Changes in splenic tissue and immune response profile of Schistosoma mansoni infected mice submitted to chronic ethanol intake.

Neglected parasitic diseases and harmful use of alcoholic beverages cause significant public health concerns in developing countries such as Brazil (WHO, 2018). Total costs for the Unified Health System in Brazil, considering illnesses related to the use of 25 g/day or more of ethanol (risk consumption) obtained in a national survey were US$ 8,262,762 per year (Coutinho et al., 2016). Schistosomiasis is a water-borne disease caused by a blood-dwelling flatworm, Schistosoma mansoni Sambon, 1907, quite dependent on host immune response. Humans become infected by exposure to contaminated water containing skin penetrating cercariae released from freshwater infected snail hosts of the genus Biomphalaria. Once inside the host, cercariae transform into schistosomula and migrate from the skin to the lungs and then to the liver, where they mature into adult egg-laying parasites within 4–5 weeks after infection. At this pre-patent phase, migrating schistosomula induce a type 1 (Th1) immune response, which is characterized by increased release of interleukins, such as IL-2, IL-6, IL-12 and IFN-γ (Schwartz and Fallon, 2018) and a high production of tumor necrosis factor (TNF-alfa) (Hoffmann et al., 2000; Pearce and MacDonald, 2002). At 4–5 weeks after infection, mated worms migrate to the mesenteric vessels, where females release immature eggs (Andrade, 2009).

During patent infections, eggs mature by crossing the mammalian intestinal wall, reaching the gut lumen to be excreted with host feces into the environment to continue the life cycle (Costain et al., 2018). However, most produced eggs remain trapped in host organs (intestine and liver), inducing a typical granulomatous inflammatory response, causing host pathology. Egg antigens induce the production of Th2 cytokines (IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13) (Pearce et al., 2004; Wolde et al., 2020). The Th2 profile also stimulates B lymphocyte proliferation, immunoglobulin E (IgE), IgG, and eosinophils and mast cells differentiation (Candido et al., 2017).This modulation in the immune response is crucial for the recruitment and activation of cell types responsible for granuloma formation (Castro et al., 2018).

Schistosomiasis is traditionally classified into an acute (0–10 weeks post-infection) and a chronic phase (about 12 weeks) (Lambertucci, 2010; Ndlovu and Brombacher, 2014). The onset of hepatic fibrosis alters the hepatic blood flow which becomes hepatofugal, resulting in enhance flow and stasis in the collateral venous system, especially in the splenic portal territory, increasing blood cell retention with consequent development of splenomegaly (Correia et al., 2009). At the acute infection, spleen enlargement and splenitis as well as diffuse hyperplasia of both red and white pulps and intense active congestion of the splenic sinuses have been reported (Andrade and Azevedo, 1987). The hepatosplenic disease is associated with an intense immune response to antigens from eggs trapped in liver tissue and also with cellular hyperplasia of the reticuloendothelial system (Cosenza-Contreras et al., 2019). In fact, red pulp congestion and atrophy/hypertrophy have been earlier described in S. mansoni-induced splenomegaly, in which CD4+ T cells subpopulation may be important (Da Silva et al., 2012).

Acute and chronic alcohol abuse can cause structural changes in several organs, such as spleen and thymus atrophy (Cook, 1998). This interferes with the immune activity by inhibiting the proliferation of CD3+ T cells, decreasing the population of CD4+ and CD8+ T cells (Lanzke et al., 2017). Although schistosomiasis patients in endemic areas are frequently heavy drinkers (Lambertucci, 2014) schistosomiasis splenomegaly was not associated with alcohol abuse (Cota et al., 2006) or to severity (Silva et al., 2016).

Experimental schistosomiasis studies have shown reduction in size of liver granulomas in mice submitted to a liquid diet or water containing 35 % or 7 % of ethanol, respectively (Castro et al., 1993; Orrego et al., 1981). Our previous study showed that S. mansoni male worms had tegumental damages (tubercles flattening, loss of tubercles, peeling and erosive lesions) and changes in the reproductive system of both males and females due to 18 % ethanol intake for 28 days in mice (Brandão-Bezerra et al., 2019). Given the impact of ethanol administration on the experimental infections, we investigated the integrity of the splenic microarchitecture and the immune response profile in acute schistosomiasis in mice.

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