuberculosis infection (LTBI) reside in the United States. An estimated 10% of individuals with LTBI are at risk of progressing to active disease. Loss of body mass, or wasting, accompanied by a significant reduction of body fat is often associated with active TB disease and is considered to be immunosuppressive and a major determinant of severity and outcome of disease. While the lungs are the primary site of M. tuberculosis infection and TB manifestation, recent reports have shown that adipose tissue serves as an important reservoir for M. tuberculosis In this article, we investigated the association between M. tuberculosis infection, adipose tissue, and TB disease progression using a transgenic inducible "fatless" model system, the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) mouse. By selectively ablating fat tissue during M. tuberculosis infection, we directly tested the role of fat cell loss and adipose tissue physiology in regulating pulmonary pathology, bacterial burden, and immune status. Our results confirm the presence of M. tuberculosis in fat tissue after aerosol infection of mice and show that loss of fat cells is associated with an increase in pulmonary M. tuberculosis burden and pathology. We conclude that acute loss of adipose tissue during LTBI may predispose the host to active TB disease.IMPORTANCE Although the lungs are the port of entry and the predominant site of TB disease manifestation, we and others have demonstrated that M. tuberculosis also persists in adipose tissue of aerosol-infected animals and directly or indirectly alters adipose tissue physiology, which in turn alters whole-body immuno-metabolic homeostasis. Our present report demonstrates a direct effect of loss of adipocytes (fat cells) on promoting the severity of pulmonary pathogenesis during TB, advancing our understanding of the pathogenic interactions between wasting and TB activation/reactivation.

Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model.

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy.

Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.

High fat diet aggravates cardiomyopathy in murine chronic Chagas disease.

Infection with Trypanosoma cruzi, the etiologic agent in Chagas disease, may result in heart disease. Over the last decades, Chagas disease endemic areas in Latin America have seen a dietary transition from the traditional regional diet to a Western style, fat rich diet. Previously, we demonstrated that during acute infection high fat diet (HFD) protects mice from the consequences of infection-induced myocardial damage through effects on adipogenesis in adipose tissue and reduced cardiac lipidopathy. However, the effect of HFD on the subsequent stages of infection - the indeterminate and chronic stages - has not been investigated. To address this gap in knowledge, we studied the effect of HFD during indeterminate and chronic stages of Chagas disease in the mouse model. We report, for the first time, the effect of HFD on myocardial inflammation, vasculopathy, and other types of dysfunction observed during chronic T. cruzi infection. Our results show that HFD perturbs lipid metabolism and induces oxidative stress to exacerbate late chronic Chagas disease cardiac pathology.

Effect of Mycobacterium tuberculosis infection on adipocyte physiology.

Tuberculosis (TB) remains as a major threat to human health worldwide despite of the availability of standardized antibiotic therapy. One of the characteristic of pathogenic Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis is its ability to persist in the host in a dormant state and develop latent infection without clinical signs of active disease. However, the mechanisms involved in bacterial persistence and the establishment of latency is not well understood. Adipose tissue is emerging as an important niche that favors actively replicating as well as dormant Mtb during acute and latent infection. This also suggests that Mtb can disseminate from the lungs to adipose tissue during aerosol infection and/or from adipose tissue to lungs during reactivation of latent infection. In this study, we report the interplay between key adipokine levels and the dynamics of Mtb pathogenesis in the lungs and adipose tissue using a rabbit model of pulmonary infection with two clinical isolates that produce divergent outcome in disease progression. Results show that markers of adipocyte physiology and function were significantly altered during Mtb infection and distinct patterns of adipokine expression were noted between adipose tissue and the lungs. Moreover, these markers were differentially expressed between active disease and latent infection. Thus, this study highlights the importance of targeting adipocyte function as potential target for developing better TB intervention strategies.

Diet Modulates Adipose Tissue Oxidative Stress in a Murine Acute Chagas Model.

Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi. T. cruzi targets adipose tissue, which serves as a reservoir of this parasite. T. cruzi infection of adipose tissue is characterized by increased lipolysis, oxidative stress, and parasitemia. High fat diet (HFD) decreases lipolysis and increases the survival rate in the mice infected with T. cruzi during acute infection. However, the effect of HFD on oxidative stress in adipose tissue has not been examined in detail. In the present study we evaluated the effect of HFD on oxidative stress markers in both white and brown adipose tissues (WAT and BAT) during acute infection. We used qPCR to examine the mRNA expression levels of genes involved in several antioxidant defence systems, such as those acting in ROS metabolism, peroxidases, and relevant oxygen transporter genes. The result of our study showed that HFD regulates the expression levels of oxidative stress genes in adipose tissues and that these effects are often different in WAT and BAT. For instance, while HFD down-regulated the levels of most antioxidant genes in both WAT and BAT, it differentially affected the expression pattern of genes involved in ROS metabolism (e.g. peroxidases) in WAT and BAT tissues of infected mice. Together with our previous studies, these findings show that infection and diet both regulate antioxidant enzymes and other oxidative stress defenses in mouse adipose tissues during acute T. cruzi infection.

Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection.

Chagas disease is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi, which affects about ten million people in its endemic regions of Latin America. After the initial acute stage of infection, 60-80% of infected individuals remain asymptomatic for several years to a lifetime; however, the rest develop the debilitating symptomatic stage, which affects the nervous system, digestive system, and heart. The challenges of Chagas disease have become global due to immigration. Despite well-documented dietary changes accompanying immigration, as well as a transition to a western style diet in the Chagas endemic regions, the role of host metabolism in the pathogenesis of Chagas disease remains underexplored. We have previously used a mouse model to show that host diet is a key factor regulating cardiomyopathy in Chagas disease. In this study, we investigated the effect of a high-fat diet on liver morphology and physiology, lipid metabolism, immune signaling, energy homeostasis, and stress responses in the murine model of acute T. cruzi infection. Our results indicate that in T. cruzi-infected mice, diet differentially regulates several liver processes, including autophagy, a stress response mechanism, with corresponding implications for human Chagas disease patients.

Antagonistic effect of atorvastatin on high fat diet induced survival during acute Chagas disease.

Chagasic cardiomyopathy, which is seen in Chagas disease, is the most severe and life-threatening manifestation of infection by the kinetoplastid Trypanosoma cruzi. Adipose tissue and diet play a major role in maintaining lipid homeostasis and regulating cardiac pathogenesis during the development of Chagas cardiomyopathy. We have previously reported that T. cruzi has a high affinity for lipoproteins and that the invasion rate of this parasite increases in the presence of cholesterol, suggesting that drugs that inhibit cholesterol synthesis, such as statins, could affect infection and the development of Chagasic cardiomyopathy. The dual epidemic of diabetes and obesity in Latin America, the endemic regions for Chagas disease, has led to many patients in the endemic region of infection having hyperlipidemia that is being treated with statins such as atorvastatin. The current study was performed to examine mice fed on either regular or high fat diet for effects of atorvastatin on T. cruzi infection-induced myocarditis and to evaluate the effect of this treatment during infection on adipose tissue physiology and cardiac pathology. Atorvastatin was found to regulate lipolysis and cardiac lipidopathy during acute T. cruzi infection in mice and to enhance tissue parasite load, cardiac LDL levels, inflammation, and mortality in during acute infection. Overall, these data suggest that statins, such as atorvastatin, have deleterious effects during acute Chagas disease.