Wild-type Puumala hantavirus infection induces cytokines, C-reactive protein, creatinine, and nitric oxide in cynomolgus macaques

Abstract

Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Approximately 200,000 cases are reported annually, and there is to date no specific treatment available. A major obstacle in studying the medical aspects of HFRS and HPS has been the lack of an adequate animal model. Here we show that infection of cynomolgus macaques by wild-type Puumala hantavirus resulted in typical signs of HFRS including lethargy, anorexia, proteinuria, and/or hematuria, in addition to cytokine (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), C-reactive protein, creatinine, and nitric oxide responses. Viral RNA was detected in plasma from days 3 to 7 postinoculation until days 24 to 28 postinoculation, infectious virus was recovered, and the virus-specific immune responses (immunoglobulin M [IgM], IgG, and neutralizing antibodies) mimicked those seen in humans. The results indicated that the monkey model will provide a valuable tool for studies of pathogenesis, candidate vaccines, and antivirals for hantavirus disease.

FIG. 1.

Temperature curve of monkey 59 infected by wild-type PUUV. Temperature was measured in the ear after anesthetization.

FIG. 2.

Clinical chemistry of monkeys infected by wild-type PUUV. (A) Plasma CRP; (B) plasma creatinine; (C) NO.

FIG. 3.

(A) Kinetics of IgM and IgG responses in monkeys infected by wild-type PUUV as determined by ELISA. (B) Kinetics of neutralizing antibody responses as determined by focus reduction neutralization assay (FRNT).

FIG. 4.

Kinetics of cytokine responses in monkeys after infection by wild-type PUUV. Cytokines were measured in sequentially drawn serum or plasma samples. (A) Serum IL-1β; (B) serum IL-6; (C) serum IL-10; (D) plasma IFN-α; (E) serum IFN-γ; (F) plasma TNF-α; (G) serum IL-12. The lower limit of detection for each assay is indicated by a baseline (test values lower than the lower limit of detection are indicated at the baseline).