1. Introduction
There are many studies in the literature, aiming elucidate the immune response in protozoan infections (Costagliola et al., 2016; da Silveira-Lemos et al., 2021; de Araujo et al., 2021; Tarannun et al., 2023), associated with diseases with high morbidity and mortality in the human population, such as those caused by members of the Trypanosomatidae family (Echeverria and Morillo, 2019; Graepp-Fontoura et al., 2020).
During the process of infection by the etiological agent of Chagas disease, the immunological networking will define the inflammatory profile and, consequently, the evolution of the disease. It is known that the absence of Chagas pathology is mainly associated with the infected host’s ability to modulate the anti-T. cruzi immune response. However, this response that controls persistent parasitemia can also contribute to the inflammatory damage that causes morbidity and clinical manifestations of Chagas disease (Sathler-Avelar et al., 2021).
Is well known that innate immune system cells as dendritic cells, monocytes and macrophages modulate the adaptive immune response, and natural killer cells are majority producers of interferon-gamma (IFN-γ) in the initial phases of T. cruzi infection (Guilmot et al., 2014). Phagocytes secrete cytokines that promote inflammation and activation of other cells involved in immunity (Macaluso et al., 2023). Despite the great importance of T cells in controlling parasitemia during the acute phase of disease, it is known that these activated cells are the main components of the inflammatory infiltrate observed in cardiac and digestive patients. Their presence and the cytokine profile secreted by them are related to the pathology during the chronic phase (Natale et al., 2021; Castro-Eiro et al., 2022). Therefore, it is consistently found in the literature that high expression and imbalance of inflammatory cytokines, such as TNF-α and IFN-γ, is related to the development of pathology, both in the cardiac and digestive clinical forms (Dutra et al., 2009; Torres et al., 2024).
Given that Chagas disease has a chronic and debilitating evolution, the consumption of alcoholic beverages could worsen clinical conditions. Although alcoholism is a serious public health problem, there are no studies in the literature that address the relationship between alcoholism and infections by Trypanosomatidae protozoa (Leishmania spp . or T. cruzi ) in human population. There are few studies in the scientific literature investigating this relationship or impact (Sandri et al., 2017; Falkowski-Temporini et al., 2017). In general, these studies report that alcohol consumption is directly related to a greater degree of morbidity from infection by these trypanosomatids. However, is important to investigate whether immunological changes resulting from ethanol use would influence the course of T. cruzi infection.
The consumption of alcohol, whether chronic or acute, results in alterations in cellular components of the innate and adaptive immune system (González-Reimers et al., 2012). Ethanol has been shown to influence both subpopulations of CD4+ T cells, or helper T lymphocytes (Th). In human alcoholics, there is an increase in Th1 responses and a decrease in Th2 responses (Krolewiecki et al., 2001; González-Reimers et al., 2014). A recent study demonstrated that ethanol impairs CD4+ T cell immunometabolism and promoting CD4+ T cell differentiation to a pro-inflammatory phenotype (MacTernan et al., 2022).
However, scientific evidence is accumulating that ethanol (EtOH) modulates the function of immune cells that circulate in the blood until recruited into tissues, in a dose and time dependent manner (Barr et al, 2016). For example, the administration of ethanol in the short term can shift the class of immune response triggered towards a type 2 reactivity, promoting a quickly increase in serum levels of IgE (Alonso et al., 2012). Our research group demonstrated that short-term high-dose EtOH administration has differential impact on APC populations. Highlighting the downregulating of splenic macrophages and DC activity in contrast to up-regulating of B lymphocyte function as APC and ultimately yielding a micro-environment that led to increased activation of CD4+ T cells and induction of allergic biomarkers, such as IL-4 and IgE (Andrade et al., 2009).
Given the significant alterations induced by alcohol consumption on the immune system, and the fact that developing countries have a high prevalence of neglected diseases, such as Chagas disease, it is highly relevant to evaluate the relation between ethanol consumption and the immune response in the face of T. cruzi infection. This study becomes even more important considering that the exact role of IL-4 inT. cruzi infection is not yet fully defined, and the fact that alcohol is a legal drug of abuse widely consumed throughout the world.