Intrapulmonary response to Histoplasma capsulatum in gamma interferon knockout mice

Abstract

We examined the immunobiological responses to Histoplasma capsulatum in lungs of gamma interferon (IFN-␥) knockout mice (GKO mice). Naive GKO mice succumbed by day 9 to intranasal challenge with 2.5 ؋ 10 6 yeasts, whereas all wild-type (WT) mice survived for 45 days. Compared to lungs of WT mice, the lungs of acutely infected GKO mice exhibited dramatically elevated numbers of CFU in lungs and significantly higher levels of tumor necrosis factor alpha (TNF-␣) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not interleukin-12 (IL-12) or IL-4. To determine if IFN-␥ is necessary in reexposure histoplasmosis, GKO and WT mice were inoculated with 10 4 yeasts intranasally and given amphotericin B for 3 weeks. Six weeks later, mice were rechallenged with 2.5 ؋ 10 6 yeasts. All GKO mice died by day 6, whereas all WT mice survived for 45 days. Lungs of GKO mice contained substantially elevated numbers of CFU and higher TNF-␣ and GM-CSF levels but not IL-12 or IL-4. Thus, IFN-␥ is requisite for control of pulmonary histoplasmosis in naive and reexposed mice.

Histoplasma capsulatummanifests preferential invasion of phagocytic subpopulations in murine lungs

“…Activation of adaptive immunity generally develops after 7 days of nonlethal pulmonary infection with H. capsulatum [31,32]. These studies were also limited to 7 days, as neutralization of TNF-␣ and IFN-␥ leads to the demise of animals between Days 8 and 14 of infection [7,14]; thus, comparisons between cytokine-deficient and cytokine-sufficient mice could only take place during the first week to avoid analysis of moribund animals.…”

Helper T‐cell responses and pulmonary fungal infections

“…Innate cytokine production is also important in early control of infection, as the neutralization of granulocyte–macrophage colony‐stimulating factor (GM‐CSF) results in an order of magnitude higher fungal burden in the lungs by 1 week post infection . Ablation of GM‐CSF also impairs the early production of tumour necrosis factor‐ α (TNF‐ α ) and IFN‐ γ , two cytokines that are likewise critical for the control of H. capsulatum infection . CCR2‐dependent inflammatory cell recruitment is also crucial for early control of infection, as CCR2 −/− mice show a significant increase in lung fungal burden by 7 days post infection, which involves tilting T helper cell immunity away from Th1 responses.…”

“…Numerous studies have demonstrated that Th1 responses are protective against H. capsulatum infection . Mice deficient in IFN‐ γ signalling are exquisitely susceptible to experimental H. capsulatum infection, dying in little more than a week after experimental infection . In immunocompetent mice, the kinetics of IFN‐ γ production from CD4 T cells correlates well with the clearance of the fungus from the lungs .…”

Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis

“…The mechanism that underlies this ability is unknown, but transcriptional analysis of RNS‐treated yeasts identified 59 genes that are up‐regulated in response to nitrosative stress . Cytokine activation of phagocytes stimulates RNS production, and reduced pro‐inflammatory cytokine levels are correlated with increased susceptibility of mice to H. capsulatum infection . These data suggest that RNS control H. capsulatum yeast, but that RNS‐based control functions during the adaptive immunity stage of infection rather than the initial infection of phagocytes.…”