Roles of alveolar macrophages in defense against experimental pulmonary infection of mice with murine cytomegalovirus

Time course of virus load in lungs following an intratracheal inoculation o f BALB/c mice with murine cytomegalovirus was divided into 4 distinct phase s. Virus titer decreased exponentially until 18 h post infection (p.i) (pha se I); it increased from 24 h p.i. up to the highest level at 48 h p.i. (ph ase II); thereafter, it remained apparently unchanged at the high level (pl ateau) until 10 d-14 d p.i. (phase III); it decreased slowly to undetectabl e level by 24 d-28 d p.i. (phase IV). One of the features unique to the pul monary infection was the presence of phase III, during which virus had alre ady been cleared from the spleen. Another unique feature was that the level of virus titer in phase III depended on viral inoculation dose. Depletion of alveolar macrophages prior to virus inoculation by intratracheal adminis tration of the liposomes enclosing dichloromethylene diphosphonate resulted in a slow decrease of virus titer in phase I, no change in the rate of the increase in virus titer in phase II, and a higher plateau of virus titer t han the plateau in undepleted mice in phase III. These results suggest that alveolar macrophages take up the inoculated virions as scavengers (phase I ), leading to a limited size of pulmonary infection (phase III) by reducing the number of initially infected cells. When alveolar macrophages were dep leted at varying times between 18 h p.i. and 10 d p.i., virus titer in phas e III increased relative to controls but after a lag of 24 days. Assuming t hat murine cytomegalovirus spreads by a direct cell-to-cell transfer, we su ggest that alveolar macrophages interfere indirectly with the virus product ion in phase TIT by infected cells, serving as a host-defense factor which prevents a progressive increase in virus load in phase III. The clearance o f virus from the lungs (phase IV) is mediated by T lymphocytes (Kimura et a l, Biomed. Res. 21, 111-115, 2000). We suggest that, in defense against pul monary infection with such an intermediately cytotoxic virus as MCMV, a non specific defense factor with a low tissue-toxicity like macrophages plays m ore important role than an antigen-specific defense factor like T cells, in order to avoid a life-threatening dysfunction of exchanging gas due to the damage of lung tissue caused by long-lasting inflammation. The present res ults are consistent with the concept of organ-specific mechanism of defense against viral infection.