**4. Pathogenesis**

In most cases, the onset of infection occurs *via* inhalation of airborne microconidia or mycelial fragments of *H. capsulatum* [133]. The portal of entry are the lungs, the fungus bypassing the innate defenses of the host (muco-ciliary clearance, nasal and pharyngeal mucus, and pulmonary surfactant) and reaching the terminal bronchioles and pulmonary alveoli [54].

Shortly after it was inhaled, triggered by the body temperature, it undergoes the dimorphic switching to the budding yeast form within hours and is deposited in macrophages [64].

It may happen that the conidia enter the alveolar macrophages and become yeast there, or the transition occurs first and then the yeast enters the macrophages.

Fungus internalization into the macrophages is determined by a couple of specific immune evasive mechanisms: i.) Histoplasma maximizes macrophages recognition through heat shock protein 60 kDa (HSP60), which mediates the fungal detection and binding by the CD18 integrin family of receptors, on the surface of the macrophages [62, 64]. ii.) Concomitantly, *H. capsulatum* minimizes detection of immunostimulatory β-glucans by Dectin-1 receptors of dendritic cells both by synthetizing an α-(1,3)-glucan layer covering its β-glucans upper layer and by secreting endoglucanase, which enzymatically removes the remained uncovered, still exposed β-glucans. Once internalized, *H. capsulatum* resides in the phagosome compartment without fusing with the lysosome, displaying several pathogenic mechanisms, and thus blocking normal phagosome maturation process in macrophages One of these mechanisms consists in alkalinization of the phagosome and phagolysosome, maintaining the pH between 6.0 and 6.5, which both inhibit the normal function of lysosomal hydrolases and maximize iron acquisition from the host transferrin. Other required strategies for growing and proliferation within nutrient-depleted phagosome compartment are the following: expressing antioxidant enzymes (superoxide dismutase 3 Sod3 and catalase B CatB) that eliminate reactive oxygen intermediates [63, 134], expressing enzymes involved in gluconeogenesis for providing energy and glucans, using amino acids as carbon, nitrogen, and sulfur sources, acquisition of essential vitamins, and trace metals (iron, zinc, and copper) [134].

Thereby, macrophages are not only ineffective in neutralizing *H. capsulatum* yeast but, on the contrary, serve the pathogen by creating a hospitable intracellular niche, in which it can unabatedly multiply and survive [62]. The intracellular deposition and proliferation of the fungus varies, depending on the yeast elements and the host cells; at some point, the multiplied yeast cells destroy the macrophage and are ingested both by new other alveolar macrophages and by other phagocytic cells recruited at the site of infection [135].

During the next 2 weeks after inhalation, when specific immunity develops [136], macrophages also act as vehicles, initially in spreading the fungus to hilar and mediastinal lymph nodes and later in hematogenous dissemination of infection to multiple organs [137].

Besides the macrophages, which are the main host cells for *H. capsulatum* [64], other host defense cells, including dendritic cells and neutrophils, are recruited at the locus of infection and interact with the fungus [62].

By releasing their azurophilic granule contents, neutrophils can inhibit *H. capsulatum* growth. In the case of a small inoculum, it has been hypothesized that this fungistatic activity of neutrophils could be sufficient to cleanse the host, without triggering the subsequent mechanisms of the adaptive immune response [138].

Dendritic cells engulf some yeast cells, *via* fibronectin receptors, and are capable to kill them, thus releasing nucleic acids of the destroyed yeasts, and recovering presentable antigens [62].

These immune responses combined with dendritic cells production of proinflammatory TNF, IL-6, IL-12, and type I interferons (IFN-I) stimulate activation of CD4+ lymphocytes [62, 139]. Once activated, this specific adaptive immune response can either clear the infection or cause the formation of epithelioid granulomas [54], with later evolution toward fibrosis and calcification, mimicking tuberculosis [97].

Like Mycoplasma tuberculosis, *H. capsulatum* could remain dormant, in a quiescent state in this fibrotic tissue, even for decades, and reactivate when cellmediated immunity is impaired by other diseases or immunosuppressive therapies [54, 68, 97].

## *Epidemiology of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110901*

Additionally, in situations where T helper lymphocytes are low or even absent, as might be found in severely immunosuppressed patients, dendritic cells can activate CD8+ cells, by cross-presenting them *H. capsulatum* antigen acquired from apoptotic macrophages [140]. In these cases, the granuloma formation is almost absent, the proliferation of macrophages occurring in the tissues, and the patients tend to develop progressive, disseminated form of disease [97].

Although humoral immunity has an unclear role in the pathogenesis of histoplasmosis, depletion of B cells has nevertheless been shown to increase the severity of histoplasmosis, while experimental treatments with monoclonal antibodies to *H. capsulatum* surface antigens have been beneficial in disease evolution in mice [16].

In conclusion, T lymphocytes and phagocytes are essential cellular elements of *H. capsulatum* pathogenesis, the outcome of infection being orchestrated by the dynamics between innate and adaptive host responses and yeast virulence factors [61, 141].
