Lipid Metabolism in Insect Vectors of Diseases.

According to the World Health Organization vector-borne diseases account for more than 17% of all infectious diseases, causing more than 700,000 deaths annually. Vectors are organisms that are able to transmit infectious pathogens between humans, or from animals to humans. Many of these vectors are hematophagous insects, which ingest the pathogen from an infected host during a blood meal, and later transmit it into a new host. Malaria, dengue, African trypanosomiasis, yellow fever, leishmaniasis, Chagas disease, and many others are examples of diseases transmitted by insects.Both the diet and the infection with pathogens trigger changes in many metabolic pathways, including lipid metabolism, compared to other insects. Blood contains mostly proteins and is very poor in lipids and carbohydrates. Thus, hematophagous insects attempt to efficiently digest and absorb diet lipids and also rely on a large de novo lipid biosynthesis based on utilization of proteins and carbohydrates as carbon source. Blood meal triggers essential physiological processes as molting, excretion, and oogenesis; therefore, lipid metabolism and utilization of lipid storage should be finely synchronized and regulated regarding that, in order to provide the necessary energy source for these events. Also, pathogens have evolved mechanisms to hijack essential lipids from the insect host by interfering in the biosynthesis, catabolism, and transport of lipids, which pose challenges to reproduction, survival, fitness, and other insect traits.In this chapter, we have tried to collect and highlight the current knowledge and recent discoveries on the metabolism of lipids in insect vectors of diseases related to the hematophagous diet and pathogen infection.

Domestic Dog Infection with Trypanosoma cruzi from Northern and Southern Regions of Mexico.

Background: Chagas disease or American trypanosomiasis, caused by Trypanosoma cruzi and vectored by triatomines, affects millions of people worldwide. In endemic countries including Mexico, infections in domestic animals, such as dogs, may affect the risk of human disease when they serve as a source of infection to vectors that subsequently infect humans. Materials and Methods: We conducted a cross-sectional study of 296 dogs from two cities near the northern and southern borders of Mexico: Reynosa, Tamaulipas, and Tuxtla Gutierrez, Chiapas. Infection was measured based on testing of blood using T. cruzi quantitative PCR (qPCR) and up to three antibody detection assays. The StatPak immunochromatographic assay was used to screen samples and the indirect fluorescent antibody (IFA) and multiplex microsphere immunoassay (MIA) tests were used as secondary tests on all samples that screened positive and a subset of negatives. Serologic positivity was defined based on reactivity on at least two independent tests. Results: Of the 280 samples tested for parasite DNA, two (0.7%) were positive, one of which (0.4%) was confirmed as T. cruzi discrete typing unit TcIV. Overall, 72 (24.3%) samples were reactive for T. cruzi antibodies via StatPak of which 8 were also positive using MIA and 2 were also positive using IFA (including one of the PCR-positive dogs). Overall, nine dogs (3.4%) met study criteria of positivity based on either/both serology or PCR tests. Positive dogs were found in both regions of Mexico; five (2.7%) from Reynosa and four (3.6%) from Tuxtla Gutierrez. We found no association between infection status and state of origin, sex, age group, breed group, neighborhood, and whether other pets lived in the home. Conclusion: Our results re-emphasize dogs' utility as sentinels for T. cruzi in Mexico and underscore the need for improved veterinary diagnostic tests and parasite surveillance at the household level in endemic countries.

Trypanosoma cruzi Vps34 colocalizes with Beclin1 and plays a role in parasite invasion of the host cell by modulating the expression of a sub-group of trans-sialidases.

Trypanosoma cruzi, the etiological agent of Chagas' disease, can infect both phagocytic and non-phagocytic cells. T. cruzi gp82 and gp90 are cell surface proteins belonging to Group II trans-sialidases known to be involved in host cell binding and invasion. Phosphatidylinositol kinases (PIK) are lipid kinases that phosphorylate phospholipids in their substrates or in themselves, regulating important cellular functions such as metabolism, cell cycle and survival. Vps34, a class III PIK, regulates autophagy, trimeric G-protein signaling, and the mTOR (mammalian Target of Rapamycin) nutrient-sensing pathway. The mammalian autophagy gene Beclin1 interacts to Vps34 forming Beclin 1-Vps34 complexes involved in autophagy and protein sorting. In T. cruzi epimastigotes, (a non-infective replicative form), TcVps34 has been related to morphological and functional changes associated to vesicular trafficking, osmoregulation and receptor-mediated endocytosis. We aimed to characterize the role of TcVps34 during invasion of HeLa cells by metacyclic (MT) forms. MTs overexpressing TcVps34 showed lower invasion rates compared to controls, whilst exhibiting a significant decrease in gp82 expression in the parasite surface. In addition, we showed that T. cruzi Beclin (TcBeclin1) colocalizes with TcVps34 in epimastigotes, thus suggesting the formation of complexes that may play conserved cellular roles already described for other eukaryotes.

Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Slow recovery rates and spatial aggregation of Triatoma infestans populations in an area with high pyrethroid resistance in the Argentine Chaco.

BACKGROUND: The emergence of pyrethroid resistance has threatened the elimination of Triatoma infestans from the Gran Chaco ecoregion. We investigated the status and spatial distribution of house infestation with T. infestans and its main determinants in Castelli, a municipality of the Argentine Chaco with record levels of triatomine pyrethroid resistance, persistent infestation over 2005-2014, and limited or no control actions over 2015-2020. METHODS: We conducted a 2-year longitudinal survey to assess triatomine infestation by timed manual searches in a well-defined rural section of Castelli including 14 villages and 234 inhabited houses in 2018 (baseline) and 2020, collected housing and sociodemographic data by on-site inspection and a tailored questionnaire, and synthetized these data into three indices generated by multiple correspondence analysis. RESULTS: The overall prevalence of house infestation in 2018 (33.8%) and 2020 (31.6%) virtually matched the historical estimates for the period 2005-2014 (33.7%) under recurrent pyrethroid sprays. While mean peridomestic infestation remained the same (26.4-26.7%) between 2018 and 2020, domestic infestation slightly decreased from 12.2 to 8.3%. Key triatomine habitats were storerooms, domiciles, kitchens, and structures occupied by chickens. Local spatial analysis showed significant aggregation of infestation and bug abundance in five villages, four of which had very high pyrethroid resistance approximately over 2010-2013, suggesting persistent infestations over space-time. House bug abundance within the hotspots consistently exceeded the estimates recorded in other villages. Multiple regression analysis revealed that the presence and relative abundance of T. infestans in domiciles were strongly and negatively associated with indices for household preventive practices (pesticide use) and housing quality. Questionnaire-derived information showed extensive use of pyrethroids associated with livestock raising and concomitant spillover treatment of dogs and (peri) domestic premises. CONCLUSIONS: Triatoma infestans populations in an area with high pyrethroid resistance showed slow recovery and propagation rates despite limited or marginal control actions over a 5-year period. Consistent with these patterns, independent experiments confirmed the lower fitness of pyrethroid-resistant triatomines in Castelli compared with susceptible conspecifics. Targeting hotspots and pyrethroid-resistant foci with appropriate house modification measures and judicious application of alternative insecticides with adequate toxicity profiles are needed to suppress resistant triatomine populations and prevent their eventual regional spread.

Drug screening and development cascade for Chagas disease: an update of in vitro and in vivo experimental models.

Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.

Chagas disease in the immunocompromised host.

PURPOSE OF REVIEW: To highlight recent advances in our understanding of Trypanosoma cruzi infection in immunocompromised individuals, a condition that is increasingly recognized as populations shift and use of immunosuppressive medications becomes more commonplace. RECENT FINDINGS: Chagas disease screening programs should include people at risk for both Chagas disease and immunocompromise, e.g. people who have resided for ≥6 months in endemic Latin America who have an immunocompromising condition such as HIV or who are planned to start an immunosuppressive medication regimen. The goal of identifying such individuals is to allow management strategies that will reduce their risk of T. cruzi reactivation disease. For people with HIV-T. cruzi coinfection, strict adherence to antiretroviral therapy is important and antitrypanosomal treatment is urgent in the setting of symptomatic reactivation. People at risk for T. cruzi reactivation due to immunosuppression caused by advanced hematologic conditions or postsolid organ transplantation should be monitored via T. cruzi qPCR and treated with preemptive antitrypanosomal therapy if rising parasite load on serial specimens indicates reactivation. Reduction of the immunosuppressive regimen, if possible, is important. SUMMARY: Chronic Chagas disease can lead to severe disease in immunocompromised individuals, particularly those with advanced HIV (CD4+ < 200 cells/mm3) or peri-transplantation.

Genetic diversity of the Chagas vector Triatoma dimidiata s.l. (Hemiptera: Reduviidae) across geographic scales in a top-priority area for control.

Population genetic structure of arthropod disease vectors provides important information on vector movement and climate or other environmental variables that influence their distribution. This information is critical for data-driven vector control. In the first comprehensive study of the genetic structure of T. dimidiata s.l. (Latreille, 1811) we focus on an area of active transmission designated as a top priority for control. We examined a high number of specimens across a broad geographic area along the border of Guatemala and El Salvador including multiple spatial scales using a high number of genome-wide markers. Measuring admixture, pairwise genetic differentiation, and relatedness, we estimated the specimens represented three genetic clusters. We found evidence of movement (migration/gene flow) across all spatial scales with more admixture among locations in El Salvador than in Guatemala. Although there was significant isolation by distance, the 2 close villages in Guatemala showed either the most or least genetic variation indicating an additional role of environmental variables. Further, we found that social factors may be influencing the genetic structure. We demonstrated the power of genomic studies with a large number of specimens across a broad geographic area. The results suggest that for effective vector control movement must be considered on multiple spatial scales along with its contributing factors.

DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents.

Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 µM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.

Evaluation and validation of a PrintrLab-based LAMP assay to identify Trypanosoma cruzi in newborns in Bolivia: a proof-of-concept study.

BACKGROUND: Vertical transmission of Trypanosoma cruzi represents approximately 20% of new Chagas disease cases. Early detection and treatment for women of childbearing age and newborns is a public health priority, but the lack of a simple and reliable diagnostic test remains a major barrier. We aimed to evaluate the performance of a point-of-care loop-mediated isothermal amplification (LAMP) assay for the detection of T cruzi. METHODS: In this proof-of-concept study, we coupled a low-cost 3D printer repurposed for sample preparation and amplification (PrintrLab) to the Eiken T cruzi-LAMP prototype to detect vertically transmitted T cruzi, which we compared with standardised PCR and with the gold-standard algorithm (microscopy at birth and 2 months and serological study several months later). We screened pregnant women from two hospitals in the Bolivian Gran Chaco province, and those who were seropositive for T cruzi were offered the opportunity for their newborns to be enrolled in the study. Newborns were tested by microscopy, LAMP, and PCR at birth and 2 months, and by serology at 8 months. FINDINGS: Between April 23 and Nov 17, 2018, 986 mothers were screened, among whom 276 were seropositive for T cruzi (28·0% prevalence, 95% CI 25·6-31·2). In total, 224 infants born to 221 seropositive mothers completed 8 months of follow-up. Congenital transmission was detected in nine of the 224 newborns (4·0% prevalence, 1·9-7·5) by direct microscopy observation, and 14 more cases were diagnosed serologically (6·3%, 3·6-10·3), accounting for an overall vertical transmission rate of 10·3% (6·6-15·0; 23 of 224). All microscopy-positive newborns were positive by PrintrLab-LAMP and by PCR, while these techniques respectively detected four and five extra positive cases among the remaining 215 microscopy-negative newborns. INTERPRETATION: The PrintrLab-LAMP yielded a higher sensitivity than microscopy-based analysis. Considering the simpler use and expected lower cost of LAMP compared with PCR, our findings encourage its evaluation in a larger study over a wider geographical area. FUNDING: Inter-American Development Bank.

Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

Outcomes of kidney transplant recipients exposed to Chagas disease under Benznidazole prophylaxis. A single center 10-year experience.

BACKGROUND: Chagas disease (ChD) is endemic in many parts of the world and can be transmitted through organ transplantation or reactivated by immunosuppression. Organs from infected donors are occasionally used for transplantation, and the best way of managing the recipients remains a subject of debate. METHODS: We present a single-center cohort study describing a 10-year experience of kidney transplantation in patients at risk of donor-derived ChD and or reactivation. Patients received prophylactic treatment with Benznidazole and were monitored for transmission or reactivation. Monitoring included assessing direct parasitemia, serology, and polymerase chain reaction (PCR). RESULTS: Fifty-seven kidney transplant recipients (KTRs) were enrolled in the study. Forty-four patients (77.2%) were at risk of primary ChD infection, nine patients (15.8%) were at risk of disease reactivation, and four patients (7.0%) were at risk of both. All patients received Benznidazole prophylaxis, starting on the first day after transplantation. Parasitemia was assessed in 51 patients (89.5%), serology also in 51 patients (89.5%), and PCR in 40 patients (70.2%). None of the patients exhibited clinically or laboratory-detectable signs of disease. A single patient experienced a significant side effect, a cutaneous rash with intense pruritus. At 1-year post-transplantation, the patient and graft survival rates were 96.5% and 93%, respectively. CONCLUSION: In this study, no donor-derived or reactivation of Trypanosoma cruzi infection occurred in KTRs receiving Benznidazole prophylaxis.

Dynamic Contrast-Enhanced Magnetic Resonance Lymphangiography for Diagnosis and Treatment of Chylopericardium After Cardiac Transplantation.

Chylopericardium is a rare complication after cardiac transplantation. We report a case of a 69-year-old woman with persistent chylopericardium after a heart transplantation due to Chagas disease. Failure of conservative treatment led to dynamic contrast-enhanced magnetic resonance lymphangiography and percutaneous radiologic intervention of the lymphatic leakage and symptoms resolution.

The Trypanosoma cruzi pleiotropic protein P21 orchestrates the intracellular retention and in-vivo parasitism control of virulent Y strain parasites.

P21 is a protein secreted by all forms of Trypanosoma cruzi (T. cruzi) with recognized biological activities determined in studies using the recombinant form of the protein. In our recent study, we found that the ablation of P21 gene decreased Y strain axenic epimastigotes multiplication and increased intracellular replication of amastigotes in HeLa cells infected with metacyclic trypomastigotes. In the present study, we investigated the effect of P21 in vitro using C2C12 cell lines infected with tissue culture-derived trypomastigotes (TCT) of wild-type and P21 knockout (TcP21-/-) Y strain, and in vivo using an experimental model of T. cruzi infection in BALB/c mice. Our in-vitro results showed a significant decrease in the host cell invasion rate by TcP21-/- parasites as measured by Giemsa staining and cell count in bright light microscope. Quantitative polymerase chain reaction (qPCR) analysis showed that TcP21-/- parasites multiplied intracellularly to a higher extent than the scrambled parasites at 72h post-infection. In addition, we observed a higher egress of TcP21-/- trypomastigotes from C2C12 cells at 144h and 168h post-infection. Mice infected with Y strain TcP21-/- trypomastigotes displayed higher systemic parasitemia, heart tissue parasite burden, and several histopathological alterations in heart tissues compared to control animals infected with scrambled parasites. Therewith, we propose that P21 is important in the host-pathogen interaction during invasion, cell multiplication, and egress, and may be part of the mechanism that controls parasitism and promotes chronic infection without patent systemic parasitemia.

Octopamine is required for successful reproduction in the classical insect model, Rhodnius prolixus.

In insects, biogenic amines function as neurotransmitters, neuromodulators, and neurohormones, influencing various behaviors, including those related to reproduction such as response to sex pheromones, oogenesis, oviposition, courtship, and mating. Octopamine (OA), an analog of the vertebrate norepinephrine, is synthesized from the biogenic amine tyramine by the enzyme tyramine ß-hydroxylase (TßH). Here, we investigate the mechanisms and target genes underlying the role of OA in successful reproduction in females of Rhodnius prolixus, a vector of Chagas disease, by downregulating TßH mRNA expression (thereby reducing OA content) using RNA interference (RNAi), and in vivo and ex vivo application of OA. Injection of females with dsTßH impairs successful reproduction at least in part, by decreasing the transcript expression of enzymes involved in juvenile hormone biosynthesis, the primary hormone for oogenesis in R. prolixus, thereby interfering with oogenesis, ovulation and oviposition. This study offers valuable insights into the involvement of OA for successful reproduction in R. prolixus females. Understanding the reproductive biology of R. prolixus is crucial in a medical context for controlling the spread of the disease.

A Case of Chagas Disease in South Dakota: Diagnosis and Treatment.

Chagas disease is a chronic, systemic parasitic infection caused by the protozoan Trypanosoma cruzi. The primary mode of transmission to humans is by the Reduviid insect, endemic to South America. Recent migration of the vector has led to increased cases in the southern United States and has prompted increased surveillance and blood donation screening. It is unusual to diagnose and treat individuals with Chagas disease in the northern United States. This case describes an immigrant female from El Salvador that was informed she had Chagas disease from a blood bank screening. Confirmation and treatment of the disease were performed by her South Dakota primary care provider thus demonstrating the importance of identifying Chagas disease in the immigrant population in regions where Chagas disease infection is uncommon.

Mechanisms controlling haemolymph circulation under resting conditions in the chagas disease vector Rhodnius Prolixus (Stål).

Chagas disease vectors can ingest several times their own volume in blood with each meal. This ad libitum feeding causes an intense process of diuresis inducing the insect to eliminate a large quantity of urine and faeces. To ensure diuresis, the speed of circulation of the haemolymph is increased. Triatominae circulatory system is quite simple, including the dorsal vessel which pumps haemolymph in an anterograde direction. The return is caused by peristaltic contractions of the anterior midgut. Triatominae insects can spend several weeks without feeding, meaning that during most of the time, the insect is in a resting condition. While the mechanisms controlling the circulation of the haemolymph during post-prandial diuresis was largely analysed, the mechanisms controlling it during resting conditions are poorly understood. In this study we analyse several canonical pathways (i.e. L-type VGCC; GPCR; RyR; IP3R) and a novel system represented by the recently characterized Piezo proteins. Our results show that during the resting condition haemolymph circulation depends on a cross-talk between myogenic activity, inhibitory and stimulatory cellular messengers, and also Piezo proteins. This report also unveils for the first time the existence of a putative Piezo protein in Hemiptera.

Life history data of four populations of Triatoma mexicana (Hemiptera: Reduviidae) from Central Mexico.

Triatomine bugs are vectors for the Trypanosoma cruzi Chagas parasites, the etiological agent for Chagas disease. This study evaluated 6 epidemiologically significant behaviors (development time, number of blood meals required for molting to the next instar, mortality rate, aggressiveness, feeding duration, and defecation delay) across 4 populations of Triatoma mexicana Herrich-Schaeffer (Heteroptera: Reduviidae), a major T. cruzi vector in Central Mexico. We collected triatomines from areas characterized by high (HP), medium (MP), medium-high (MHP), and low (LP) prevalence of human T. cruzi infection. The MHP population had the shortest development time, <290 days. Both the HP and MP populations required the most blood meals to molt to the next instar, with a median of 13. Mortality rates varied across all populations, ranging from 44% to 52%. All of the tested populations showed aggressive behavior during feeding. All populations shared similar feeding durations, with most exceeding 13 min and increasing with each instar. Quick defecation, during feeding, immediately after or less than 1 min after feeding, was observed in most nymphs (78%-90%) from the MP and MHP populations and adults (74%-92%) from HP, MP, and MHP populations. Though most parameters suggest a low potential for T. mexicana to transmit T. cruzi, unique feeding and defecation behaviors in 3 populations (excluding the LP group) could elevate their epidemiological importance. These population-specific differences may contribute to the varying prevalence rates of T. cruzi infection in areas where T. mexicana is found.

Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy.

Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-ß (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-ß inhibitor, IC50 114.3 µM), losmapimod (p38 inhibitor, IC50 17.6 µM) and SP600125 (c-Jun inhibitor, IC50 3.9 µM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.

Quantitative Proteomic Analysis of Macrophages Infected with Trypanosoma cruzi Reveals Different Responses Dependent on the SLAMF1 Receptor and the Parasite Strain.

Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi. This disease affects mainly rural areas in Central and South America, where the insect vector is endemic. However, this disease has become a world health problem since migration has spread it to other continents. It is a complex disease with many reservoirs and vectors and high genetic variability. One of the host proteins involved in the pathogenesis is SLAMF1. This immune receptor acts during the infection of macrophages controlling parasite replication and thus affecting survival in mice but in a parasite strain-dependent manner. Therefore, we studied the role of SLAMF1 by quantitative proteomics in a macrophage in vitro infection and the different responses between Y and VFRA strains of Trypanosoma cruzi. We detected different significant up- or downregulated proteins involved in immune regulation processes, which are SLAMF1 and/or strain-dependent. Furthermore, independently of SLAMF1, this parasite induces different responses in macrophages to counteract the infection and kill the parasite, such as type I and II IFN responses, NLRP3 inflammasome activation, IL-18 production, TLR7 and TLR9 activation specifically with the Y strain, and IL-11 signaling specifically with the VFRA strain. These results have opened new research fields to elucidate the concrete role of SLAMF1 and discover new potential therapeutic approaches for Chagas disease.