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Title: DEPLETION OF LYMPHOCYTES AND DIMINISHED CYTOKINE PRODUCTION IN MICE INFECTED WITH A HIGHLY VIRULENT INFLUENZA A (H5N1) VIRUS ISOLATED FROM HUMANS

Author
item Tumpey, Terrence
item KATZ, JACQUELINE - CENTERS FOR DIS CONTROL
item LU, XIUHUA - CENTERS FOR DIS CONTROL
item MARKEN, TIMOTHY - CENTERS FOR DIS CONTROL
item ZAKI, SHERIF - CENTERS FOR DIS CONTROL

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2000
Publication Date: 7/1/2000
Citation: N/A

Interpretive Summary: In 1997 in Hong Kong, avian influenza A (H5N1) viruses were identified as the cause of 18 cases of human respiratory illness, including six deaths. The H5N1 virus infections in humans resulted in a spectrum of clinical disease, ranging from mild respiratory symptoms to respiratory failure and death. The question is why some of the Hong Kong H5N1 isolates are lethal, whereas others are not. Experiments were performed in mice to compare two H5N1 viruses of varying lethality for their ability to reduce the number of circulating white blood cells. It was found that infection of mice with a lethal virus (A/Hong Kong/483/97), but not a non-lethal virus (A/Hong Kong/486/97) resulted in a significant decrease in the total number of circulating leukocytes detected in mouse blood. The identification of mechanism(s) by which influenza H5N1 viruses cause disease and death in humans could lead to the development of effective vaccines directed to such hlethal viruses.

Technical Abstract: To compare H5N1 viruses of varying pathogenicity for their ability to alter the mammalian immune system, mice were infected with either A/Hong Kong/483/97 (HK/483; lethal) or A/Hong Kong/486/97 virus (HK/486; nonlethal) and monitored for lymphocyte depletion in the blood, lung 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 post-infection. Differential blood counts demonstrated up to an 80 percent 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 compared with HK/486 infected mice. Evidence of apoptosis in the spleen and lung of HK/483 infected mice was detected , 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.