Impaired CD4 T Cell Memory Response to Streptococcus pneumoniae Precedes CD4 T Cell Depletion in HIV-Infected Malawian Adults

Objective: Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African Adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease. Methods: Peripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-c, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot. Results: We find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25highFoxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154. Conclusion: Asymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers

Maternal‐Fetal DNA Admixture Is Associated with Intrapartum Mother‐to‐Child Transmission of HIV‐1 in Blantyre, Malawi

The mechanism of HIV-1 mother-to-child transmission (MTCT) is not well described

The ability of Interleukin–10 to negate haemozoin-related pro-inflammatory effects has the potential to restore impaired macrophage function associated with malaria infection

Background: Although pro-inflammatory cytokines are involved in the clearance of Plasmodium falciparum during the early stages of the infection, increased levels of these cytokines have been implicated in the pathogenesis of severe malaria. Amongst various parasite-derived inducers of inflammation, the malarial pigment haemozoin (Hz), which accumulates in monocytes, macrophages and other immune cells during infection, has been shown to significantly contribute to dysregulation of the normal inflammatory cascades. Methods: The direct effect of Hz-loading on cytokine production by monocytes and the indirect effect of Hz on cytokine production by myeloid cells was investigated during acute malaria and convalescence using archived plasma samples from studies investigating P. falciparum malaria pathogenesis in Malawian subjects. Further, the possible inhibitory effect of IL-10 on Hz-loaded cells was examined, and the proportion of cytokine-producing T-cells and monocytes during acute malaria and in convalescence was characterized. Results: Hz contributed towards an increase in the production of inflammatory cytokines, such as Interferon Gamma (IFN-γ), Tumor Necrosis Factor (TNF) and Interleukin 2 (IL-2) by various cells. In contrast, the cytokine IL-10 was observed to have a dose-dependent suppressive effect on the production of TNF among other cytokines. Cerebral malaria (CM) was characterized by impaired monocyte functions, which normalized in convalescence. CM was also characterized by reduced levels of IFN-γ-producing T cell subsets, and reduced expression of immune recognition receptors HLA-DR and CD 86, which also normalized in convalescence. However, CM and other clinical malaria groups were characterized by significantly higher plasma levels of pro-inflammatory cytokines than healthy controls, implicating anti-inflammatory cytokines in balancing the immune response. Conclusions: Acute CM was characterized by elevated plasma levels of pro-inflammatory cytokines and chemokines but lower proportions of cytokine-producing T-cells and monocytes that normalize during convalescence. IL-10 is also shown to have the potential to indirectly prevent excessive inflammation. Cytokine production dysregulated by the accumulation of Hz appears to impair the balance of the immune response to malaria and exacerbates pathology

Correction: The ability of Interleukin–10 to negate haemozoin-related pro-inflammatory effects has the potential to restore impaired macrophage function associated with malaria infection

Correctio

MOESM1 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 1. Consort diagram of patient recruitment and study design. All cases were recruited from QECH in Blantyre, Malawi. Cases were included in the study if they attended their assigned 30-day follow-up appointment and fit the comparable age and sex distributions (for adjusted comparison) between groups

MOESM3 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 3. Annotations of PfEMP1/var genes and domains encoded

MOESM5 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 5. Reactivity to markers of prior malaria exposure and antigens of interest in control populations

MOESM4 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 4. Assessment of P. falciparum and total Ig levels by age and sex. (a) Spearman correlations comparing age vs. acute total IgG level, age vs. 30-day convalescent total IgG level, and total IgG levels across timepoints show significant linear trends. (b) Volcano plots comparing the effect of age (> 5 years/≤ 5 years) on IgG, IgM seroreactivity to P. falciparum and PfEMP1 antigens indicates that for IgG in acute infection, age affects the magnitude of seroreactivity to a few P. falciparum antigens and a general non-significant trend for higher antibodies to all proteins in older children during acute infection (CM + UM total n = 48). (c) Volcano plots of inverse unadjusted P-values (y-axis) and linear regression effect estimates (x-axis) for comparing the effect of sex (male/female) on IgG, IgM seroreactivity to P. falciparum and PfEMP1 antigens indicate that sex does not have a significant effect on seroreactivity in our patient population in acute infection or convalescence, although non-significant trends for higher overall P. falciparum-specific IgG and IgM in males during acute infection and lower PfEMP1-specific IgG in males for both time points could be observed (CM + UM total n = 48). Dashed lines represent unadjusted P-value of 0.05. Points are highlighted in bold, red if significant after adjustment for the false discovery rate

MOESM6 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 6. Seroreactivity to PfEMP1 antigens in pooled control serum vs. paediatric malaria cases

MOESM7 of Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

Additional file 7. CIDR IgG responders at time of acute P. falciparum infection