Pathogenesis and immune responses in gnotobiotic calves after infection with the genogroup ii.4-hs66 strain of human norovirus
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2008-02
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We previously characterized the pathogenesis of two host-specific bovine enteric caliciviruses (BEC), the
GIII.2 norovirus (NoV) strain CV186-OH and the phylogenetically unassigned NB strain, in gnotobiotic (Gn)
calves. In this study we evaluated the Gn calf as an alternative animal model to study the pathogenesis and host
immune responses to the human norovirus (HuNoV) strain GII.4-HS66. The HuNoV HS66 strain caused
diarrhea (five/five calves) and intestinal lesions (one/two calves tested) in the proximal small intestine (duo-
denum and jejunum) of Gn calves, with lesions similar to, but less severe than, those described for the Newbury
agent 2 (NA-2) and NB BEC. Viral capsid antigen was also detected in the jejunum of the proximal small
intestine of one of two calves tested by immunohistochemistry. All inoculated calves shed virus in feces (five/five
calves), and one/five had viremia. Antibodies and cytokine (proinflammatory, tumor necrosis factor alpha
[TNF-␣]; Th1, interleukin-12 [IL-12] and gamma interferon [IFN-␥]; Th2, IL-4; Th2/T-regulatory, IL-10)
profiles were determined in serum, feces, and intestinal contents (IC) of the HuNoV-HS66-inoculated calves
(n ⴝ 5) and controls (n ⴝ 4) by enzyme-linked immunosorbent assay in the acute (postinoculation day 3 [PID
3]) and convalescent (PID 28) stages of infection. The HuNoV-HS66-specific antibody and cytokine-secreting
cells (CSCs) were quantitated by ELISPOT in mononuclear cells of local and systemic tissues at PID 28.
Sixty-seven percent of the HuNoV-HS66-inoculated calves seroconverted, and 100% coproconverted with
immunoglobulin A (IgA) and/or IgG antibodies to HuNoV-HS66, at low titers. The highest numbers of
antibody-secreting cells (ASC), both IgA and IgG, were detected locally in intestine, but systemic IgA and IgG
ASC responses also occurred in the HuNoV-HS66-inoculated calves. In serum, HuNoV-HS66 induced higher
peaks of TNF-␣ and IFN-␥ at PIDs 2, 7, and 10; of IL-4 and IL-10 at PID 4; and of IL-12 at PIDs 7 and 10,
compared to controls. In feces, cytokines increased earlier (PID 1) than in serum and TNF-␣ and IL-10 were
elevated acutely in the IC of the HS66-inoculated calves. Compared to controls, at PID 28 higher numbers of
IFN-␥ and TNF-␣ CSCs were detected in mesenteric lymph nodes (MLN) or spleen and Th2 (IL-4) CSCs were
elevated in intestine; IL-10 CSCs were highest in spleen. Our study provides new data confirming HuNoV-HS66
replication and enteropathogenicity in Gn calves and reveals important and comprehensive aspects of the
host’s local (intestine and MLN) and systemic (spleen and blood) immune responses to HuNoV-HS66.
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SOUZA, M.; AZEVEDO, M. S. P.; JUNG, K.; CHEETHAM, S.; SAIF, L. J. Pathogenesis and immune responses in gnotobiotic calves after infection with the genogroup ii.4-hs66 strain of human norovirus. Journal of Virology, Washington, v. 82, n. 4, p. 1777-1786, Nov. 2008.