**3. Pathogenesis**

Similar to other systemic fungal infections, the primary infection occurs in the lung after inhalation of the aerosolized microconidia. When the conidia reach the alveoli, the innate immune response is activated and the fungus binds to the CD11-CD18 family of integrins and is engulfed by neutrophils and macrophages [44, 45]. Once inhaled, the conidia transforms within hours into the parasitic yeast phase [18, 46]. Even though neutrophils emigrate early into infected foci of the lungs, these defense cells are fungistatic, not fungicidal, against Histoplasma capsulatum [47]. Macrophages and dendritic cells are the principal effector cells in host resistance to this fungus [44, 46], with a dual role in host defense for macrophages. H. capsulatum is able to replicate in macrophages until T cells will be activated, so the first role is to contain the yeast. The second role comes after cellular activation when several endogenous cytokines are released (IL-12, IFN-γ, TNF-α, and GM-CSF) and macrophages inhibit intracellular growth and harbor H. capsulatum, with granulomas formation [48, 49]. It is a protective mechanism to annihilate this fungus but also a repository for H. capsulatum that could lead to reactivation [48, 49]. Like tuberculosis, there is an early transport to regional lymph nodes with formation of a primary complex.

The link between innate and adaptive immunity is represented by dendritic cells that reside in the lung, as they are more potent than alveolar macrophages as antigenpresenting cells [50]. Dendritic cells have fungicidal activity and after phagocytosis will present H. capsulatum antigen to T cells, once they leave the tissues and travel to the lymph nodes. That generates the phase of adaptive immunity with lymphocyte proliferation and induction of cell-mediated immunity [51, 52]. T cells are crucial in clearance of H. capsulatum and this major implication is demonstrated by several experimental studies [53, 54]. Both CD4+ cells and CD8+ cells are necessary to induce a robust immune response [52, 55]. The adaptive immune response can either clear the organism of fungus or lead to granuloma formation. If the latter occurs, there is the potential for reactivation of the yeast. Reactivation is a response to impaired immunity. The primary contribution of T cells to host defense is the release of cytokines (IFN-γ, TNF-α, and GM-CSF) that will activate mononuclear phagocytes in order to control the infection.

HIV-infected patients are the perfect hosts for histoplasmosis especially in the late stage of AIDS. Depletion of CD4+ T cells and qualitative CD4+ T-cell dysfunction independent of T-cell depletion are the main mechanism that explains the increased susceptibility of these patients to opportunistic infections [56, 57]. Also, HIV decreases the circulating pool of effector and memory CD8+ T-cells that are able to combat viral infection with a final goal to enable CD8+ T-cell function [58]. In HIV patients, the depletion of T cells and their impaired activity are associated with lower level of cytokines such as IFN-γ and TNF-α that allow progressive disseminated histoplasmosis with increased fungal burden and mortality [44].

Macrophages resist HIV-1 infection much better than CD4+ T cells [59], but they have impaired activity against H. capsulatum [18, 44]. They bind fewer yeasts than cells from uninfected individuals as the HIV glycoprotein 120 envelope is responsible for this inhibition. A direct correlation is described between the CD4+ T-cell count and the capacity of macrophages to bind yeast cells. Once engulfed, yeasts grow more rapidly within macrophages from HIV-infected persons than in non-infected [44], and macrophages are not able to perform de second part of their defense in order to destroy H. capsulatum [60]. With a default immune response, macrophages cannot sterilize the infection, and dormant fungi from granuloma will be prone to reactivate.

The common histopathologic profile in HIV/AIDS co-infected patients with H. capsulatum is lack of organized inflammatory response with massive influx of macrophages and scarce number of lymphocytes. Thus, well-defined granulomas are infrequently present [61].
