Biology subjects

Dooley, N. L.

Publications and source records attributed to Dooley, N. L..

4 recordsLinked to original sources

bioRxiv2026

Circulating T-follicular helper and type I regulatory T cells have overlapping phenotypes in P. falciparum malaria and are maintained by parasite exposure.

Immunity to P. falciparum malaria develops slowly, requiring repeated infection in areas of high transmission, and wanes rapidly in the absence of parasite exposure. Key to this immunity, is the development of antibodies which is supported by CD4 T follicular helper (Tfh) cells that drive robust germinal centre responses. However, in malaria, the malaria-specific CD4 T cell compartment in peripheral blood is dominated by Type 1 regulatory T cells (Tr1), which produce high levels of IL-10 in response to parasites. Tr1-like Tfh cells (Tfh10) have been reported in several settings of repeated antigen stimulation but have not been investigated in malaria. Here we used single-cell RNA sequencing and multiparameter flow cytometry to characterise malaria-specific Tfh and Tr1 cells in a longitudinal cohort of highly exposed individuals and assessed their persistence after transmission interruption. Malaria-specific Tfh and Tr1 cells shared overlapping profiles, and Tr1 cell-like transcriptional signatures and phenotypes were detectable within the Tfh cell compartment. Tfh10 cell subsets were the dominant phenotype of malaria-specific Tfh cells. Following disruption of malaria transmission, the frequencies of malaria-specific Tr1 and Tfh10 cells declined. These findings highlight a close relationship between Tfh and Tr1 cells and show that the Tfh cell compartment in malaria is dominated by Tfh10 cells. The rapid waning of these cells in the absence of continuous exposure is consistent with requirements of persistent antigen in maintaining regulatory CD4 T cell phenotypes.

immunology↗

bioRxiv2026

Latent cytomegalovirus disrupts NK cell responses to P. falciparum and impairs parasite control

BackgroundNK cells are major innate and adaptive responders to malaria, with multiple roles in protection. Function of NK cells is heterogeneous, underpinned by expression of a diversity of receptors. One driver of NK cell heterogeneity is latent CMV infection, which drives the expansion of memory-like NK cells. We have recently reported that latent CMV infection can negatively impact the adaptive immune response to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. MethodsWe investigated the impact of latent CMV infection on NK cell response to the malaria parasite Plasmodium falciparum in vitro, and in CMV seronegative and seropositive individuals during controlled human malaria infection. We analysed NK cell activation, cytotoxicity and NK cell receptor expression. Additionally, we investigated the impact of CMV serostatus on cytokine production in response to TLR stimulation in the myeloid cell compartment. The impact of CMV and NK cell responses on parasite control and malaria symptoms was investigated. ResultsNK cells from CMV seropositive individuals had reduced responsiveness to P. falciparum parasites in vitro and had reduced activation during controlled human infection. Reduced activation was not restricted to NK subsets modulated by CMV but occurred across the entire NK cell compartment. Consistent with global NK cell attenuation, IL-12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cells expressing perforin were associated with parasite control in CMV seronegative individuals. ConclusionCMV infection modulates NK cell responses during malaria by disruption of IL-12, leading to reduced parasite control.

immunology↗

bioRxiv2025

Defining the roles of NKG7 expressed by CD4+ and CD8+ T cells during malaria

Malaria, caused by Plasmodium parasites, is a significant global health issue. CD4+ and CD8+ T cells are important for immunity against Plasmodium infections, but the specific roles of many immune-related effector molecules in T cells remain poorly defined. Here, we investigated the function of NK cell granule protein 7 (NKG7) in T cells during malaria, focusing on its role in CD4+ and CD8+ T cells in Plasmodium blood-stage responses. In a non-lethal malaria model, NKG7 played a protective role in CD4+ T cell responses, affecting pro-inflammatory T helper 1 (Th1), IL-10-producing type 1 regulatory (Tr1), and T follicular helper cell development. In a model of cerebral malaria, NKG7 was shown to have a cell-intrinsic role in CD4+ T cells for perforin and granzyme B expression, as well as the development of Tr1 cells. Human investigations involving peripheral blood mononuclear cells from volunteers participating in controlled human P. falciparum malaria infection studies, as well as endemic country patients with P. falciparum and P. vivax malaria, corroborated these findings. High NKG7 expression in T cells from Plasmodium-infected humans was observed, as well as differences in NKG7 expression based on the infecting Plasmodium species. NKG7 expression was associated with both cytotoxic and non-cytotoxic T cells, indicating varied functions following infection. These results advance our understanding about NKG7s role in T cell-mediated malaria immunity and suggest potential for targeting NKG7 to improve outcomes following Plasmodium infection.

immunology↗

bioRxiv2022

Malaria drives unique regulatory responses across multiple immune cell subsets

Plasmodium falciparum malaria results in immunoregulatory responses across multiple cell subsets, which protects the individual from inflammatory mediated immunopathogenesis. However, these anti-inflammatory responses also hamper the development of effective anti-parasitic immunity. Understanding malaria induced tolerogenic responses in specific cell subsets may inform the development of strategies to boost protective immunity during drug treatment and vaccination. Here, we analysed the immune landscape with single cell RNA sequencing of peripheral blood mononuclear cells during falciparum malaria and at convalescence in children and adults from a low malaria transmission area in Malaysia. To understand malaria driven changes specific to each immune cell subset, we interrogated transcriptional changes in sub-clustered major immune cell types during infection. We found that malaria drove development of immunosuppressive monocytes, alongside NK and {gamma}{delta} T cells which regulated inflammatory function but maintained cytolytic capacity. IL10-producing CD4 T cells and IL10-producing regulatory B cells were also induced. Type I interferon responses were identified across all cell types, linking Type I interferon signalling with the induction of immunoregulatory networks during malaria. Together, these findings provide insights into cell-specific and shared immunoregulatory changes induced during malaria, and provides a data set resource for additional analysis of anti-parasitic immunity and disease pathogenesis.

immunology↗