Programmed cell death in thymus during experimental paracoccidioidomycosis

Abstract

Many works have shown that immunosuppressive effects induced by systemic mycosis can be related to primary lymphoid organ damage. Previous studies in our laboratory showed that Paracoccidioides brasiliensis was able to invade the thymus, inducing a severe atrophy with significant reduction of cortical area along with a loss of cortico-medullary boundary. The objective of the present study was to investigate whether thymic atrophy is caused by programmed cell death (PCD) and to examine the ultrastructural characteristics of the thymus in experimentally infected BALB/c mice. The results revealed an eightfold increase in the apoptotic index occurring by day 5 post infection, i.e., during early stages of the infection, shown by immunohistochemistry. In addition, typical cell alterations of autophagic PCD were observed by transmission electron microscopy. Taken together, these results reinforce the idea that thymic alterations may be involved in the immunosuppressive phenomenon frequently associated with paracoccidioidomycotic infection.

Acute Thymic Involution and Mechanisms for Recovery

“…Increased apoptotic index triggered by autophagic programmed cell death Thymus growth-stimulatory factor extracted from S. involvens, a fern Brito et al 2003;Gayathri et al 2011;MendesGiannini et al 2008;Savino 2006;Souto et al 2003 Bacteria Immune reaction to the thymic infection Borges et al 2012;Nobrega et al 2007Nobrega et al , 2010Reiley et al 2012 Francisella tularensis, F. tularensis an analogous patho-physiological model similar to HIVinfected human in terms of disease progression (Policicchio et al 2016). During infection of newborn rhesus macaques with SIV, ATI-associated events (including enhanced death and depletion of thymocytes by various apoptotic mechanisms) very similar to those described in HIV-infected humans (Rosenzweig et al 2000) are observed.…”

“…This invasion was associated with severe ATI as a primary event that was characterized by a decrease in thymus weight, an increase in number of histiocytes, limited distinction of the cortico-medullary junction along with degenerative changes in the thymic cortex . Mechanistically, ATI during experimental paracoccidioidomycosis was caused by apoptosis, as indicated by a significant increase in the apoptotic index as well as typical cellular changes that were triggered by autophagic programmed cell death (Mendes-Giannini et al 2008;Souto et al 2003). Gayathri et al (2011) investigated the effect of an extract of a fern known as Selaginella involvens that was shown to have thymus growth-stimulatory properties and found that this substance protected cortisone-treated immuno-compromised mice from an infection with Aspergillus fumigatus.…”

“…However, ATI in experimental animal models has been reported to occur not only during gestational periods (Kunzmann et al 2010;between ATI in adult experimental subjects and ageassociated thymic atrophy during the mid-phase of life in human beings is that the former occurs due to an increase in the death of thymocytes and has the ability to recover after the removal of the insult (Duan et al 2015;Lee et al 2011;Park et al 2007), whereas the latter is characterized by the substitution of lymphoid tissue with fat (adipose tissue) in a progressive time-dependent manner (Bodey et al 1997;Henry and Anderson 1987;Quaglino et al 2014). ATI is a common and well-known feature in various fungal Mendes-Giannini et al 2008;Souto et al 2003), viral (Duan et al 2015;Falkenberg et al 2014;Gao et al 2015) and bacterial infectious diseases (LeyvaRangel et al 2015;Ross et al 2012;Savino 2006). ATI can also be caused by immune suppression (Billard et al 2011;Zhou et al 2016), hunger (Gavia-García et al 2015;Savino et al 2007), chemotherapy, radiography (DeBo et al 2015;Lynch et al 2009), pregnancy (Ekin et al 2016;Jacques et al 2014Jacques et al , 2015, transplant rejection (Gracia-Ahufinger et al 2015;Krenzien et al 2015) and other severe disease conditions (Wang et al 2016).…”

Thymic atrophy and fungal virulence during experimental paracoccidioidomycosis

“…A/J and B10.A male mice from CEMIB/UNICAMP were intraperitoneally inoculated with 5x10 6 yeasts of Pb (highly Pb18 or slight Pb265 strain) or sterile phosphate buffered saline (control). Lots of 5 mice were weighted and sacrificed at 1, 3, 5, 7 and 14 days post-infection (pi).…”

“…In BALB/c mice, we observed that a virulent isolate of Pb is able to invade the thymic microenvironment inducing severe atrophy, depletion of the cortical layer, loss of the corticomedullary delimitation, and medullary and subcapsular inflammatory infiltrate (1). Also, an increase in programmed cell death (PCD) by apoptosis and autophagy was observed (6). In this work, we evaluated thymic alterations induced by highly and slightly virulent isolates of Pb in susceptible (B10.A) and resistant mice (A/J).…”