Virus infection stages and distinct Th1 or Th17/Th22 T-cell responses in malaria/SHIV coinfection correlate with different outcomes of disease - PubMed (original) (raw)
Virus infection stages and distinct Th1 or Th17/Th22 T-cell responses in malaria/SHIV coinfection correlate with different outcomes of disease
Bridgett Ryan-Payseur et al. J Infect Dis. 2011 Nov.
Abstract
Background: Malaria and AIDS represent 2 leading causes of death from infectious diseases worldwide, and their high geographic overlap means coinfection is prevalent. It remains unknown whether distinct immune responses during coinfection with malaria and human immunodeficiency virus (HIV) affect clinical outcomes.
Methods: We tested this hypothesis by employing macaque models of coinfection with malaria and simian-human immunodeficiency virus (SHIV).
Results: Plasmodium fragile malaria coinfection of acutely SHIV-infected macaques induced hyperimmune activation and remarkable expansion of CD4+ and CD8+ T effector cells de novo producing interferon γ or tumor necrosis factor α. Malaria-driven cellular hyperactivation/expansion and high-level Th1-cytokines enhanced SHIV disease characterized by increasing CD4+ T-cell depletion, profound lymphoid depletion or destruction, and even necrosis in lymph nodes and spleens. Importantly, malaria/SHIV-mediated depletion, destruction, and necrosis in lymphoid tissues led to bursting parasite replication and fatal virus-associated malaria. Surprisingly, chronically SHIV-infected macaques without AIDS employed different defense mechanisms during malaria coinfection, and mounted unique ∼200-fold expansion of interleukin 17+/interleukin 22+ T effectors with profound Th1 suppression. Such remarkable expansion of Th17/Th22 cells and inhibition of Th1 response coincided with development of immunity against fatal virus-associated malaria without accelerating SHIV disease.
Conclusions: These novel findings suggest that virus infection status and selected Th1 or Th17/Th22 responses after malaria/AIDS-virus coinfection correlate with distinct outcomes of virus infection and malaria.
Figures
Figure 1.
Malaria coinfection of acutely simian-human immunodeficiency virus (SHIV)–infected macaques led to fatal virus-associated malaria; chronically SHIV-infected macaques developed moderately enhanced parasitemia without fatal outcome after malaria coinfection. A, Malaria/acute SHIV–coinfected macaques (left) had significantly higher parasite levels than malaria-only controls (center, P = .0004 at day 20). All acutely SHIV-infected macaques developed life-threatening malaria, and all but 1 (subject 7284) became moribund despite receiving chloroquine treatment. Malaria/chronicSHIV–coinfected macaques without AIDS (right) had higher parasitemia than that of malaria-only controls (P = .0245 at day 20), but much lower parasitemia than that of malaria/acute SHIV–coinfected macaques (P = .0034).* indicates chloroquine treatment. B, Hematocrit data for macaques as indicated on the top of the panels. Note that the macaques with fatal malaria had extremely low levels of hematocrit despite chloroquine treatment. All moribund macaques had clinical signs of severe anemia, although some were not tested for hematocrit at endpoints. C, Survival curves for the malaria/acute SHIV, malaria-only, and malaria/chronic SHIV groups. Only 1 macaque (subject 7284) in the malaria/acute SHIV group survived life-threatening malaria after chloroquine treatment. All macaques without AIDS in the malaria/chronic-SHIV group survived, with 2 (subjects 7393 and 7418) treated with chloroquine at day 20. The single macaque with prior AIDS (subject 7409) in the malaria/chronic SHIV group did not survive despite chloroquine treatment at day 19, and was euthanized on day 22. Abbreviation: pRBC, parasitized red blood cells.
Figure 2.
Malaria coinfection of acutely simian-human immunodeficiency virus (SHIV)–infected animals resulted in severe and rapid lymphoid depletion in the lymph nodes, spleen, and rectal mucosa. A, B, Histopathology images indicating lymphoid depletion/destruction in lymph nodes (top, 50× magnification) and spleens (bottom, 50× magnification) of 2 representative macaques (subjects 7282, 7289) in the malaria/acutely SHIV–coinfected group. Note the destruction of lymphoid structures, the disappearance of both germinal centers and T-cell zones, and apparent necrosis in lymph nodes and spleens collected at necropsy at day 21 after the coinfection. Shown on the left are 2 sets of control images (25× magnification). The first set from a representative uninfected macaque indicated normal structures of T-cell zones/germinal centers in the lymph node and white/red pulps in the spleen. The other set from SHIV-only macaque (subject 7351, necropsied on day 627 post-SHIV infection) showed enlarged germinal centers, but no lymphoid destruction or necrosis. A lack of necrosis and marked lymphoid depletion was also seen in acute viral infection phase of SHIV-only controls. Of note, acute SHIV infection of macaques did not cause lymphoid destruction, necrosis, or disappearances of germinal centers despite the minor decreases in cell density in T-cell zones and subtle paracortical hyperplasia were seen in lymph nodes collected 1 month after SHIV infection (data not shown). All samples were formalin-fixed sections stained by hematoxylin and eosin. Red arrows indicate germinal centers; green arrows indicate necrotic regions without germinal centers/T-cell zones or normal structures; and yellow arrows indicate depleted germinal centers and necrosis in spleen. Ci, Histopathology images of rectal mucosa collected at day 21 after SHIV from representative SHIVinfected control (left 2 panels) and malaria/acute SHIV–coinfected macaques (right 2 panels). Malaria/acute SHIV–coinfected macaques shows decreased densities of lymphoid cells in gut mucosa overall, with fewer lymphocytes seen (400× magnification).
Figure 3.
Malaria coinfection of acutely simian-human immunodeficiency virus (SHIV)–infected macaques enhanced SHIV disease; malaria coinfection of chronically SHIV-infected macaques induced only a transient increase in viral loads with stable CD4+ T-cell counts. Top: Plasma SHIV RNA levels detected in individual malaria/acute SHIV–coinfected macaques (left, n = 4), individual malaria/chronic SHIV–coinfected macaques (n = 5), and the SHIV-only group (means ± SD, n = 6). Bottom: Numbers of CD4+ T cells in malaria/acute SHIV and malaria/chronic SHIV macaques, and the SHIV-only group (means ± standard deviation [SD], n = 6). Data for the chronic SHIV-only group were derived from a 6-week period of chronic infection. The transient ∼1 log increase in SHIV level during the chronic SHIV coinfection was not statistically significant when compared with baseline. Absolute CD4+ T cell counts in malaria/acute SHIV coinfected macaques appeared to reach a lower level than those in SHIV-only controls. P = .0154 day 19 malaria/acute-SHIV vs day 22 SHIV-only (a progressive decline of CD4 T cell counts usually is most striking at weeks 3–5 after SHIV89.6P). No significant declines of CD4+ T cell counts in malaria/chronic SHIV-coinfected macaques were noted.
Figure 4.
Hyperactivation/expansion of Th1 effector cells during malaria/acute simian-human immunodeficiency virus (SHIV) coinfection coincided with accelerated SHIV disease and fatal AIDS-associated malaria; suppressed Th1 T effector function associated with uncomplicated malaria and ”stabilized” SHIV infection in malaria/chronic SHIV–coinfection. A, Representative histograms showing increases in CD4+ and CD4-(CD8+) T effector cells producing interferon (IFN) γ at day 22 postinfection in malaria/acute SHIV–coinfected macaque (left) and malaria-only control (center), but not malaria/chronic SHIV–coinfected macaque (right). Data were gated on CD3. Numbers in upper right and brackets were percentages of CD3+ T cells and of CD4+ T cells, respectively. B, Hyperactivation/expansion of IFNγ+CD4+ T-effector cells in malaria/acute SHIV–coinfected macaques (left, coinfected, P = .0096, baseline vs day 15, n = 4; P = .0665, baseline vs day 22, n = 2) and malaria-only controls (center, n = 4, P < .0001, baseline vs day 15; P = .0018, baseline vs day 22). Almost no CD4+ T effectors were detected in malaria/chronic SHIV–coinfected macaques (right, P = .0008 compared with malaria/acute SHIV group, and P = .0004 compared with malaria-only group at day 22, n = 5). SHIV-only controls had few or no IFNγ+ CD4+ T effector cells measured by intracellular cytokine staining (ICS) without Ag stimulation (n = 6, P = .0001 at day 22 compared with malaria/acute SHIV coinfected group). Data are presented as fold increase % IFNγ+ cells among CD4+ T cells. C, Hyperactivation/expansion of IFNγ+CD8+ T effectors (CD8 Ab used for ICS) in malaria/acute SHIV coinfected and malaria-only infected macaques (P = .0099 for malaria/acute SHIV-coinfected macaques, baseline vs day 15, n = 4; P < .0001 for malaria-only infected macaques, baseline vs day 15, n = 2). Much lower increases of CD8+ T effectors were detected in malaria/chronic SHIV-coinfected macaques (right, P = .0002 compared with malaria/acute-SHIV group, and P = .0015 compared with malaria-only group at day 22). SHIV-only controls (n = 6) showed very few or no IFNγ+ CD8+ T effector cells (P = .0004 at day 22, compared with malaria/acute SHIV coinfected group). D, Hyperactivation/expansion of tumor necrosis factor (TNF) α+CD4+ T effectors in malaria/acute SHIV coinfected and malaria-only macaques (P = .0100, baseline vs day 22; malaria/acute SHIV n = 2 at day 22, malaria-only n = 4). However, few TNFα+CD4+ T effectors were detected in malaria/chronic-SHIV (n = 5 at day 22) group (right, P = .005 compared with malaria/acute-SHIV group, and P = .0030 compared with malaria-only group at day 22). E, The absolute number of IFNγ+CD4+ and IFNγ+CD8+ T effectors increased 50- to 100-fold and 100- to 300-fold, respectively, in malaria/acute SHIV-coinfected macaques and malaria-only infected macaques by day 21. The fold increase in malaria/chronic SHIV-coinfected macaques was much less significant.
Figure 5.
Malaria induced high-level Th1 proinflammatory cytokines in acute simian-human immunodeficiency virus (SHIV) coinfection, whereas Th1 cytokine responses were suppressed in chronic SHIV coinfection. A, Plasma interferon (IFN) γ increased in malaria/acute SHIV-coinfected macaques (left), but not malaria-only controls (middle) or malaria/chronic SHIV-coinfected macaques (right). IFNγ was not detectable in acute SHIV-only controls. B, There was no increase in plasma interleukin 4 (IL-4) in malaria/acute SHIV-coinfected macaques except the chloroquine-treated survivor (left) or malaria-only controls (middle) or malaria/chronic SHIV-coinfected macaques (right). C, Overall, there was no significant increase in plasma IL-2 in malaria/acute-SHIV (left), malaria-only (middle), or malaria/chronic-SHIV groups of macaques (right) detected. D, There was no significant difference in the development of malaria–specific Ab responses between malaria/acute-SHIV (left), malaria-only (middle), and malaria/chronic-SHIV groups of macaques (right). Shown were the data of MSP-1-specific immunoglobulin G (IgG) and immunoglobulin M (IgM) Ab levels (optical density [OD] values) derived from ELISA using antimonkey IgG and IgM as second Ab. A lack of differences in total Abs between groups suggests that humoral immune responses did not appear to correlate with clinical outcomes of malaria coinfection.
Figure 6.
Remarkable expansion of Th17 cells and unique increases in interleukin (IL) 22+ T effector cells coincided with the absence of fatal malaria and enhanced simian-human immunodeficiency virus (SHIV) disease in malaria/chronic SHIV–coinfection. A, IL-17–producing CD4+ T effector cells increased remarkably up to 200-fold during malaria/chronic SHIV–coinfection (right; P = .0167 at day 15, n = 6; P = .0021 at day 22, n = 5), and the magnitude was much greater than that in malaria-only group (P = .0181 at day 15; P = .0173 at day 22, using fold-change data) or malaria/acute SHIV–coinfected group (P = .0294 at day 15; P = .0757 at day 22, using fold-change data). SHIV-only infected animals did not show any detectable IL-17– or IL-22–producing T cells during the acute and chronic SHIV infection ([20], and data not shown). B, The absolute number of IL-17+CD4+ T cells increased < 25-fold in malaria/acute SHIV-coinfected macaques and malaria-only–infected macaques. In contrast, the absolute number increased up to 200-fold in malaria/chronic SHIV-coinfected macaques. C, Malaria/chronic SHIV–coinfected macaques also developed marked increases in IL-17–producing CD3+CD4-(CD8+) T effectors (P = .0181, baseline vs day 15, n = 5; P = .0081 baseline vs day 22, n = 5), and the expansion magnitude was significantly greater than that of the malaria-only group (P = .0218 at day 15, P = .0338 at day 22, using fold change data) and malaria/acute SHIV coinfection (P = .0440 at day 15; P = .1990 at day 22, using fold-change data). D, IL-22–producing CD4+ T cells are increased significantly, ≤ 22-fold from baseline, after malaria infection of chronically SHIV-infected macaques (P = .0038 at day 15, n = 5; P = .035 at day 22, n = 5). In contrast, the frequency of IL-22–producing CD4+ T effector cells actually decreased after malaria infection of acutely SHIV-infected or SHIV-naive macaques. Baseline IL-22–producing T effector cells were low in chronic SHIV-infected macaques, a finding similarly seen in simian immunodeficiency virus (SIV)–infected macaques [26]. No detectable IL-22–producing T cells during the chronic SHIV-only infection without malaria coinfection ([19], and data not shown). E, IL-22–producing CD3+CD4-(CD8+) T cells increased during malaria infection of chronically SHIV-infected macaques (P = .0260 at day 15, n = 5; P = .0097 at day 22, n = 5). Conversely, IL-22–producing CD3+CD4-(CD8+) T effector cells did not significantly increase during malaria/acute SHIV–coinfection and actually decreased during malaria-only infection (P = .0323 at day 15, n = 4). Similar trends of fold changes and P values were seen by comparative analyses of absolute numbers of T effectors.
Figure 7.
Overreactive Th1 responses coincided with progressive simian-human immunodeficiency virus (SHIV) disease (lymphoid depletion/destruction/necrosis) and fatal AIDS-associated malaria, whereas marked expansion of Th17 cells and unique increases in interleukin (IL) 22+ T effector cells with Th1 suppression correlated with uncomplicated malaria and stable SHIV infection. A, Spiking interferon γ–producing CD4+ T-cell levels representing hyperactivation of T cells correlated with CD4+ T cell depletion (top), bursting SHIV replication (middle), and high parasitemia (bottom) in malaria/acute SHIV–coinfected macaques. Increases in SHIV levels were seen earlier than those in detectable expansion of CD4+ T effector cells. This might be because virus replication was enhanced dramatically on cellular activation and that CD4+ T cells underwent activation events before they proliferated to a detectable expansion. Note that at week 3 after malaria coinfection of acutely SHIV-infected macaques, lymphoid depletion and destruction/necrosis occurred (Figure 2). B, High-frequency Th17 cells and IL-22–producing CD4+ T effector cells correlated with stable CD4+ T cell counts (top), subtle change in plasma SHIV RNA (middle), and moderate parasitemia in malaria/chronic SHIV–coinfected macaques. No or few Th1 cells also coincided with the uncomplicated SHIV/malaria diseases (Figures 3). Abbreviation: pRBC, parasitized red blood cells.
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