Inhibition of In Vitro Leukocyte Proliferation by Morbilliviruses

Abstract

Immune suppression associated with morbillivirus infections may influence the mortality rate by allowing secondary bacterial infections that are lethal to the host to flourish. Using an in vitro proliferation assay, we have shown that all members of the genus Morbillivirus inhibit the proliferation of a human B-lymphoblast cell line (BJAB). Proliferation of freshly isolated, stimulated bovine and caprine peripheral blood lymphocytes is also inhibited by UV-inactivated rinderpest (RPV) and peste-des-petits ruminants viruses. As for measles virus, coexpression of both the fusion and the hemagglutinin proteins of RPV is necessary and sufficient to induce immune suppression in vitro.Morbillivirus infections induce severe disease in their natural hosts, causing high morbidity and mortality. (3,4). These morbilliviruses infect mammalian hosts, and disease is generally confined to one order of mammals; e.g., MV infects solely primates, while RPV and PPRV naturally infect only Artiodactyla (cloven-hoofed animals), and CDV naturally infects Carnivora (2).Despite widespread use of an effective live attenuated vaccine, MV remains a major killer disease of infants in developing countries, accounting for over 1 million deaths per annum. The main cause of death is secondary bacterial infections that flourish due to MV-induced immunosuppression. Although MV is rapidly cleared from the host, lymphoproliferative responses to mitogens and recall antigens are suppressed for up to several months postinfection. Both B and T subsets of leukocytes are affected, but not the CD4 ϩ /CD8 ϩ ratio (1). MV infection interferes with the differentiation and specialization of lymphocyte functions but does not alter those already established (11). In the case of RPV, lymphodepletion in the thymus, Peyer's patches, spleen, and pulmonary lymph nodes indicates that these infections also induce immunosuppression in infected hosts (27). Recently, we showed that cattle infected with a virulent strain of RPV also show reduced responses of leukocytes to mitogens ex vivo (15). As for MV, lung infections with bacterial secondary infection are common features of PPRV (12,19), and morbillivirus infections in marine mammals result in a severe pulmonary distress with increased levels of opportunistic bacteria, evidence of immunosuppression in these animals (5, 6).Many theories have been proposed to account for MVinduced nonresponsiveness of the immune system, although there is little agreement about the mechanisms involved (7,14,22,23,26). It is likely that there are many factors that contribute to immunosuppression in vivo. During the course of acute MV infection, only a small proportion of peripheral blood leukocytes are infected, indicating that indirect mechanisms, rather than the direct infection and destruction of lymphoid cells, are involved in the widespread immune unresponsiveness. Using a two-cell system, Schlender and colleagues showed that small numbers of MV-infected, UV-irradiated, lymphocyte presenter cells (PC) could inhibit the proliferation...

Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes

“…Decreased levels of the cyclins D1, D3 and E were observed after co-culture of PBMCs with Chicago-1 MV or co-culture of PBMCs with Chicago-1 MV and HIV-1 BaL (Fig. 4a), consistent with a block in cell-cycle progression into the S phase induced by MV (Engelking et al, 1999;Heaney et al, 2002;Naniche et al, 1999).…”

Lymphotropism and host responses during acute wild-type canine distemper virus infections in a highly susceptible natural host

“…It should be taken into account that the severe lymphopenia provoked in the highly virulent wild-type infections is probably induced by a number of mechanisms, including virus contact-mediated inhibitions of T-cell proliferation (Griffin, 2007;Heaney et al, 2002;Yanagi et al, 2006). The effects of the latter inhibitions could, in turn, alter the ratio of cytokine-positive to -negative cells in vivo.…”

“…The molecular events behind morbillivirus-induced perturbation of the immune system have been studied extensively and, based on in vitro studies, several mechanisms have been proposed to be involved (Heaney et al, 2002;Schneider-Schaulies & Dittmer, 2006;Yanagi et al, 2006). Thus, accumulating evidence strongly links immunosuppression and lymphopenia not only to direct effects following infection and subsequent destruction of signalling lymphocytic activating molecule (SLAM)-positive immune cells and precursor cells in the acute phase of the infections, but also to indirect effects modulating the host innate and adaptive immune systems (Cruz et al, 2006;Devaux et al, 2008;Heaney et al, 2005;Karp et al, 1996;Schlender et al, 1996;Tatsuo et al, 2001;von Messling et al, 2006).…”

“…Members of the genus Morbillivirus within the family Paramyxoviridae include Measles virus (MV) of primates, Canine distemper virus (CDV) of carnivores and Rinderpest virus (RPV) of cloven-hoofed animals. Natural infections by all of these share common features, including lymphopenia and inhibition of lymphocyte proliferation in the acute phase (Griffin, 2007;Heaney et al, 2002;von Messling et al, 2003;Yanagi et al, 2006). Although live vaccines have effectively reduced the incidence of disease, the highly contagious morbilliviruses are still a major problem in human and veterinary medicine (Greene & Appel, 2006;Rima & Duprex, 2006).…”

“…Acute clinical morbillivirus disease often takes a fatal course in highly susceptible natural hosts such as young dogs, mink and ferrets due to the highly multisystemic virulence, which includes central nervous system (CNS) involvement and profound immunosuppression, favouring opportunistic secondary pathogens (Appel, 1969;Blixenkrone-Møller, 1989;Kauffman et al, 1982;von Messling et al, 2006). Despite the clinically relevant immunosuppression, another hallmark of virulent morbillivirus infections is the induction of efficient and lifelong humoral and cellular immunity in hosts that eventually survive and appear to clear the virus (Appel et al, 1982;Griffin, 2007).The molecular events behind morbillivirus-induced perturbation of the immune system have been studied extensively and, based on in vitro studies, several mechanisms have been proposed to be involved (Heaney et al, 2002;Schneider-Schaulies & Dittmer, 2006;Yanagi et al, 2006). Thus, accumulating evidence strongly links immunosuppression and lymphopenia not only to direct effects following infection and subsequent destruction of signalling lymphocytic activating molecule (SLAM)-positive immune cells and precursor cells in the acute phase of the infections, but also to indirect effects modulating the host innate and adaptive immune systems (Cruz et al, 2006;Devaux et al, 2008;Heaney et al, 2005;Karp et al, 1996;Schlender et al, 1996;Tatsuo et al, 2001;von Messling et al, 2006).…”