| Summary: | Group B coxsackieviruses (CVB) are etiological agents of a febrile
exanthematous disease that may be complicated by viral myocarditis, pancreatitis, and
encephalitis. CVB infections are notable for being extremely severe in the very young
compared to adult hosts. Preliminary work in mice has shown that macrophages
contribute to host resistance to CVB3, since depletion of macrophages in vivo resulted in
a more exacerbated infection. Based on this finding, the overall objective of this study
was to dissect the specific properties of macrophages which participated in resistance
against CVB3 and to compare them between young and adult CD-I mice. It was found
that macrophages from young CD-I mice were less efficient in inactivating CVB3 in
vitro than adult mice. Comparison of NO production by macrophages from young and
adult CD-I mice in vitro demonstrated that young mice were not impaired in their ability
to produce this antiviral molecule; in fact, the younger animals produced significantly
greater levels of NO following induction by IFN-γ, or LFN- γ plus TNF-α. In conjunction
with this, the importance of NO in CVB3 resistance in vivo was determined by treatment
of young and adult CD-I mice with a NOS enzyme inhibitor, L-NMMA. The resulting
diminished activity of NOS caused a more severe infection in both the young and adult
CD-I mice, with the effects generally more pronounced in the younger animals.
Comparison of TNF-α production by macrophages from young and adult CD-I mice in
vitro showed that the younger animals produced less of the cytokine following induction
by IFN- γ plus LPS. Strain variation was also found in macrophage functions between
CD-I mice and BALB/c mice (the latter being extremely susceptible to CVB3 resulting
in mortality). It was found that virus inactivation by macrophages from young and adult BALB/c mice was markedly different, with macrophages from the younger mice being
permissive to viral replication. In addition, TNF-α was produced in greater quantities by
macrophages from the young mice, contrary to the results obtained with the CD-I mice.
NO production by macrophages from BALB/c mice, however, followed a similar trend to
the CD-I mice, with the younger animals producing more NO than the older animals.
The mechanism for the extreme susceptibility (and mortality) in the BALB/c may involve
the relatively high levels of TNF-α and NO generated by the younger mice, which may
produce detrimental effects, like shock.
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