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Cryptococcus neoformans var. grubii isolates recovered from persons with AIDS demonstrate a wide range of virulence during murine meningoencephalitis that correlates with the expression of certain virulence factors

Cornelius J. Clancy^1,3,

M. Hong Nguyen^1,3,

¹ Department of Medicine, Division of Infectious Diseases, University of Florida College of Medicine, FL, USA
² Department of Pathology, University of Florida College of Medicine, FL, USA
³ VA Medical Center, Gainesville, FL, USA
⁴ University of Texas Health Science Center, and the Audie Murphy Memorial Hospital, San Antonio, TX, USA

Correspondence
Cornelius J. Clancy
clancyn{at}medicine.ufl.edu

Cryptococcus neoformans is a common cause of meningoencephalitis among AIDS patients. Several C. neoformans virulence factors have been identified, but the relative importance of particular factors is unknown. This study examined the corrrelation of the virulence of 18 C. neoformans var. grubii isolates from AIDS patients with the expression of several well-described virulence factors. The LD₅₀ at 15 days after intracranial inoculation of ICR mice was <100 c.f.u. for 22 % of isolates, 100–1000 for 28 %, 1000–10 000 for 11 % and >20 000 for 39 %. Higher cryptococcal concentrations in brains were noted for isolates with lower LD₅₀ (P=0.002). In survival studies, no immunocompetent BALB/c mice (nu/–) infected with 3xLD₅₀ of three virulent isolates (LD₅₀=62, 99, 1280) survived beyond 23 days, whereas 100 %, 90 % and 90 % of mice infected with 20 000 c.f.u. of three hypovirulent isolates (LD₅₀>20 000) survived for 60 days (P<0.0001). Even among BALB/c nude (nu/nu) mice, survival rates over 60 days were 100 %, 70 % and 50 %, respectively, for the hypovirulent isolates. Growth rate at 37 °C and capsule size within brains correlated with LD₅₀ by univariate (P=0.0001 and 0.028, respectively) and multivariate (P=0.017 and 0.016, respectively) analyses. There was no correlation between LD₅₀ and capsule size in vitro, phospholipase activity, melanin formation, proteinase activity and fluconazole MIC. In conclusion, AIDS patients are susceptible to infection by C. neoformans isolates of wide-ranging virulence, including isolates that are markedly hypovirulent. The virulence of a given isolate reflects a composite of factors rather than the contribution of a dominant factor. Growth at 37 °C and capsule size in vivo make particularly important contributions.

These authors contributed equally to this work.