Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Abstract

Rhesus macaques infected with the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) serve as a model for human infection with Lassa fever virus. To identify the earliest events of acute infection, rhesus macaques were monitored immediately after lethal infection for changes in peripheral blood mononuclear cells (PBMCs). Changes in CD3, CD4, CD8 and CD20 subsets did not vary outside the normal fluctuations of these blood cell populations; however, natural killer (NK) and γδ T cells increased slightly on day 1 and then decreased significantly after two days. The NK subsets responsible for the decrease were primarily CD3 -CD8 + or CD3 -CD16 + and not the NKT (primarily CD3 + CD56 + ) subset. Macaques infected with a non-virulent arenavirus, LCMV-Armstrong, showed a similar drop in circulating NK and γδ T cells, indicating that this is not a pathogenic event. Vγ9 T cells, representing the majority of circulating γδ T cells in rhesus macaques, displayed significant apoptosis when incubated with LCMV in cell culture; however, the low amount of cell death for virus-co-cultured NK cells was insufficient to account for the observed disappearance of this subset. Our observations in primates are similar to those seen in LCMV-infected mice, where decreased circulating NK cells were attributed to margination and cell death. Thus, the disappearance of these cells during acute hemorrhagic fever in rhesus macaques may be a cytokine-induced lymphopenia common to many virus infections. Keywords: NK cells -γδ T -rhesus macaque -LCMV -hemorrhagic feverArenaviruses are rodent-borne pathogens that have occasionally been known to cause lethal diseases in human beings (Oldstone 2002, Salvato & Rodas 2005. Every year, Lassa fever and the South American hemorrhagic fever viruses account for almost half a million cases worldwide, with approximately 16% mortality (Jahrling et al. 1985, McCormick et al. 1986, Fisher-Hoch et al. 2000. Although rodents serve as a reservoir for arenaviruses, studies of hemorrhagic fever have relied on guinea pig, hamster and primate models rather than mouse models because the disease mechanism is fundamentally different in non-reservoir species (Peters et al. 1987).Numerous murine studies of viral persistence and cell-mediated immunity have involved the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV) , Ahmed et al. 1984, Salvato et al. 1991. The WE strain of LCMV is hepatotropic in mice, guinea pigs and primates (Riviere et al. 1985, Zinkernagel et al. 1986, Lukashevich et al. 2002, but in contrast to murine LCMV infections, LCMV-WE infection of rhesus macaques can resemble Lassa hemorrhagic fever in human beings (Jahrling et al. 1980, Peters et al. 1987, Lukashevich et al. 2002. The Armstrong (ARM) strain of LCMV does not cause overt disease in monkeys, even after intravenous inoculation (Danes et al. 1963, Peters et al. 1987, Lukashevich et al. 2002.Several immunological studies have shown the importance of CD8 T lymphocytes in both protection and in induction of immuno-pathogenesis i...

Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections

“…A decrease in NK cells was shown in animal models [5] and recently suggested in humans by a molecular profiling approach [20]. Moreover, a specific early loss of both NK and γδ T-cells was described also in other acute hemorrhagic fever models [21,22]. The dramatic loss of innate (Vδ2 and NK) and adaptive immune cells [23] during EBOV infection may explain the paralysis of the immune system and its inability to initiate and maintain a protective immune response.…”

Association of γδ T Cells with Disease Severity and Mortality in Septic Patients

“…We know that lymphopenia has been associated with mortality in patients with sepsis of all ages (35,36), but no study to date has investigated which specific cell subsets are related to mortality. A decrease has been reported in ␥␦ T cells and natural killer T cells after viral infection in rhesus macaques (37). Little is known about the implications of these T cell subsets in humans, and even less in septic patients.…”

Lymphocytic choriomeningitis virus (LCMV) infection of macaques: A model for Lassa fever

“…Primate V 2 cells proliferate in response to the small phosphoantigens that are byproducts of cholesterol biosynthesis and components of bacterial cell walls (Cairo et al, 2005; Li H et al, 2008), but rodent T cells do not respond to phosphoantigens (Bonneville et al, 2010). The V 2 subset disappears from the circulation within the first week after infection with HIV, SIV (Bordon et al, 2004), or LCMV (Rodas et al, 2010), yet it is restored in primates vaccinated with benign arenaviruses (Rodas et al, 2009) and in HIV elite controllers (Reidel et al, 2009). Although the T cells comprise only 1-4% of all circulating T cells, their normal role in bridging innate and acquired immunity and rapid disappearance following LCMV infection suggests their involvement in the pathogenesis of VHF.…”

“…Although the T cells comprise only 1-4% of all circulating T cells, their normal role in bridging innate and acquired immunity and rapid disappearance following LCMV infection suggests their involvement in the pathogenesis of VHF. NK cells in rhesus monkeys also decreased two days after LCMV infection with a more dramatic decrease after LCMV-WE (virulent) infection than after LCMV-ARM (benign) infection (Rodas et al, 2009). Similarly, in Lassa-infected cynomolgus macaques, NK cell decreases were more dramatic in fatal outcomes (Baize et al, 2009).…”