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Journal of Virology, July 2000, p. 6105-6116, Vol. 74, No. 13
0022-538X/00/$04.00+0

Depletion of Lymphocytes and Diminished Cytokine Production in Mice Infected with a Highly Virulent Influenza A (H5N1) Virus Isolated from Humans

Terrence M. Tumpey,1,dagger Xiuhua Lu,1 Timothy Morken,2 Sherif R. Zaki,2 and Jacqueline M. Katz1,*

Influenza Branch1 and Infectious Disease Pathology Activity,2 Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 30333

Received 27 January 2000/Accepted 21 March 2000

Previously, we observed that several virulent influenza A (H5N1) viruses which caused severe or fatal disease in humans were also lethal in BALB/c mice following dissemination of the virus to solid organs, including the brain. In contrast, one particular human H5N1 virus was nonlethal in mice and showed no evidence of systemic spread. To compare H5N1 viruses of varying pathogenicity for their ability to alter the mammalian immune system, mice were infected with either influenza A/Hong Kong/483/97 (HK/483) (lethal) or A/Hong Kong/486/97 (HK/486) (nonlethal) virus and monitored for lymphocyte depletion in the blood, lungs, and lymphoid tissue. Intranasal infection with HK/483 resulted in a significant decrease in the total number of circulating leukocytes evident as early as day 2 postinfection. Differential blood counts demonstrated up to an 80% drop in lymphocytes by day 4 postinfection. In contrast, nonlethal HK/486-infected mice displayed only a transient drop of lymphocytes during the infectious period. Analysis of lung and lymphoid tissue from HK/483-infected mice demonstrated a reduction in the number of CD4+ and CD8+ T cells and reduced synthesis of the cytokines interleukin-1beta and gamma interferon and the chemokine macrophage inflammatory protein compared with HK/486-infected mice. In contrast, the cytokine and chemokine levels were increased in the brains of mice infected with HK/483 but not HK/486. Evidence of apoptosis in the spleen and lung of HK/483-infected mice was detected in situ, suggesting a mechanism for lymphocyte destruction. These results suggest that destructive effects on the immune system may be one factor that contributes to the pathogenesis of H5N1 viruses in mammalian hosts.

* Corresponding author. Mailing address: Influenza Branch, Mailstop G-16, DVRD, NCID, Centers for Disease Control and Prevention, 1600 Clifton Rd., N.E., Atlanta, GA 30333. Phone: (404) 639-3591. Fax: (404) 639-2334. E-mail: jmk9{at}cdc.gov.

dagger Present address: Southeast Poultry Research Laboratory, U.S. Department of Agriculture, Athens, Ga.

Journal of Virology, July 2000, p. 6105-6116, Vol. 74, No. 13
0022-538X/00/$04.00+0


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