Host Response and Pathogenesis
In contrast with the epidemiological features of P. brasiliensis infecting their hosts by aerial propagules (Lacaz et al. 1986) (Chap. 6), L. loboi in humans and P. brasiliensis var.
ceti in dolphins are restricted to the subcutaneous tissues. This fact suggests that environmental propagules of both pathogens are more likely introduced by traumatic implantation of such elements in the subcutaneous tissues of the infected hosts. Accounts of humans with lacaziosis after traumatic lesions involving contaminated plants, snake bites, insect bites, stingray trauma, and others support this hypothesis (Almeida and Lacaz 1948-49; Azulay et al. 1976; Baruzzi et al. 1973; Lacaz et al. 1986; Rodriguez-Toro 1993; Talhari and Talhari 2012). Once these environmental propagules reach the subcutaneous tissues, L. loboi and P. brasiliensis var. ceti switch to a yeast-like form and successfully establish in the host subcutaneous tissues.According to many observations (Bossart et al. 2015; Daura-Jorge and Simoes- Lopes 2011; De Vries and Laarman 1973; Silva and Brito 1994; Talhari and Talhari 2012; Woods et al. 2010), both pathogens increase in size very slowly and could take months or even years to produce large granulomatous parakeloidal lesions. The disease rarely disseminates to other organs (Azulay et al. 1976; Opromolla et al. 2003). It has been found that yeast-like cells of both pathogens actively proliferate inside inflammatory cells (macrophages, mainly giant cells) activating the release of transforming growth factor β1 (TGF-β1), a powerful cytokine involved in immunosuppressive events (Francesconi et al. 2014; Reif et al. 2009; Vilani-Moreno et al. 2004a; Xavier et al. 2008), and can block the release of nitric oxide in giant cells and macrophages, also inhibiting the production of interferon gamma (IFN-γ) and thus locking the immune response in a Th2 subset, a typical reaction observed in both infected humans and dolphins (Goihman-Yahr et al.
1989; Vilani-Moreno et al. 2004b, 2011). The subcutaneous granulomas in infected humans and dolphins showed numerous branching yeast-like cells uniform in size and arranged in chains, surrounded by inflammatory cells and heavy fibrosis (Francesconi et al. 2014; Goihman-Yahr et al. 1989; Pecher et al. 1979; Reif et al. 2009; Vilani-Moreno and Opromolla 1997). It is believed that the proliferation of CD8 T cells promoted by TGF-β1 is responsible also for the production of immunoglobulins and other factors that favor the process of fibrosis giving the external parakeloidal appearance of the cutaneous lesions.The presence of IL-10, IL-4 and IL-6 has been found in infected humans, an evidence that the immune response is locked into a Th2 subset (Lacaz et al. 1986; Vilani-Moreno et al. 2007). It is likely that the Th2 events are triggered by metabolites released by the fungus during its in vivo reproduction, but those factors are yet to be investigated. Mendoza et al. (2008) detected several antigens using sera from experimentally inoculated mice and infected humans and dolphins. The study found a ~193kD gp43-like antigen in infected humans and dolphins. The presence of melanin in the cell wall of L. loboi and P. brasiliensis var. ceti is believed to protect the pathogens from the host immune response (Taborda et al. 1999b). Vilani- Moreno and Opromolla (1997) reported that the viability of L. loboi yeast-like cells in humans is reduced, and probably only ~40% of the cells are still viable in the infected host tissues. A similar finding was reported in infected dolphins (Lane et al. 2014; Reif et al. 2006). A dramatic decrease in the number of circulating B- and T-helper cells was observed, which might contribute to impairment of adaptive immunity. Antibodies against P. brasiliensis var. ceti were found to crossreact with the antigens of the culturable P. brasiliensis isolates (Landman et al. 1988; Mendes etal. 1986; PucciaandTravassos 1991; Silvaetal. 1968; Vidaletal. 1997).
9.4