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The role of macrophages in the age-dependent susceptibility to coxsackievirus B3 infection Girn, Jaskamal

Abstract

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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