Robust Th1 and Th17 Immunity Supports Pulmonary Clearance but Cannot Prevent Systemic Dissemination of Highly Virulent Cryptococcus neoformans H99

Abstract

The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. In contrast, the IL-4/13 ؊/؊ mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activation of macrophages. The development of a robust Th1/Th17 response and classical activation of macrophages resulted in significant containment of H99 in the lungs of IL-4/13 ؊/؊ mice compared with unopposed growth of H99 in the lungs of wild-type mice. However, IL-4/13 ؊/؊ mice showed only 1-week longer survival compared with wild-type mice. The comparison of brain and spleen cryptococcal loads at weeks 2, 3, and 4 postinfection revealed that the systemic dissemination in IL-4/13 ؊/؊ mice occurred with an approximate 1-week delay but subsequently progressed with similar rate as in the wild-type mice. Furthermore, wild-type and IL-4/13 ؊/؊ mice developed equivalently severe meningitis/encephalitis at the time of death. These data indicate that the Th2 immune bias is a crucial mechanism for pulmonary virulence of H99, whereas other mechanisms are largely responsible for its central nervous system tropism and systemic dissemination.

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

“…Visual inspection of cytospins prepared from sorted populations confirmed that both AMs and ExMs were large cells (12)(13)(14)(15)(16)(17)(18) m) with abundant cytoplasm and round/oval nuclei ( Figure 1D). AMs displayed largely smooth cell membranes and contained few intracellular vacuoles.…”

TLR9 Signaling Is Required for Generation of the Adaptive Immune Protection in Cryptococcus neoformans-Infected Lungs

“…In contrast, alternatively activated macrophages (AAM) harbor C. neoformans. 11,[32][33][34] Generation of CAM/AAM has been postulated to be regulated by Th1/Th2 bias; 11,22,23,30,33,35 however, differential activation of macrophages can also occur in response to other factors, such as stimulation of toll-like receptors (TLRs) by microbial products. 36,37 TLRs have been found to be critical for immune recognition and clearance of viral, bacterial, protozoan, and fungal pathogens.…”

Regulating the T-Cell Immune Response Toward the H99 Strain of Cryptococcus neoformans

“…6 These data led to the hypothesis that if a Th1-mediated immune reaction to C. neoformans strain H99 in the lungs could be achieved, then infected hosts would not develop fatal central nervous system disease. 7,8 In the manuscript by Zhang et al 9 in this issue of American Journal of Pathology, the authors present data contrary to this belief. Using a murine model, Zhang et al 9 substantiated their previous findings that a Th2 immune reaction to C. neoformans strain H99 is responsible for this organism's virulence.…”

“…7,8 In the manuscript by Zhang et al 9 in this issue of American Journal of Pathology, the authors present data contrary to this belief. Using a murine model, Zhang et al 9 substantiated their previous findings that a Th2 immune reaction to C. neoformans strain H99 is responsible for this organism's virulence. Moreover, they established that mice deficient in two Th2 cytokines, IL-4 and IL-13, which lacked a measurable Th2 response to H99 including absence of pulmonary eosinophilia and elevated IgG, switched to a Th1 (as well as Th17) immune response and switched from alternative to classic macrophage activation.…”

“…We can look forward to additional studies such as that presented by Zhang et al 9 to further our understanding (and even lack of understanding) of the Th1/Th2 immune responses, especially as it relates to our future management of infectious diseases.…”