Article
Proinflammatory
response during Ebola virus infection of primate models: possible
involvement of the tumor necrosis factor receptor superfamily.
Pathology Division, US Army Medical Research Institute of Infectious
Diseases (USAMRIID), Attn: MCMR-UIP-D, 1425 Porter Street, Fort Detrick,
MD 21702-5011, USA.
Immunology Letters (Impact Factor: 2.34). 03/2002; 80(3):169-79. DOI: 10.1016/S0165-2478(01)00327-3
ABSTRACT
Ebola virus (EBOV) infections are characterized by dysregulation of
normal host immune responses. Insight into the mechanism came from
recent studies in nonhuman primates, which showed that EBOV infects
cells of the mononuclear phagocyte system (MPS), resulting in apoptosis
of bystander lymphocytes. In this study, we evaluated serum levels of
cytokines/chemokines in EBOV-infected nonhuman primates, as possible
correlates of this bystander apoptosis. Increased levels of interferon
(IFN)-alpha, IFN-beta, interleukin (IL)-6, IL-18, MIP-1alpha, and
MIP-1beta were observed in all EBOV-infected monkeys, indicating the
occurrence of a strong proinflammatory response. To investigate the
mechanism(s) involved in lymphoid apoptosis, soluble Fas (sFas) and
nitrate accumulation were measured. sFas was detected in 4/9 animals,
while, elevations of nitrate accumulation occurred in 3/3 animals. To
further evaluate the potential role of these factors in the observed
bystander apoptosis and intact animals, in vitro cultures were prepared
of adherent human monocytes/macrophages (PHM), and monocytes
differentiated into immature dendritic cells (DC). These cultures were
infected with EBOV and analyzed for cytokine/chemokine induction and
expression of apoptosis-related genes. In addition, the in vitro EBOV
infection of peripheral blood mononuclear cells (PBMC) resulted in
strong cytokine/chemokine induction, a marked increase in lactate
dehydrogenase (LDH) activity, and an increase in the number of apoptotic
lymphocytes examined by electron microscopy. Increased levels of sFAS
were detected in PHM cultures, although, <10 by="" cells="" contrast="" immunohistochemistry.="" in="" of="" positive="" the="" were="">90% of EBOV-infected
PHM were positive for tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL) by immunohistochemistry, RNA analysis,
and flow cytometry. Inactivated EBOV also effected increased TRAIL
expression in PHM, suggesting that the TNF receptor superfamily may be
involved in apoptosis of the host lymphoid cells, and that induction may
occur independent of viral replication. In further studies with
infected PHM, expression of MHC II was remarkably suppressed after 6
days, an additional correlate of immunological dysregulation. In
conclusion, our findings suggest that infection of mononuclear
phagocytes is critical, triggering a cascade of events involving
cytokines/chemokines and oxygen free radicals. It is the consequence of
these events rather than direct viral infection that results in much of
the observed pathology. Identification of cytokine/chemokine, nitric
oxide, and reactive oxygen species involvement in the observed filoviral
pathogenesis may lend insight into the rational design of therapeutic
countermeasures of filoviral pathogenesis.
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