Chronic Infection and Reactivation in a Pulmonary Challenge Model of Histoplasmosis

Durkin, Michelle; Köhler, Stephan; Schnizlein-Bick, Carol T.; LeMonte, Ann M.; Connolly, Patricia; Goldberg, Jay; Garringer, Todd; Wheat, L. Joseph

doi:10.1086/320720

Cited by 17 publications

(17 citation statements)

References 8 publications

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“…These animals manifested a high burden of infection (Ͼ10 4 to 10 6 CFU) in lungs and spleens for Ͼ3 mo; 50% of them reactivated spontaneously with a fatal outcome (29). In contrast, the fungal burden in C57BL/6 mice before reactivation was Ͻ10 2 CFU/organ and unprovoked reactivation did not transpire during the 98 days of observation.…”

Section: Discussionmentioning

confidence: 99%

B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

Allen

Deepe

2006

The Journal of Immunology

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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-γ, TNF-α, 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 γδ 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.

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Section: Discussionmentioning

confidence: 99%

B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

Allen

Deepe

2006

The Journal of Immunology

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“…Latin American strains were from patients with AIDS from Sao Paulo, Brazil (5). The intratracheal infection model with B6C3F 1 mice used an inoculum of 10 4 yeast cells for survival, 10 3 yeast cells for fungal burden and pathology, and 50 yeast cells for chronic infection, as described previously (2,4). Briefly, the inoculum, prepared freshly from frozen yeast and containing single cells or doublets, was introduced intratracheally.…”

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confidence: 99%

“…Chronic disease following infection with 50 yeast cells (4) was unique to the North American strain. Four of ten mice infected with the North American strain died between the 6th and 12th months, and the fungal burden remained high in the six survivors (Fig.…”

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confidence: 99%

Pathogenic Differences between North American and Latin American Strains of Histoplasma capsulatum var. capsulatum in Experimentally Infected Mice

Durkin¹,

Connolly²,

Karimi³

et al. 2004

J Clin Microbiol

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“…Although the isolate from the laryngeal lesion was not preserved for this study, the genetic relationship between the ITS regions of the isolate and of the laryngeal lesion has clearly established the recurrent nature of infection. Recurrent histoplasmosis is rare even in AIDS patients (4,12). Recurrence or reactivation of histoplasmosis has been reported for patients with antifungal therapy of inadequate duration and dosage (1, 2, 9, 10, 13).…”

Section: Case Reportmentioning

confidence: 99%

Molecular Evidence of Recurrent Histoplasmosis with 9-Year Latency in a Patient with Addison's Disease

et al. 2005

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We present a case of fatal histoplasmosis in a patient with Addison's disease and long-term use of corticosteroid. The patient acquired Histoplasma capsulatum in China and initially presented with a laryngeal mass. He developed fulminant pneumonia and respiratory failure 9 years later. Nucleotide sequences of internal transcribed spacer regions of rRNA genes of the H. capsulatum isolate recovered from biopsied lung tissue and of the extracted fungal DNA from the laryngeal lesion were identical, indicating the recurrent nature of infection. CASE REPORTAn 86-year-old male retired engineer from Taiwan was a heavy smoker. Before his retirement in 1983, he visited several countries in Asia, including Indonesia, Thailand, and Saudi Arabia. After his retirement, he continued to live in Taiwan but visited mainland China every 2 to 3 years. Addison's disease was diagnosed in 1992, and he began lifelong corticosteroid treatment (7.5 mg every day). Pulmonary tuberculosis was diagnosed in 1993, and he remained well after a 9-month course of antituberculosis agents. A laryngeal tumor was found in 1994, and culture of the laryngeal tissue grew Histoplasma capsulatum. A chest radiograph showed no active lung lesions. Surgical removal of the laryngeal mass was performed, and ketoconazole (400 mg every day) was given for 2 months postoperatively. No evidence of recurrence of histoplasmosis was found thereafter.In early December 2002, a progressive cough with yellowish sputum developed 3 weeks after he returned from a 1-month visit to China. He did not have fever, dyspnea, or sore throat. A chest radiograph taken after arrival at the emergency department on 3 January 2003 showed bilateral pneumonia with multiple cavities (Fig. 1A). Gram-and acid-fast-stained smears of sputum collected on 5 January 2003 were negative for significant pathogens. Recurrence of tuberculosis was suspected, and empirical treatment with antituberculosis agents (isoniazid, rifampin, ethambutol, and pyrazinamide) was administered. However, aggravated dyspnea and intermittent fever (up to 38.2°C) occurred despite therapy with these agents. His white blood cell count was 10.50 ϫ 10 9 /liter (neutrophils, 92.0%; lymphocytes, 2.3%). Intravenous ampicillin/sulbactum (1.5 g every 6 h) was added. Chest computed tomography showed multiple ill-defined consolidations and cavitations in all of the lobes of both lungs and absence of mediastinal lymphadenopathy. Transthoracic lung aspiration and a biopsy were performed on 7 February. Pathology study showed many budding yeasts within and outside the histiocytes (Fig. 1B). Recurrent histoplasmosis with severe pneumonia was suspected. No abnormality was found other than the previously excised laryngeal lesion. A Gram-stained smear of the sputum specimen collected on 5 January 2003 was rechecked, and many unstained yeasts with hyphae were found (Fig. 1C). Cultures of sputum specimens and the biopsied lung tissue both grew H. capsulatum 10 days after inoculation.Amphotericin B (30 mg/day) was started on 10 February 2003 but...

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Chronic Infection and Reactivation in a Pulmonary Challenge Model of Histoplasmosis

Cited by 17 publications

References 8 publications

B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

Pathogenic Differences between North American and Latin American Strains of Histoplasma capsulatum var. capsulatum in Experimentally Infected Mice

Molecular Evidence of Recurrent Histoplasmosis with 9-Year Latency in a Patient with Addison's Disease

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