B cells and CD4-CD8- T cells are key regulators of the severity of reactivation histoplasmosis.
The fungus, Histoplasma capsulatum, produces a persistent infection. Reactivation histoplasmosis is largely a result of impaired immunity, but the perturbations associated with escape of the fungus from host defenses remain ill-defined. We analyzed a murine model of reactivation to elucidate the host defects that permit reactivation. C57BL/6 mice were infected intranasally and, 42 days later, they were depleted of CD4(+) and CD8(+) cells. Elimination of these cells, but not either alone, produced a persistent infection over several weeks. Neutralization of IFN-gamma, TNF-alpha, or both did not induce reactivation. Endogenous IL-10 exacerbated reactivation. Depletion of T cells in B cell(-/-) mice induced a markedly higher burden in organs when compared with wild type. However, the infection remained persistent. Elimination of CD4(+) cells alone or neutralization of cytokines increased the fungal load. The persistent infection was not dependent on gammadelta T cells or NK cells. Elimination of Thy-1.2(+) cells in mice given mAb to CD4 and CD8 transformed reactivation into a progressive, lethal infection in B cell(-/-) and wild-type mice, but the tempo of progression was accelerated in the former. The data reveal the complex control by the host to prevent reactivation of this fungus.
Allen
Holly L
HL
Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Deepe
George S
GS
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D006658:Histoplasma / Q000254:growth & development; D006660:Histoplasmosis / Q000276:immunology* / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000502:physiology; D012008:Recurrence; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D009569:Nitric Oxide