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. 2002 Nov;110(10):1461-71.
doi: 10.1172/JCI16318.

The Staphylococcus Aureus Map Protein Is an Immunomodulator That Interferes With T Cell-Mediated Responses

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Free PMC article

The Staphylococcus Aureus Map Protein Is an Immunomodulator That Interferes With T Cell-Mediated Responses

Lawrence Y Lee et al. J Clin Invest. .
Free PMC article

Abstract

Staphylococcus aureus (SA) is an opportunistic pathogen that affects a variety of organ systems and is responsible for many diseases worldwide. SA express an MHC class II analog protein (Map), which may potentiate SA survival by modulating host immunity. We tested this hypothesis in mice by generating Map-deficient SA (Map(-)SA) and comparing disease outcome to wild-type Map(+)SA-infected mice. Map(-)SA-infected mice presented with significantly reduced levels of arthritis, osteomyelitis, and abscess formation compared with control animals. Furthermore, Map(-)SA-infected nude mice developed arthritis and osteomyelitis to a severity similar to Map(+)SA-infected controls, suggesting that T cells can affect disease outcome following SA infection and Map may attenuate cellular immunity against SA. The capacity of Map to alter T cell function was tested more specifically in vitro and in vivo using native and recombinant forms of Map. T cells or mice treated with recombinant Map had reduced T cell proliferative responses and a significantly reduced delayed-type hypersensitivity response to challenge antigen, respectively. These data suggest a role for Map as an immunomodulatory protein that may play a role in persistent SA infections by affecting protective cellular immunity.

Figures

Figure 1
Figure 1
Mean weight loss from MapSA- and Map+SA-infected mice. Mice were intravenously infected with either 107 MapSA or Map+SA. Weights were taken before infection and every 7 days after infection for 4 weeks. Data are expressed as the mean ± SE of the mean of 26 and 24 mice/group for MapSA– and Map+SA–infected mice, respectively. *P < 0.05, Student t test.
Figure 2
Figure 2
The number of bacteria isolated from various tissues. CFUs from blood, heart, kidneys, and joints were determined from mice infected with either MapSA (open squares) or Map+SA (filled squares) at various times after infection. Data are expressed as the mean CFU ± SE of the mean of 4 mice/group at each time point. There was no statistical differences between infection groups at any of the time points examined (Student t test). *The bacterial density in the joints harvested from MapSA–infected mice 4 days after infection was 5,750 ± 2,453.
Figure 3
Figure 3
Hematoxylin- and eosin-stained tissue sections from MapSA– or Map+SA–infected mice. (a) Severe osteomyelitis (BALB/c mouse infected with Map+SA). (b) No arthritis or osteomyelitis (BALB/c mouse infected with MapSA). (cd) Severe arthritis (nu/nu and nu/+ mice infected with either MapSA or Map+SA, respectively). (ef) Kidney sections (BALB/c mice infected with MapSA or Map+SA, respectively) and (gh) heart sections (BALB/c mice infected with MapSA or Map+SA, respectively).
Figure 4
Figure 4
Native Map-mediated inhibition of DTH. DbpA-immunized mice were treated with native Map on the day of immunization (day 0) and on days 2, 4, and 6 after immunization. On day 7, mice were challenged with DbpA, and footpads were measured 0 and 24 hours after challenge. Mice treated with supernatant from Map+SA had a significantly reduced DTH response compared with immunized and challenged mice (*P < 0.0001; Student t test). Data are expressed as the mean ± SE of five mice.
Figure 5
Figure 5
Recombinant Map19-mediated inhibition of DTH. DbpA-immunized mice were treated with recombinant Map19 on the day of immunization (day 0) and on days 2, 4, and 6 after immunization. On day 7, mice were challenged with DbpA and footpads were measured 0 and 24 hours after challenge. Mice treated with recombinant Map19 had a significantly reduced DTH response compared with immunized and challenged mice (*P < 0.0001; Student t test). Data are expressed as the mean ± SE of five mice.
Figure 6
Figure 6
Dose-dependent inhibition of DTH. DbpA-immunized mice were treated with various doses of Map19 (1–500 μg) or Ace19 (500 μg), as described previously. On day 7, mice were challenged with DbpA, and the footpads measured 0 and 24 hours after challenge. Significant values are indicated by an asterisk (P < 0.05; Student t test). Data are expressed as the mean ± SE of five mice.
Figure 7
Figure 7
DTH following adoptive T cell transfer. DbpA-immunized mice were treated with either Map19 or Ace40, as described above. On day 7, mice were sacrificed and spleens were harvested and enriched for T cells by nylon wool purification. Cells (5 × 107) were injected intraperitoneally into syngeneic recipients. Twenty-four hours later, recipient mice were challenged with DbpA, and the DTH response was assessed as described above. T cells from DbpA-immunized Ace40-treated or T cells from DbpA-immunized (untreated) mice elicited a significant DTH response compared with unimmunized but challenged mice or to naive T cell–recipient mice (*P < 0.04; Student t test). T cells from DbpA-immunized, Map19-treated mice did not elicit a significant DTH response compared with positive control treatment groups (**P < 0.001; Student t test). Data are expressed as the mean ± SE of five mice.
Figure 8
Figure 8
Map-induced inhibition of T cell proliferation. BAT2.2 T cell proliferation was measured after 48 hours in culture in the presence of APCs, and antigen in the presence of Map 19 or Acel9 at various concentrations. *P < 0.0001 compared with all other treatment groups; Student t test. Data are expressed as the mean absorbance ± SE of triplicate wells.
Figure 9
Figure 9
The effect of Map19 on annexin V/PI staining. BAT2.2 cells (106) (5 U IL-2/ml) were incubated in media alone (a) or in the presence of either 400 μg of either Ace40 (b) or Map19 (c) for 24 hours and analyzed by FACS following incubations with annexin V-FITC and PI.
Figure 10
Figure 10
Map-induced apoptosis of BAT2.2 T cells. BAT2.2 cells (2 × 106) (5 U IL-2/ml) were incubated in media alone (lane 2) or in the presence of either 100 μg Map19 (lane 3) or Ace40 (lane 4). DNA from U937 cells were used as a positive control (lane 5). Lane 1, 100-bp ladder.

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