Fig. 2:
theoretical proposal of cytokine-mediated pathways fueling infection of glial cells by Trypanosoma cruzi and contributing to behavioral and neurocognitive abnormalities. (A) Schematic proposal. In chronic Chagas disease (CD) the out/in input of inflammatory mediators (such as the blood-borne cytokines IL-6, IFNγ and TNF) in the central nervous system (CNS) may activate glial cells (microglia - IBA-1+NPRL3+- and/or astrocytes - GFAP+NPRL3-),4040. Silva RR, Mariante RM, Silva AA, dos Santos ALB, Roffê E, Santiago H, et al. Interferon-gamma promotes infection of astrocytes by Trypanosoma cruzi. PLoS One. 2015; 10(2): e0118600.,101101. Pacheco AL, Vicentini G, Matteucci KC, Ribeiro RR, Weinlich R, Bortoluci KR. The impairment in the NLRP3-induced NO secretion renders astrocytes highly permissive to T. cruzi replication. J Leukoc Biol. 2019; 106(1): 201-7.,103103. Silva AA, Silva RR, Gibaldi D, Mariante RM, Dos Santos JB, Pereira IR, et al. Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu. J Neuroinflammation. 2017; 14(1): 1-15. creating a self-sustaining cytokine-driven inflammatory milieu putatively implicated in parasite persistence4040. Silva RR, Mariante RM, Silva AA, dos Santos ALB, Roffê E, Santiago H, et al. Interferon-gamma promotes infection of astrocytes by Trypanosoma cruzi. PLoS One. 2015; 10(2): e0118600.,103103. Silva AA, Silva RR, Gibaldi D, Mariante RM, Dos Santos JB, Pereira IR, et al. Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu. J Neuroinflammation. 2017; 14(1): 1-15. and inducing neurochemical alterations, such as indoleamine 2,3-dioxygenase enzyme (IDO) upregulation,7979. Vilar-Pereira G, Silva AA, Pereira IR, Silva RR, Moreira OC, de Almeida LR, et al. Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions. Brain Behav Immun. 2012; 26(7): 1136-49. oxidative stress7878. Vilar-Pereira G, Barrios LC, Silva AA, Batista AM, Pereira IR, Moreira OC, et al. Memory impairment in chronic experimental Chagas disease: benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue. PLoS One. 2021; 16(1): e0244710. and neuromediator changes (to be identified). These inflammatory alterations may trigger behavioral and neurocognitive abnormalities (anxiety, depression and memory loss).7878. Vilar-Pereira G, Barrios LC, Silva AA, Batista AM, Pereira IR, Moreira OC, et al. Memory impairment in chronic experimental Chagas disease: benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue. PLoS One. 2021; 16(1): e0244710.,7979. Vilar-Pereira G, Silva AA, Pereira IR, Silva RR, Moreira OC, de Almeida LR, et al. Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions. Brain Behav Immun. 2012; 26(7): 1136-49.,8080. Vilar-Pereira G, Ruivo LAS, Lannes-Vieira J. Behavioural alterations are independent of sickness behaviour in chronic experimental Chagas disease. Mem Inst Oswaldo Cruz. 2015; 110(8): 1042-50. Cytokines and inflammatory mediators such as cytokines (IL-6, IFNγ and TNF) and nitric oxide (NO) may take part in parasite persistence in the central nervous system, fueling parasite growth.4040. Silva RR, Mariante RM, Silva AA, dos Santos ALB, Roffê E, Santiago H, et al. Interferon-gamma promotes infection of astrocytes by Trypanosoma cruzi. PLoS One. 2015; 10(2): e0118600.,103103. Silva AA, Silva RR, Gibaldi D, Mariante RM, Dos Santos JB, Pereira IR, et al. Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu. J Neuroinflammation. 2017; 14(1): 1-15. TNF/TNFR1 signaling may be crucial for parasite infection and persistence in astrocytes.103103. Silva AA, Silva RR, Gibaldi D, Mariante RM, Dos Santos JB, Pereira IR, et al. Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu. J Neuroinflammation. 2017; 14(1): 1-15. (B) Representative dot plots of inflammatory cytokines in the serum of non-infected, and chronically Colombian-infected C57BL/6 mice showing clinical signs of behavioral and neurocognitive alterations,7878. Vilar-Pereira G, Barrios LC, Silva AA, Batista AM, Pereira IR, Moreira OC, et al. Memory impairment in chronic experimental Chagas disease: benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue. PLoS One. 2021; 16(1): e0244710.,7979. Vilar-Pereira G, Silva AA, Pereira IR, Silva RR, Moreira OC, de Almeida LR, et al. Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions. Brain Behav Immun. 2012; 26(7): 1136-49. detected as previously described.137137. Pedra-Rezende Y, Barbosa JMC, Bombaça ACS, Dantas-Pereira L, Gibaldi D, Vilar-Pereira G, et al. Physical exercise promotes a reduction in cardiac fibrosis in the chronic indeterminate form of experimental Chagas disease. Front Immunol. 2021; 12: 712034.
Fig. 3:
theoretical proposal of IL-6/TNF participation in physiology and pathology in several infectious diseases. Elevated levels of IL-6 and TNF in the acute phase of infection (weeks or months) may take part in microbial control (beneficial), but also contribute to behavioral and/or neurocognitive alterations, which may be total or partially recovered. However, long-lasting (years) IL-6- and TNF-enriched systemic inflammation may access the central nervous tissue and lead to long-term behavioral and neurocognitive changes (detrimental). Elevated levels of cytokines in serum may be a common trait in several infectious diseases such as Covid-19,6565. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497-506.,105105. Bhaskar S, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS, et al. Cytokine storm in COVID-19-immunopathological mechanisms, clinical considerations, and therapeutic approaches: The REPROGRAM Consortium Position Paper. Front Immunol. 2020; 11: 1648. septic shock,106106. Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013; 50(1): 23-36.,107107. Stolarski AE, Kim J, Zhang Q, Remick DG. Cytokine Drizzle - The rationale for abandoning "Cytokine Storm". Shock. 2021; 56(5): 667-72. leprosy,108108. Moubasher AD, Kamel NA, Zedan H, Raheem DD. Cytokines in leprosy, I. Serum cytokine profile in leprosy. Int J Dermatol. 1998; 37(10): 733-40.,109109. Angst DBM, Pinheiro RO, Vieira JSS, Cobas RA, Hacker MAV-B, Pitta IJR, et al. Cytokine levels in neural pain in leprosy. Front Immunol. 2020; 11: 23. and Chagas disease (CD).6262. Pérez-Fuentes R, Guégan JF, Barnabé C, López-Colombo A, Salgado-Rosas H, Torres-Rasgado E, et al. Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically infected individuals. Int J Parasitol. 2003; 33(3): 293-9.,6363. Pérez A, Silva-Barbosa S, Berbert L, Revelli S, Beloscar J, Savino W, et al. Immunoneuroendocrine alterations in patients with progressive forms of chronic Chagas disease. J Neuroimmunol. 2011; 235(1-2): 84-90.,7777. Neves EG, Koh CC, da Silva JLP, Passos LS, Villani FN, Dos Santos JS, et al. Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies. Cytokine. 2021; 148: 155711.