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. 2017 Jan 3;91(2):e01386-16.
doi: 10.1128/JVI.01386-16. Print 2017 Jan 15.

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Jenny W Che  1 , Keith A Daniels  1 , Liisa K Selin  1 , Raymond M Welsh  2
Affiliations

Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

Jenny W Che et al. J Virol. .

Abstract

One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of heterologous immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study heterologous immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV+MCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMV+LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57727-734, and the normally subdominant LCMV epitope L2062-2069, indicating a profound private specificity effect in heterologous immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus.

Importance: This study extends our understanding of heterologous immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as MCMV. We found that the history of LCMV infection intensifies MCMV immunopathology, enhances MCMV burden in multiple organs, and suppresses MCMV-specific T cell memory inflation. In the reverse infection sequence, we show that some of the long-term MCMV-immune mice mount a robust CD8 T cell cross-reactive response between a newly defined putative MCMV epitope sequence and a normally subdominant LCMV epitope. These results further illustrate how a history of infection can substantially influence the immune responses and immune pathology associated with infections with an unrelated virus.

Keywords: CD8 T cell; cross-reactivity; heterologous immunity; lymphocytic choriomeningitis virus; memory inflation; mouse; murine cytomegalovirus.

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Figures

FIG 1
FIG 1
MCMV infection significantly reduces the number and frequency of LCMV-specific memory CD8 and CD4 T cells at 4 days (a and b) and 9 weeks (c to h) after MCMV inoculation. LCMV-immune mice were infected i.p. with 5 × 105 PFU of MCMV or given salivary gland homogenate from naive mice (nsg) as controls. Memory CD8 and CD4 T cells from spleens were examined at day 4 post-MCMV infection by ICS (a) and tetramer staining (b). Memory CD8 T cells from spleens (c and d) and bone marrow (e and f) and memory CD4 T cells from spleens (g and h) were examined at 9 weeks post-MCMV infection by ICS. The phenomenon of LCMV-specific memory reduction was observed in two other similarly designed experiments in cells harvested at 6 and 24 weeks after MCMV infection. *, P < 0.05, for results in the MCMV-infected group compared to those in the nsg-treated sham control group (n = 5).
FIG 2
FIG 2
MCMV persistence does not further erode LCMV-specific memory CD8 or CD4 T cells (LCMV+MCMV). LCMV-immune mice were infected i.p. with 5 × 105 PFU of MCMV or given salivary gland homogenate from naive mice as controls. Memory CD8 T cells specific for GP33–41, NP396–404, and GP118–125, (a to d) and memory CD4 T cells specific for GP61–80 from the spleen (e) were examined at weeks 6, 12, 23, and 48 post-MCMV infection by ICS (n = 5). The complete experiment was done once, but a similar observation was made in a separate experiment in cells harvested at weeks 9 and 24 post-MCMV inoculation.
FIG 3
FIG 3
A history of LCMV infection suppresses the generation of MCMV-specific inflationary memory T cells, alters immunopathology, and weakens viral control of MCMV infection (LCMV+MCMV). LCMV-immune C57BL/6 mice and BHK supernatant-treated controls were infected with 5 × 105 PFU of MCMV. (a and b) MCMV-specific inflationary and noninflationary memory CD8 T cells in the spleens were examined by ICS after in vitro peptide stimulation at week 12 (day 84) postinfection. (c) Total CD8 T cells were also enumerated at days 12, 21, 42, and 84 postinfection. (d) The necrosis in the fat pad was measured on a scale of 0 to 7 as published previously (6): 1 to 2 indicates mild disease with only a few spots on the lower abdominal fat pad, 3 to 4 indicates moderate disease with larger white patches extending out to the upper quadrant of the fat pad, 5 to 6 indicates more severe disease with infiltration of inflammatory cells throughout the fat pad, and 7 indicates that the organs are sticking together. (e and f) MCMV copy number was measured by qPCR on DNA extracted from snap-frozen spleen, liver, kidney, and lung on day 4 postinfection and from salivary glands on days 4, 12, 21, 42, and 84 postinfection, as indicated. The complete experiment was done once. Viral burden and acute fatty necrosis scores on days 4 and 21 are representative of data in two other separate experiments. The analysis of memory T cells at weeks 3, 6, and 12 (days 21, 42, and 84, respectively) is representative of data in three other separate experiments. *, P < 0.05, for results in the LCMV-immune group compared to those in the BHK control group (n = 5). Arb, arbitrary.
FIG 4
FIG 4
The magnitude of T cell responses to acute LCMV infection declines with age whether or not mice were previously infected with MCMV (MCMV+LCMV). Mice at 6 weeks of age were inoculated with MCMV or injected with naive salivary gland homogenate. MCMV-immune and nsg-treated control mice were infected with 5 × 104 PFU of LCMV at multiple different time points post-MCMV infection and analyzed at day 8 after LCMV infection by ICS. The total number and frequency of CD8 T cell responses to GP33–41 (a and e), GP276–286 (b and f), and NP396–404 (c and g) and CD4 T cell responses to GP61–80 (d and h) are shown with means and SEM (n = 3). The entire long-term immune experiment was done once, but similar observations were made in experiments with separately inoculated 29-week, 80-week, and 120-week MCMV-immune mice.
FIG 5
FIG 5
Infecting long-term MCMV-immune mice with LCMV (MCMV+LCMV) identifies a new MCMV epitope, M57727–734, that is probably cross-reactive to LCMV L2062–2069. (a) MCMV-6-week-immune mice and age-matched nsg-treated controls were infected with 5 × 104 PFU LCMV. Splenocytes were analyzed by ICS at day 8 postinfection. Each vertical bar represents one mouse. Data represent one of two similar experiments. (b) MCMV-75-week-immune mice and nsg-treated controls were analyzed at 8 days after LCMV infection by ICS. (c) Three MCMV peptides with sequence homology to L2062–2069 were chosen for experiments. (d) Five 105-week MCMV-immune mice and one nsg-treated control mouse were analyzed at 8 days after LCMV infection by ICS. About 50% of the major LCMV-specific response was found specific for L2062–2069 in the same mouse that showed over 50% of the major MCMV-specific response specific for M57727–734. (e) MCMV-120-week-immune (mouse 8 and 10) and nsg-treated control (mouse 7) mice were analyzed at day 9 post-LCMV infection by ICS. A putative cross-reactive response between L2062–2069 and M57727–734 was observed in mouse 10. The frequencies of IFN-γ- and Vβ-positive T cells (percentage of CD8 CD44hi T cells) were compared by different Vβ chains in each mouse. Cross-reactivity was observed at different time points in the initial long-term experiment, and hence a separate group of long-term MCMV-immune mice was examined at additional time points for cross-reactive responses after LCMV infection.
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