The inflammatory macrophage response to murine cytomegalovirus in genetically susceptible mice

Abstract

Adherent suppressor cells have often been implicated in the depression of immunocompetence following CMV infections. We have reported that high levels of cytostatic macrophages in the peritoneal cavities of infected mice correlate with genetically-based sensitivity to CMV disease, suggesting they may modulate protective immune responses. This study investigates the properties and kinetics of such cells. Genetically-susceptible BALB/c mice infected with MCMV accumulated activated peritoneal macrophages, 7 days post-infection. These cells suppressed 3H-thymidine-incorporation and lymphokine production in syngeneic lymphocyte cultures and hence appeared to have depressed accessory cell function, although interleukin-1 production and the capacity to take up colloidal gold were enhanced. The cytostatic activity was located in a low density fraction (1.05 g/ml), which was expanded by MCMV infection. The lowest density cells had higher frequencies of infection but the proportion of cells releasing virus (less than 0.2%) was below the proportion activated, as shown by the shift in the density profile or enhanced colloidal gold uptake. A comparable accumulation of cytostatic activated peritoneal macrophages occurred in mice treated with cyclosporine A, but nude mice showed macrophage activation without cytostasis, so the role of T cells is not resolved. The spleens of infected mice maintaining high levels of virus in this organ atrophied, and the remaining cells were unable to proliferate in culture. In contrast, mice clearing the virus developed splenomegaly and restricted responsiveness, which may be governed by cytostatic cells equivalent to those in the peritoneal cavity. The spread of virus to the lymph nodes was limited and MCMV-primed cells were readily demonstrable.

Depression of humoral responses by murine cytomegalovirus infection

“…Responses to Con-A and LPS were depressed in proportion to the duration of infection, as observed in our earlier studies (9). Priming with OA-AI(OH)3 increased responses to LPS and slightly depressed responses to Con-A relative to those produced by mice given PVP (Table 9), or no antigen (9). This may be associated with the A1(OH)3 adjuvant and did not influence the depressive effect of MCMV infection.…”

“…As this study was confined to responses recorded on day 8, IgG levels followed the trends described by IgM, and are therefore not shown. Responses to Con-A and LPS were depressed in proportion to the duration of infection, as observed in our earlier studies (9). Priming with OA-AI(OH)3 increased responses to LPS and slightly depressed responses to Con-A relative to those produced by mice given PVP (Table 9), or no antigen (9).…”

“…data). From our studies of the capacity of lymphocytes from infected mice to respond to proliferative stimuli in vitro (8,9), viral replication in macrophages and the associated loss of accessory cell function may contribute to the ablation of splenic cell responsiveness seen in severe infections. The infection of endothelial cells in such animals may also compromise lymphocyte trapping in the spleen, leading to atrophy.…”

Adrenalitis and the adrenocortical response of resistant and susceptible mice to acute murine cytomegalovirus infection

“…with a second peak on day 7, but have not yet completed comparative studies. Both cytokines have been detected in BALB/c serum at this time, with TNF declining to baseline levels by day 3 ( [27,32]; S. Yerkovich et al, submitted). However, we were unable to prevent death of AG-treated mice by administering soluble TNF or IL-1 receptors, as would be required to establish that rapid down-regulation of these cytokines was critical for survival and mediated by corticosteroids.…”

“…[3,4]. Damage to the spleen of BALB/c mice occurs in a context of high levels of viral replication, largely in the stromal cells, with a clear potential for impeding the trapping of recirculating cells leading to splenic atrophy [27]. In contrast, less than 1% of cells in the thymus and bone marrow are infected, so damage to the stroma cannot directly explain a loss of up to 80% of cells from these sites.…”