Pathogens 2023, 12, 282. https://doi.org/10.3390/pathogens12020282 www.mdpi.com/journal/pathogens Review A Review on the Immunological Response against Trypanosoma cruzi Giusi Macaluso †, Francesca Grippi † , Santina Di Bella *, Valeria Blanda *, Francesca Gucciardi, Alessandra Torina, Annalisa Guercio and Vincenza Cannella Istituto Zooprofilattico Sperimentale della Sicilia “A. Mirri”, 90129 Palermo, Italy * Correspondence: santina.dibella@izssicilia.it (S.D.B.); valeria.blanda@izssicilia.it (V.B.) † These authors contributed equally to this work. Abstract: Chagas disease is a chronic systemic infection transmitted by Trypanosoma cruzi. Its life cycle consists of different stages in vector insects and host mammals. Trypanosoma cruzi strains cause different clinical manifestations of Chagas disease alongside geographic differences in morbidity and mortality. Natural killer cells provide the cytokine interferon‐gamma in the initial phases of T. cruzi infection. Phagocytes secrete cytokines that promote inflammation and activation of other cells involved in defence. Dendritic cells, monocytes and macrophages modulate the adaptive immune response, and B lymphocytes activate an effective humoral immune response to T. cruzi. This review focuses on the main immune mechanisms acting during T. cruzi infection, on the strategies activated by the pathogen against the host cells, on the processes involved in inflammasome and virulence factors and on the new strategies for preventing, controlling and treating this disease. Keywords: Trypanosoma cruzi; immunity; toll‐like receptors; virulence factors; inflammasome 1. Introduction The infection by Trypanosoma cruzi is responsible for a chronic and systemic disease known as Chagas disease that is recognized as a neglected disease by the World Health Organization. The parasite can infect humans and a lot of different species of wild and domestic animals and is mainly transmitted by bloodsucking reduviid insects of the Triatominae subfamily through three overlapping cycles: domestic, peridomestic and wild [1]. Triatoma infestans, Rhodnius prolixus and Triatoma dimidiata are the only competent vectors able to transmit T. cruzi to humans. Triatoma infestans is mainly spread in the sub‐ Amazonian endemic regions, R. prolixus is reported in South and Central America and T. dimidiata is reported in Mexico [2,3]. Other transmission routes to humans involve blood transfusion and vertical transmission [4,5]. In rare cases, ingestion of contaminated foods or liquids or raw meat with a massive parasite infestation can represent an additional transmission route [6]. The life cycle of T. cruzi includes several stages in vector insects and host mammals. In insects, the parasite assumes two typical forms identified as replicative epimastigotes and metacyclic tripomastigotes. In mammals, the typical forms are non‐replicative blood tripomastigotes and replicative intracellular mastigotes [7]. Various T. cruzi strains circulate in mammalian hosts and in insect vectors. This heterogeneity can be responsible for the different clinical manifestations of Chagas disease as well as the differences in morbidity and mortality reported in different geographic areas [8,9]. In humans, Chagas disease usually evolves through an acute phase that can last up to two months, followed by an asymptomatic phase, also called an intermediate or indeterminate phase, and finally, a chronic phase. In most cases, patients affected by T. cruzi are asymptomatic or show mild symptoms. However, 10–30% of infected Citation: Macaluso, G.; Grippi, F.; Di Bella, S.; Blanda, V.; Gucciardi, F.; Torina, A.; Guercio, A.; Cannella, V. A Review on the Immunological Response against Trypanosoma cruzi. Pathogens 2023, 12, 282. https:// doi.org/10.3390/pathogens12020282 Academic Editors: Wanderley De Souza, Fernando Villalta and Carlos Robello Received: 5 December 2022 Revised: 1 February 2023 Accepted: 6 February 2023 Published: 8 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/ by/4.0/).publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/ by/4.0/).